Update from Fife Area Drug and Therapeutics Committee December 2011-March 2012 AREA DRUG & THERAPEUTICS BULLETIN Prescribing of Newer Oral Anticoagulants There are now 2 newer oral anticoagulants, dabigatran and rivaroxaban, that have been licensed and approved for use by the Scottish Medicines Consortium (SMC) 1,2 for use as alternatives to warfarin for the prevention of stroke in non-valvular atrial fibrillation (AF). Both drugs should only be prescribed in line with previous advice issued by Healthcare Improvement Scotland (HIS) 3 i.e. only in patients who have true intolerance to warfarin and other coumarins and in those who continue to have poor INR control even though they are complying with their warfarin treatment. Rivaroxaban Efficacy Rivaroxaban is direct factor Xa inhibitor which prevents the formation of thrombin. The key evidence to support the use of rivaroxaban for this indication comes from the Rocket-AF study which was a randomised, double-blind, double-dummy, phase 3 study comparing rivaroxaban 20mg v warfarin in patients with non-valvular AF and considered to be at moderate to high risk of stroke. The study found that rivaroxaban was non-inferior to warfarin in preventing stroke or systemic embolism. Safety There was no difference in major and non-major bleeding between rivaroxaban and warfarin. However, rivaroxaban was found to cause signifi cantly more GI bleeding but signifi cantly less fatal bleeding or intracranial haemorrhage. A lower dose of rivaroxaban (15mg) should be used in patients with moderate renal impairment. There is no specifi c antidote to rivaroxaban. Cost p.a. Rivaroxaban 20mg daily 764 Warfarin 13-39 depending on dose. Dabigatran Efficacy Dabigatran is a direct thrombin inhibitor. The key evidence to support the use of dabigatran comes from the RE-LY study which was a phase 3, multi-centre study comparing 2 different doses of dabigatran (150mg,110mg) v open label warfarin. Dabigatran 110mg twice daily was shown to be non-inferior to warfarin in the prevention of stroke and systemic embolism, while dabigatran 150mg was shown to be superior to warfarin (although the absolute difference was small - 0.6%). Dabigatran was found to be more effective where patients had poorer INR control with warfarin. Safety The overall major bleeding rate was lower in both dabigatran groups than in warfarin but was only statistically signifi cant with the lower 110mg dose of dabigatran. GI bleeding was numerically higher in both dabigatran groups compared to warfarin and was statistically higher with the dabigatran 150mg dose. The rate of bleeding with dabigatran was found to increase with increasing age and was highest in patients aged over 80 years. More patients experienced dyspepsia with dabigatran than with warfarin. Dabigatran is contraindicated in patients with severe renal impairment. A lower dose of dabigatran (110mg) should be used in patients with moderate renal impairment. There is no specifi c antidote to dabigatran. Cost p.a. Dabigatran 110mg or 150mg twice daily 917* Warfarin 13-39 depending on dose. In This Issue: NHS FIFE GUIDANCE ON THE DIAGNOSIS AND MANAGEMENT OF INFANTS WITH SUSPECTED COW S MILK
Local Preference There is no comparative data to review the effi cacy of dabigatran v rivaroxaban. Although the trials had similar end-points the methodologies were different.the ADTC have considered all the evidence for both agents and have decided that rivaroxaban should be the preferred agent in Fife due to the following factors approved for the prevention of DVT. Local guidance is currently being developed providing advice to prescribers on how to convert patients from rivaroxaban/ dabigatran to warfarin/parenteral anticoagulants and vice-versa. The guidance will also advise how to manage bleeding with the newer anticoagulants in both primary and secondary care settings. Key Messages 1. Warfarin remains the preferred oral anticoagulant agent. 2. Rivaroxaban is the preferred newer oral anticoagulant for the prevention of stroke in patients with non-valvular AF. 3. Rivaroxaban should only be considered in patients who are truly intolerant of warfarin or other coumarins and only in patients who have poor INR control even though they have good compliance with their warfarin therapy. 4. Overall the effi cacy of rivaroxaban and dabigatran is non-inferior to warfarin. Both agents cause more GI bleeding than warfarin. 5. The newer agents are considerably more expensive than warfarin even when taking into account additional monitoring costs with warfarin. 6. There is concern about the lack of antidote with the newer agents if a patient was to present with a life-threatening haemorrhage or require emergency surgery. *Price correct as of March 2012. References 1. SMC advice (672/11) September 2011 www.scottishmedicines.org.uk/smc_advice/advice/672_11_dabigatran_pradaxa/dabigatran_pradaxa 2. SMC advice (756/12) January 2012 www.scottishmedicines.org.uk/smc_advice/advice/756_12_rivaroxaban_xarelto_atrial/rivaroxaban_xarelto_atrial 3. HIS national consensus statement www.healthcareimprovementscotland.org/programmes/cardiovascular_disease/dabigatran_consensus_statement.aspx Formulary Changes New Formulary Sub-Section for Chapter 9 Oral Nutritional Supplements A new formulary section on the use of oral nutritional supplements (ONS) has been fi nalised and approved by the ADTC. substances contract. review. recommended otherwise by a dietician. going prescribing would occur in primary care e.g. products for dysphagia; energy/protein dense ONS, products for use with tube feeds. Copies of the section have been distributed to all staff via e-mail. Copies of the formulary section can be accessed / downloaded from the ADTC website www.fi feadtc.scot.nhs.uk/ by clicking on the link for Fife Formulary or via the Fife Formulary link on the NHS Fife intranet homepage. Page 2 December 2011-March 2012
Guidance NHS Fife Guidance on Appropriate use of Oral Nutritional Supplements in the Community (Adults) (Appendix 9A) A new guidance document has been developed by the dietetic department to ensure the appropriate prescribing of oral nutritional supplements in adults. This guidance provides information relating to the following areas maintain calorie intake, nourishing drinks, high calorie snack list and a patient guide to nutritional supplements and Substance Misuse NHS Fife Guidance on the Diagnosis and Management of Infants with Suspected Cow s Milk Protein Allergy (CMPA) (Appendix 9B) A new guidance document has been developed by the paediatric dieticians to ensure the appropriate prescribing of special baby formulas in infants with suspected cows milk protein allergy to the following areas basis. Copies of the above guidance documents have been distributed to all staff via e-mail. Further copies can be accessed / downloaded from the ADTC website www.fi feadtc.scot.nhs.uk/ or the Fife Formulary link on the NHS Fife intranet homepage by clicking on the link for Fife Formulary. SMC Recommendations Medicines accepted for use by SMC Formulary Choices Products that are recommended within Fife and should be used in the majority of patients. Restricted Use Products that have been approved by the SMC for a limited indication or for a niche group of patients. Appropriate for them to be prescribed for patient groups that have been approved by the SMC / Fife ADTC. Not Preferred Products that have been approved by the SMC but agreed in Fife that suitable Formulary choices are already available. These products should only be used when Formulary products have been ineffective, not tolerated or are contra-indicated. Product Indication assessed Fife ADTC decisions & comments Rivaroxaban 15 and 20mg filmcoated tablets (Xarelto ) Rivaroxaban 15 and 20mg filmcoated tablets (Xarelto ) Paliperidone palmitate 50mg, 75mg, 100mg and 150mg prolonged release suspension for injection (Xeplion) Telaprevir 375mg film-coated tablets (Incivo ) Telaprevir, 375mg, film-coated tablets (Incivo ) Boceprevir 200mg capsule (Victrelis ) Treatment experienced patients The prevention of stroke and systemic embolism in adult patients with non-valvular atrial fi brillation with one or more risk factors, such as congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. Treatment of deep vein thrombosis (DVT), and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults. Maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone. In selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, it may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a longacting injectable treatment is needed. In combination with peginterferon alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis) who are treatment naïve. In combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis) who have previously been treated with interferon alfa (pegylated or non-pegylated) alone or in combination with ribavirin, including relapsers, partial responders and null responders. Treatment of chronic hepatitis C (HCV) genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease who have failed previous therapy. Add to Formulary for restricted use only. Restricted to patients in whom there is poor INR control with warfarin unrelated to compliance or in patients who are genuinely intolerant of warfarin/ coumarins. Refer to local guidance. Approved for new licensed indication. Treatment duration to be a maximum of 6 months. Specialist initiation only. Alternative atypical depot injection to Risperdal Consta.In patients where the use of a monthly depot will be advantageous. Specialist initiation only. 1st line use. 1st line use. 2nd line use where telaprevir is unsuitable. contd... Page 3 December 2011-March 2012
Product Indication assessed Fife ADTC decisions & comments Boceprevir 200mg capsule (Victrelis ) Treatment naïve patients Rilpivirine 25mg film-coated tablet (Edurant ) Emtricitabine 200mg, tenofovir disoproxil (as fumarate) 245mg, rilpivirine (as hydrochloride) 25mg, film-coated tablet (Eviplera ). Golimumab 50mg solution for injections prefilled pen (auto-injector) or pre-filled syringe (Simponi ) Golimumab (Simponi ) Tocilizumab, 20mg/mL concentrate for solution for infusion (RoActemra ) Adalimumab (Humira ), 40mg solution for injection in pre-filled syringe or pen, 40mg/0.8ml solution for injection vial for paediatric use Nevirapine 50mg, 100mg, 400mg prolonged release tablets (Viramune prolonged release tablets ) Ranibizumab, 10mg/mL solution for injection (Lucentis ) Somatropin 5.83mg/ml and 8mg/ ml solution for injection (Saizen ) Treatment of chronic hepatitis C (HCV) genotype 1 infection, in combination with peginterferon and ribavirin, in adult patients with compensated liver disease who are previously untreated. In combination with other antiretroviral medicinal products, is indicated for the treatment of human immunodefi ciency virus type1 (HIV 1) infection in antiretroviral treatment naïve adult patients with a viral load 100,000 HIV 1 RNA copies/ml. Treatment of human immunodefi ciency virus type 1 (HIV-1) infection in antiretroviral treatment-naive adult patients with a viral load 100,000 HIV-1 RNA copies/ml. In combination with methotrexate, for the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease modifying antirheumatic drug therapy including methotrexate has been inadequate. SMC restriction: golimumab is restricted for use in accordance with British Society for Rheumatology guidance on prescribing TNFa blockers in adults with rheumatoid arthritis (2005). Golimumab is restricted to use at a dose of 50 mg only. Treatment of severe, active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy. Treatment of active systemic juvenile idiopathic arthritis (sjia) in patients 2 years of age and older, who have responded inadequately to previous therapy with nonsteroidal anti-infl ammatory drugs (NSAIDs) and systemic corticosteroids. Tocilizumab can be given as monotherapy (in case of intolerance to methotrexate or where treatment with methotrexate is inappropriate) or in combination with methotrexate. In combination with methotrexate for the treatment of active polyarticular juvenile idiopathic arthritis, in children and adolescents aged 4 to 17 years who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Adalimumab can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Adalimumab has not been studied in children aged less than 4 years. In combination with other anti-retroviral medicinal products for the treatment of HIV-1 infected adults, adolescents, and children three years and above and able to swallow tablets. Treatment of visual impairment due to macular oedema (MO) secondary to retinal vein occlusion (RVO) (branch RVO or central RVO) in adults. SMC restriction: restricted to use in patients with macular oedema secondary to central retinal vein occlusion (CRVO). Growth failure in children, adolescents and adults. This new formulation has been shown to be bioequivalent to the previously available freeze-dried formulation and is available at an equivalent cost. It is available in a ready to use cartridge and does not require reconstitution. 2nd line use where telaprevir is unsuitable. HIV Specialist use only. To be used in patients with a C/I, unable to tolerate efavirenz therapy. Add to formulary. HIV Specialist use only. To be used in line with SMC approval/ BHIVA guidance. Add to the restricted list. Restricted to patients where the use of a once monthly injection would be advantageous to the patient/ service provider. Only the 50mg strength inj. is approved for use. Certolizumab is currently the preferred TNF alpha inhibitor for RA patients. Hospital specialist use only. Add to restricted list. Restricted to patients where the use of a once monthly injection would be clinically advantageous to the patient/service provider. Only the 50mg strength inj. is approved for use. Adalimumab is currently the preferred TNF alpha inhibitor for use in ankylosing spondylitis. Etanercept or infliximab are 2nd line choices. Hospital, specialist use only. Add to restricted list for this indication. Specialist use only. New licensed indication noted. To be used 2nd line in patients where etanercept has been ineffective. Hospital, specialist use only. New formulation noted. New formulation noted. HIV specialist use only. To be used in line with SMC approval/ BHIVA guidance. New licensed indication noted. Approved for use in patients with macular oedema secondary to central retinal vein occlusion (CRVO). Use in patients with BRVO would require IPTR approval. Hospital specialist use only. Advice contingent on the ongoing availability of the approved Patient Access Scheme. New formulation noted. contd... Page 4 December 2011-March 2012
Product Indication assessed Fife ADTC decisions & comments Tenofovir disoproxil (as fumarate) (Viread ) Erlotinib 25, 100 and 150mg filmcoated tablets (Tarceva ) Midazolam oromucosal solution (Buccolam ) Dabigatran etexilate (Pradaxa ) Apixaban 2.5mg film-coated tablet (Eliquis ) Abatacept (Orencia ), 250mg powder for concentrate for solution for injection Exenatide 2mg powder and solvent for prolonged-release suspension for injection (Bydureon ) Treatment of chronic hepatitis B in adults with decompensated liver disease. First-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations. Treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to <18 years). Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fi brillation with one or more of the following risk factors: previous stroke, transient ischaemic attack, or systemic embolism; left ventricular ejection fraction <40%; symptomatic heart failure, New York Heart Association (NYHA) Class 2; age 75 years; age 65 years associated with one of the following: diabetes mellitus, coronary artery disease or hypertension Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery. In combination with methotrexate, abatacept for the treatment of moderate to severe active polyarticular juvenile idiopathic arthritis (JIA) in paediatric patients 6 years of age and older who have had an insuffi cient response to other disease modifying antirheumatic drugs (DMARDs) including at least one tumour necrosis factor (TNF) inhibitor. It has not been studied in children under 6 years old. As a 3rd line option in the treatment of type 2 diabetes mellitus in combination with other agents. New indication noted. Specialist use only. Await decision from SCAN. Decision deferred. Awaiting further comments from local specialists. NHS Fife preferred newer oral anticoagulant is rivaroxaban. Formulary choice (non-warfarin) oral anticoagulant for this indication is rivaroxaban. Not preferred for this indication. NHS Fife choices for this indication are 1st line Etanercept 2nd line Adalimumab Fife Formulary choices are daily exenatide or liraglutide. Linagliptin, 5mg film-coated tablet (Trajenta ) Fentanyl 50, 100, 200 microgram single dose nasal spray (Instanyl ) The treatment of type 2 diabetes mellitus to improve glycaemic control in adults. Management of breakthrough pain in adults already receiving maintenance opioid therapy for chronic cancer pain. Breakthrough pain is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain. SMC restriction: to patients who are unsuitable for other short-acting oral opioids (e.g. oral morphine) as an alternative to other buccal and sublingual fentanyl preparations. Formulary choices are sitagliptin and saxagliptin. Current preferred nasal spray preparation in NHS Fife is Pecfent. Pecfent is restricted to use when oral morphine and buccal fentanyl products are unsuitable/ineffective. For specialist use only. Medicines not recommended by SMC Aprepitant (Emend ) is not recommended as part of combination therapy, for prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. (Aprepitant has previouslly been approved for use in prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy). Lack of clinical and economic benefits. Aztreonam lysine (Cayston ) is not recommended for the suppressive therapy of chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fi brosis (CF) aged 18 years and older. Lack of economic benefits. Cabazitaxel solution for infusion (Jevtana ) is not recommended in combination with prednisone or prednisolone, for the treatment of patients with hormone refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Lack of economic benefits. Denosumab (Xgeva ) is not recommended for prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours. Non-submission by the manufacturer. Dexamethasone intravitreal implant (Ozurdex ) is not recommended for treatment of adult patients with macular oedema following either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Lack of evidence of clinical and economic benefits. Dexamethasone (Ozurdex ) 0.7 mg intravitreal implant is not recommended for the treatment of adult patients with infl ammation of the posterior segment of the eye presenting as non-infectious uveitis. Non-submission by the manufacturer. Page 5 December 2011-March 2012
Medicines not recommended by SMC (contd) Eculizumab (Soliris ) is not recommended for the treatment of patients with atypical haemolytic uremic syndrome (ahus). Nonsubmission by the manufacturer. Entecavir (Baraclude ) is not recommended for treatment of chronic hepatitis B virus (HBV) infection in adults with decompensated liver disease. Lack of evidence of economic benefits. Lapatinib (Tyverb ) 250 mg film-coated tablets is not recommended for the treatment of patients with breast cancer, whose tumours overexpress HER2 (ErbB2) in combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy. Non-submission by the manufacturer. Naproxen 500mg/esomeprazole 20mg (Vimovo ) is not recommended for the symptomatic treatment of osteoarthritis (OA), rheumatoid arthritis (RA) and ankylosing spondylitis (AS), Lack of economic benefits. Panitumumab (Vectibix ) is not recommended for the treatment of patients with wild-type KRAS metastatic colorectal cancer (mcrc) in fi rst-line in combination with FOLFOX; in second-line in combination with FOLFIRI for patients who have received fi rst-line fl uoropyrimidinebased chemotherapy (excluding irinotecan). Non-submission by the manufacturer. Pemetrexed (Alimta ) is not recommended as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Non-submission by the manufacturer. Prednisone (Lodotra ) is not recommended for the treatment of moderate to severe, active rheumatoid arthritis in adults particularly when accompanied by morning stiffness. Non-submission by the manufacturer. Ranolazine (Ranexa ) is not recommended as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to fi rst-line antianginal therapies (such as beta-blockers and/or calcium antagonists). Lack of clinical and economic benefits. Saxagliptin (Onglyza ) is not recommended for adult patients aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control in combination with insulin (with or without metformin), when this regimen alone, with diet and exercise, does not provide adequate glycaemic control. Non-submission by the manufacturer. Tapentadol (Palexia ) immediate release tablets is not recommended for relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics. Non-submission by the manufacturer. Dates for 2012 ADTC Meetings ADTC meeting 4th April 27th June 15th August 17th October 19th December Deadline for submission of papers and agenda items 19th March 11th June 30th July 28th September 3rd December Contact the Clinical Effectiveness Pharmacist on 01592 226915 for advice on making a formulary submission or for clarification on the process for approval of guidance documents. The information provided in this bulletin is correct at the time of publishing but is subject to change as new clinical information becomes available. If you require this newsletter in alternative formats please telephone 01592 226915 Produced By: Ishtiaq Mohammed, Clinical Effectiveness Pharmacist All comments welcome - email: or visit our website: sandra.macdonald@nhs.net www.fifeadtc.scot.nhs.uk