Guidance for prescribing of Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) and Apixaban (Eliquis ) in Patients with Non-Valvular AF

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1 Guidance for prescribing of Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) and Apixaban (Eliquis ) in Patients with Non-Valvular AF Lesley Davey Staffordshire and Lancashire CSU November 2013 (Review November 2016) 0

2 VERSION CONTROL Version Number Date Amendments made Version 1.1 Nov 13 Updated contraindications and warnings for all three drugs issued by MRHA October 2013 Version 1.2 Dec 13 Rivaroxaban dose amended from 5mg to 15mg Apixaban renal function creatinine clearance amended from 30+ ml to >30 ml / min Dronedarone included on the contra-indications for Dabigatran. Box 2 page 3 extended to complete the sentence (SEE) removed as always used in full Guidelines put into Standard Guidelines covers Review date amended to November 2016 Contents VERSION CONTROL... 1 DOSE... 3 RENAL FUNCTION... 3 CONTRA-INDICATIONS AND INTERACTIONS - Rivaroxaban... 4 CONTRA-INDICATIONS AND INTERACTIONS Apixaban... 4 CONTRA-INDICATIONS AND INTERACTIONS - Dabigatran... 4 UPDATED CONTRAINDICATIONS AND WARNINGS FOR ALL THREE DRUGS ISSUED BY MHRA OCTOBER CONVERSION FROM RIVAROXABAN TO WARFARIN... 4 CONVERSION FROM DABIGATRAN TO WARFARIN... 4 CONVERSION FROM APIXABAN TO WARFARIN... 4 CONVERSION FROM WARFARIN TO RIVAROXABAN... 5 CONVERSION FROM WARFARIN TO DABIGATRAN... 5 CONVERSION FROM WARFARIN TO APIXABAN... 5 DISCONTINUATION OF DABIGATRAN... 5 DISCONTINUATION OF RIVAROXABAN... 5 DISCONTINUATION OF APIXABAN... 5 FURTHER PRESCRIBER GUIDANCE FOR DABIGATRAN (Pradaxa )... 6 FURTHER PRESCRIBER GUIDANCE FOR RIVAROXABAN (Xarelto )... 7 FURTHER PRESCRIBER GUIDANCE FOR APIXABAN (Eliquis )... 8 REFERENCES ACKNOWLEDGEMENTS

3 Strategic Clinic Network Lancashire Guidance for prescribing of Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) and Apixaban (Eliquis ) in Patients with Non-Valvular AF NICE TAGs 249, 256 and 275 recommends dabigatran*, rivaroxaban and apixaban respectively, as an option for prevention of stroke with non valvular AF if they have one or more of the following risk factors: Previous stroke or TIA, Age 75 Years or older, congestive heart failure, hypertension or diabetes. The clinician should discuss the risks and benefits of dabigatran, rivaroxaban or apixaban compared to warfarin or other coumarin before considering initiating or switching. NB. For patients with stable INR already on warfarin or coumarin it may be appropriate to remain on warfarin. *For Dabigatran, NICE and SPC stipulates: heart failure of NYHA class 2 or above and age of over 65 with diabetes, CAD or hypertension. For Apixaban, NICE and SPC stipulates:heart failure of NYHA class 2 or above Dabigatran Age < 80yrs 150mg twice a day Age > 80yrs 110mg twice a day (Not suitable to be placed in an MDS) DOSE Rivaroxaban 20mg once a day egfr > 50ml/min 15mg once a day egfr 15 49ml/min Apixaban 5mg twice a day 2.5mg twice a day if Creatinine clearance 15-29ml/min 2.5mg twice a day for patients with 2 of the following : Age >/= 80 years Body weight,</=60kg Se Creatinine >/=1.5mg/dl (133micromole / L) RENAL FUNCTION DABIGATRAN RIVAROXABAN, AND APIXABAN ARE POWERFUL ANTI-COAGULANTS WHICH CANNOT BE EASILY REVERSED. BEFORE CONSIDERATION PATIENTS MUST HAVE AN UP TO DATE RENAL FUNCTION TEST Dabigatran egfr < 30 - Dabigatran is contra-indicated: Do not proceed With less severe renal impairment, dabigatran may increase the risk of bleed, therefore prescribe the lower dose and use with caution. NB. Renal function can decline while on treatment should be monitored annually or more often in high risk patients. Rivaroxaban egfr <15 - Rivaroxaban is contra-indicated:do not proceed With severe renal impairment, rivaroxaban may increase the risk of bleed, therefore use with caution and avoid drugs that increase plasma rivaroxaban levels. In patients with moderate (creatinine clearance ml/min) or severe (creatinine clearance ml/min) renal impairment the following dosage recommendations apply: For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2). Limited clinical data for patients with severe renal impairment (creatinine clearance ml/min) indicate that rivaroxaban plasma concentrations are significantly increased, therefore, use with caution. Use is not recommended in patients with creatinine clearance < 15 ml/min (egfr< 15) (see sections 4.4 and 5.2). (Please ensure SPC for 15/20mg is consulted.) NB. Renal function can decline while on treatment should be monitored annually or more often in high risk patients. The information on dosage adjustment in the BNF is expressed in terms of egfr for most drugs. Although the two measures of renal function are not interchangeable, in practice, egfr (MDRD formula ) can be used to determine dosage adjustments. In patients at both extremes of weight (BMI of less than 18.5 kg/m 2 or greater than 30 kg/m 2 ) the absolute glomerular filtration rate or creatinine clearance (calculated from the Cockcroft and Gault formula) should be used to adjust drug dosages. Apixaban Creatinine Clearance <15ml / min Apixaban is contra-indicated: Do not proceed No dose adjustment is necessary in patients with a Creatinine Clearance of >30 ml / min With less severe renal impairment, apixaban may increase the risk of bleed, use with caution. NB. Renal function can decline while on treatment should be monitored annually or more often in high risk patients. As there is no clinical experience in patients with creatinine clearance < 15 ml/min, or in patients undergoing dialysis, apixaban is not recommended in these patients 3

4 CONTRA-INDICATIONS AND INTERACTIONS - Dabigatran Hypersensitivity to the active substance Patients with less severe renal impairment, egfr < 30 Clinically significant active Organic lesion at risk of Spontaneous or pharmacological impairment of haemostasis Hepatic impairment or liver disease expected to have any impact on survival Concomitant treatment with systemic ketoconazole, ciclosporin, itraconazole tacrolimus, and dronedarone - refer to SPC for full list CONTRA-INDICATIONS AND INTERACTIONS - Rivaroxaban Hypersensitivity to the active substance Patients with severe renal impairment egfr < 15 Clinically significant active Organic lesion at risk of Hepatic disease associated with coagulopathy and clinically relevant risk Pregnancy and breast feeding Concomitant treatment with systemic: ketoconazole, voriconazole, itraconazole and dronedarone refer to SPC for full list CONTRA-INDICATIONS AND INTERACTIONS Apixaban Hypersensitivity to the active substance Patients with severe renal failure egfr < 15 Clinically significant active Organic lesion at risk of Hepatic disease associated with coagulopathy and clinically relevant risk Concomitant treatment with systemic: diclofenac, ketorolac, ketoconazole, HIV protease inhibitors, sulfinpyrazone, refer to SPC for full list Caution with acetylsalicylic acid UPDATED CONTRAINDICATIONS AND WARNINGS FOR ALL THREE DRUGS ISSUED BY MHRA OCTOBER 2013 A lesion or condition, if considered a significant risk factor for major may include: Current or recent gastrointestinal ulceration Presence of malignant neoplasm at high risk of Recent brain or spinal injury Recent brain, spinal, or ophthalmic surgery Recent intracranial haemorrhage Known or suspected oesophageal varices Arteriovenous malformation Vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities Concomitant treatment with any other anticoagulant agent for example: unfractionated heparin, low molecular weight heparin (such as enoxaparin or dalteparin), heparin derivatives (such as fondaparinux) or oral anticoagulants (such as warfarin). Exceptions are switching of therapy to or from the medicine, or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter CONVERSION FROM DABIGATRAN TO WARFARIN When converting from dabigatran to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows: For CrCl>50mL/min, start warfarin 3 days before discontinuing dabigatran. For CrCl 31-50mL/min, start warfarin 2 days before discontinuing dabigatran. For CrCl 15-30mL/min, start warfarin 1 day before discontinuing dabigatran For CrCl<15mL/min, no recommendations can be made consult with on call haematologist. Because dabigatran can contribute to an elevated INR, the INR will better reflect warfarin s effect after dabigatran has been stopped for at least 2 days. PTO CONVERSION FROM RIVAROXABAN TO WARFARIN There is a potential for inadequate anticoagulation during the transition from rivaroxaban to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that rivaroxaban can contribute to an elevated INR. In patients converting from rivaroxaban to warfarin, warfarin should be given concurrently until the INR is 2.0. For the first two days of the conversion period, standard initial dosing of warfarin should be used followed by warfarin dosing guided by INR testing. While patients are on both rivaroxaban and warfarin, the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of rivaroxaban. Once rivaroxaban is discontinued INR testing may be done reliably at least 24 hours after the last dose. PTO 4 CONVERSION FROM APIXABAN TO WARFARIN When converting from apixaban to warfarin, continue apixaban for at least 2 days after starting warfarin therapy. After 2 days of co-administration of apixaban and warfarin, obtain an INR prior to the next scheduled dose of apixaban. Continue co-administration of apixaban and warfarin until the INR is 2 or more PTO

5 CONVERSION FROM WARFARIN TO DABIGATRAN When converting patients from warfarin therapy to dabigatran, discontinue warfarin and start dabigatran when the (INR) is below 2.0 (this usually occurs 3-5 days after discontinuing warfarin when a patient has been stable in INR range 2-3). CONVERSION FROM WARFARIN TO RIVAROXABAN When converting patients from warfarin to rivaroxaban, warfarin treatment should be stopped and rivaroxaban initiated when INR is 3.0 or less. INR values will be falsely elevated after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activity of rivaroxaban, and therefore should not be used. CONVERSION FROM WARFARIN TO APIXABAN When converting patients from warfarin to apixaban, warfarin treatment should be stopped and apixaban initiated when INR is below 2 DISCONTINUATION OF DABIGATRAN Renal function (CrCl ml/min) Half-life (hours) (see b) Timing of discontinuation after last dose of dabigatran before surgery Standard risk of High risk (see c) (11-22) 24 hours 2 days 50 to < (12-34) hours 2-3 days >30 to < (13-23) hours 4 days 30 (see a) 27 (22-35) 2 5 Days > 5 days CrCl = creatinine clearance a) Dabigatran etexilate is contraindicated for use in these patients. b) Half-life data from renal impairment study in healthy volunteers (Strainger et al). c) Types of surgery associated with a high risk of (or in major surgery where complete haemostasis may be required) include but is not limited to cardiac surgery, neurosurgery, abdominal surgery or those involving a major organ. Other procedures such as spinal anaesthesia may also require complete haemostatic function. Other important determinants of risk include advancing age, co-morbidities (e.g. major cardiac, respiratory or liver disease), low body weight (< 50kg) and concomitant use of antiplatelet therapy. Reference: Straingier J, Rathgen K, Stahle H, et al. Influence of renal impairment on the pharmacokinetics nand pharmacodynamics of oral dabigatran etexilate. Clin Pharmacokinet 2010;49: eferences DISCONTINUATION OF RIVAROXABAN If an invasive procedure or surgical intervention is required, rivaroxaban should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician. If the procedure cannot be delayed the increased risk of should be assessed against the urgency of the intervention. Rivaroxaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. DISCONTINUATION OF APIXABAN Surgery and invasive procedures Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of including interventions for which any that occurs is expected to be minimal, non-critical in its location or easily controlled. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of against the urgency of intervention. Apixaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. 5

6 FURTHER PRESCRIBER GUIDANCE FOR DABIGATRAN (Pradaxa ). Interactions with other medicines and other relevant interactions Anticoagulants and antiplatelets - concomitant use of other oral or parenteral anticoagulants increases major rates with both dabigatran etexilate and warfarin by approximately 2.5-fold. NSAIDs - due to the risk of haemorrhage, notably with NSAIDs with elimination half-lives > 12 hours, close observation for signs of is recommended. Concomitant administration of strong P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole and clarithromycin) is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance (looking for signs of or anaemia) is required when dabigatran is coadministered with strong P-gp inhibitors. Close monitoring should be exercised when dabigatran etexilate is combined with clarithromycin and particularly in the occurrence of, notably in patients having a mild to moderate renal impairment. Itraconazole, tacrolimus and cyclosporine are contra-indicated. Inadequate clinical data is available regarding the co-administration of dabigatran and dronedarone and their coadministration is not recommended. Concomitant administration of a P-gp inducer (such as rifampicin, St. John s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be avoided. Protease inhibitors including ritonavir and its combinations with other protease inhibitors affect P-gp (either as inhibitor or as inducer) have not been studied and are therefore not recommended for concomitant treatment with dabigatran. SSRIs and SNRIs increased the risk of in RE-LY in all treatment groups. In case of intolerability to dabigatran, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and systemic embolism associated with atrial fibrillation. Patients between years should be treated with 150 mg capsule twice daily. A dose of 110 mg capsule twice daily can be individually considered, at the discretion of the physician, when the thromboembolic risk is low and the risk is high. When clinically relevant occurs, treatment should be interrupted. Bleeding can occur at any site during therapy with dabigatran. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a site. For subjects with gastritis, oesophagitis, or gastroesophageal reflux, the dose of 110 mg capsule twice daily may be considered due to the elevated risk of major gastro-intestinal with dabigatran. As with warfarin, coadministration of aspirin, clopidogrel and NSAID increases risk of. The administration of a PPI can be considered to help prevent GI. Patients with elevated liver enzymes > 2 upper limit of normal were excluded in the study investigating the prevention of stroke and systemic embolism associated with atrial fibrillation. No treatment experience is available for this subpopulation of patients and therefore the use of dabigatran is not recommended in this population. 6

7 FURTHER PRESCRIBER GUIDANCE FOR RIVAROXABAN (Xarelto ). Interactions with other medicines and other relevant interactions The use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azoleantimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp. Interactions with Clarithromycin, erythromycin and fluconazole are not considered clinically significant (SPC). Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided. Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the risk. No pharmacokinetic interaction was observed between warfarin and rivaroxaban. The concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to reduced rivaroxaban plasma concentrations. Strong CYP3A4 inducers should be co-administered with caution. In case of intolerability to rivaroxaban, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and systemic embolism associated with atrial fibrillation. Safety and efficacy of rivaroxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity. Due to the potential reproductive toxicity, the intrinsic risk of and evidence that rivaroxaban crosses the placenta, rivaroxaban is contraindicated during pregnancy. When clinically relevant occurs, treatment should be interrupted. Bleeding can occur at any site during therapy with rivaroxaban. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a site For subjects with gastritis, oesophagitis, or gastroesophageal reflux, the lower dose of 15mg may be considered due to the elevated risk of major gastro-intestinal. As with warfarin, co-administration of aspirin, clopidogrel and NSAID increases risk of. The administration of a PPI can be considered to help prevent GI. If a dose is missed the patient should take rivaroxaban immediately and then continue the following day with once daily intake as before. No double dose should be taken to make up for a missed dose. Caution - Concomitant administration of strong CYP3A4 and P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole and clarithromycin) is expected to result in increased rivaroxaban plasma concentrations and potential increase in risk 7

8 FURTHER PRESCRIBER GUIDANCE FOR APIXABAN (Eliquis ) Interaction with other medicinal products affecting haemostasis Due to an increased risk, concomitant treatment with any other anticoagulants is contraindicated Agents associated with serious are not recommended concomitantly with apixaban, such as: thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran and sulfinpyrazone. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, especially in elderly patients because of a potentially higher risk. Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with apixaban. In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with apixaban. In a clinical trial of patients with atrial fibrillation, concomitant use of acetylsalicylic acid increased the major risk on apixaban almost 2-fold In a clinical trial of high-risk post acute coronary syndrome patients, who received acetylsalicylic acid or the combination of acetylsalicylic acid and clopidogrel, apixaban related major was reported to be two and a half fold higher than placebo. The use of Apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir) No dose adjustment for apixaban is required when co-administered with less potent inhibitors of CYP3A4 and/or P-gp such as diltiazem, maproxen, amiodarone, verapamil, quinidine Co-administration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and C max, respectively. The concomitant use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John's Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such agents, however strong inducers of both CYP3A4 and P-gp should be coadministered with caution Other concomitant therapies No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was coadministered with atenolol or famotidine. Effect of apixaban on other medicinal products Apixaban is not expected to alter the clearance of co-administered drugs metabolised by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 > 45 μm) CYP2C19 (IC50 > 20 μm) Apixaban is not a significant inhibitor of P-gp. In studies conducted in healthy subjects, as described below, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, or atenolol. Spinal/epidural anaesthesia or puncture Experience with neuraxial blockade is limited and extreme caution is therefore recommended when using apixaban. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. To reduce the risk of thromboembolic complications, indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of apixaban. The risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of apixaban. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent diagnosis and treatment is necessary. There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. In case there is such need, a time interval of hours (i.e., 2 x half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter removal. 8

9 There is no antidote to apixaban. Activated charcoal may be useful in the management of apixaban overdose or accidental ingestion. Overdose of apixaban may result in a higher risk of. If occurs, discontinue treatment and investigate the source of. The initiation of appropriate treatment, e.g., surgical haemostasis or the transfusion of fresh frozen plasma should be considered. If life-threatening cannot be controlled by the above measures, administration of recombinant factor VIIa may be considered. However, there is currently no experience with the use of recombinant factor VIIa in individuals receiving apixaban. Re-dosing of recombinant factor VIIa could be considered and titrated depending on improvement of. As with other anticoagulants, patients taking apixaban are to be carefully observed for signs of. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Apixaban administration should be discontinued if severe haemorrhage occurs. Although treatment with apixaban does not require routine monitoring of exposure, the Rotachrom anti-fxa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery. Prior to initiating apixaban, liver function testing should be performed. Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant risk. It is not recommended in patients with severe hepatic impairment. It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). It should be used with caution in patients with elevated liver enzymes ALT/AST > 2 x ULN or total bilirubin 1.5 x ULN as they were excluded from clinical trials. If a dose is missed, the patient should take apixaban immediately and then continue with twice daily intake as before. There are no data from the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during pregnancy. Breast-feeding It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio (C max about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to newborns and infants cannot be excluded. A decision must be made to either discontinue breast-feeding or to discontinue/abstain from apixaban therapy. Fertility Studies in animals dosed with apixaban have shown no effect on fertility. 9

10 REFERENCES 1. NICE Technology Appraisal SPC Xarelto accessed via 3. NICE Technology Appraisal SPC Pradaxa accessed via NICE Technology Appraisal SPC Eliquis accessed via ACKNOWLEDGEMENTS NHS Somerset PCT NHS Fife Area DTC Lisa Rogan on behalf of Lancashire and Cumbria Health Economy New Medicines and Treatments Group September Updated by Lesley Davey on behalf of Lancashire Medicines Management Group to include apixaban May This guidance does not override the individual responsibility of health professionals to make decisions in exercising their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. For full prescribing information please refer to the BNF and SPC ensuring correct SPC according to dose is consulted. Leads for this guidance: Name: Medicines Management Organisation: Staffordshire and Lancashire CSU Version 10 (Available online at click on Guidelines ) Ratified by Lancashire Medicines Management Group Guidance effective from November 2013 Date of next review As required minimum 3 yearly 10