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Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information. Copyright © Midlands and Lancashire Commissioning Support Unit Medicines Safety Assurance Tool September 2017 To request this safety tool, or for more information about this tool, to make a comment, or share a safety issue please contact [email protected]

Error with the barcodes on selected batches of 8 medicinal products Proposed action Central Alerting System | 04 Sep 2017 Newsletter Optimise Rx/ScriptSwitch l Focus Pharmaceuticals has identified an error with the barcodes on the cartons of the listed batches of products. When scanned, Practice audit/search Other (please specify) the barcodes may identify the wrong product. The other product details on the carton, including the name, strength and pharmaceutical form of the medicine are correct. https://www.gov.uk/drug-device-alerts/error-with-the-barcodes-on-selected-batches-of-8-medicinal-products-by-focus- pharmaceuticals-distribute-to-pharmacy-and-wholesaler-level Action taken

Status Action due date Date completed 1

Guidance for the Correct Use and Disposal of Batteries Used in Health and Social Care Equipment Proposed action Central Alerting System | 06 Sep 2017 Newsletter Optimise Rx/ScriptSwitch l The use and incorrect disposal of batteries may result in equipment/devices emitting smoke and fumes, not functioning Practice audit/search Other (please specify) normally, quickly running out of power, being permanently damaged and, in certain circumstances, there may be a fire. https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102843

Action taken

Status Action due date Date completed 1 All Accu-Chek® Insight insulin pumps - risk of alarm failure Proposed action Central Alerting System | 21 Sep 2017 Newsletter Optimise Rx/ScriptSwitch l Manufactured by Roche Diabetes Care – the audible and/or vibration alarms might not function, which may lead to Practice audit/search Other (please specify) hyperglycaemia if the user doesn’t see the notification message on the pump. https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102845

Action taken

Status Action due date Date completed 1

Miconazole (Daktarin): over-the-counter oral gel contraindicated in patients taking warfarin Proposed action MHRA Drug Safety Update | 26 Sep 2017 Newsletter Optimise Rx/ScriptSwitch l Patients taking warfarin should not use over-the-counter miconazole oral gel (Daktarin). If you plan to prescribe miconazole oral Practice audit/search Other (please specify) gel in a patient on warfarin, you should closely monitor them and advise that if they experience any sign of bleeding, they should stop miconazole oral gel and seek immediate medical attention. https://www.gov.uk/drug-safety-update/miconazole-daktarin-over-the-counter-oral-gel-contraindicated-in-patients-taking- warfarin Action taken

Status Action due date Date completed 1 Loperamide (Imodium): reports of serious cardiac adverse reactions with high doses of loperamide associated with abuse or misuse Proposed action l MHRA Drug Safety Update | 26 Sep 2017 Newsletter Optimise Rx/ScriptSwitch There have been reports of cardiac events including QT prolongation, torsades de pointes, and cardiac arrest in patients who Practice audit/search Other (please specify) have taken high or very high doses of loperamide as a drug of abuse or for self-treatment of opioid withdrawal. https://www.gov.uk/drug-safety-update/loperamide-imodium-reports-of-serious-cardiac-adverse-reactions-with-high-doses-of- loperamide-associated-with-abuse-or-misuse

Action taken

Status Action due date Date completed 1

Xarelto 20 mg film-coated tablets - CLASS 2 MEDICINES RECALL Proposed action Central Alerting System | 28 Sep 2017 Newsletter Optimise Rx/ScriptSwitch l Strathclyde Pharmaceuticals Ltd has received a report of a rogue blister strip of 15 mg tablets within Practice audit/search Other (please specify) two packs of 20 mg tablets and has decided to recall this batch. https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102848

Action taken

Status Action due date Date completed 1 What is the risk of interaction between opioids and monoamine oxidase inhibitors (MAOIs)? Proposed action South West Medicines Information and Training | 27th September 2017 Newsletter Optimise Rx/ScriptSwitch l This article considers the risks of interaction between opioids and monoamine oxidase inhibitors. Practice audit/search Other (please specify) https://www.sps.nhs.uk/articles/what-is-the-risk-of-interaction-between-opioids-and-monoamine-oxidase-inhibitors-maois/

Action taken

Status Action due date Date completed 1

Summary of Product Characteristics Updates Proposed action electronic Medicines Compendium | Sep 2017 Newsletter Optimise Rx/ScriptSwitch l Practice audit/search Other (please specify) Aranesp (darbepoetin) – all formulations Severe cutaneous adverse reactions (frequency not known) including Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be life-threatening or fatal, have been reported in association with epoetin treatment. Treatment should be withdrawn immediately. http://www.medicines.org.uk/emc/medicine/30617 Action taken

Calcichew (calcium carbonate) 500mg Chewable Tablets The SPC has been updated to remove aspartame and sorbitol from the list of excipients, and to remove the warning that it Status Action due date Date completed should be avoided by patients with phenylketonuria. Xylitol and sucralose are included as new excipients. 1 http://www.medicines.org.uk/emc/medicine/28505

Calcichew-D3 Forte Chewable Tablets Sorbitol and aspartame have been removed from the list of excipients. The warning that Calchichew D3 Forte may be harmful to people with phenylketonuria has been removed (aspartame is a source of phenylalanine) http://www.medicines.org.uk/emc/medicine/28502

Decapeptyl SR 22.5mg (triptorelin pamoate) A number of sections have been updated due to the addition of a new indication for central precocious puberty. http://www.medicines.org.uk/emc/medicine/24154

Dianette (cyproterone acetate; ethinylestradiol) Concomitant use with medicines containing ombitasvir/paritaprevir/ritonavir or dasabuvir is now contra-indicated as this may increase the risk of transaminase (ALT) elevations (seen more frequently in women using ethinylestradiol-containing medications in clinical trials). http://www.medicines.org.uk/emc/medicine/1814 Decapeptyl SR 22.5mg (triptorelin pamoate) A number of sections have been updated due to the addition of a new indication for central precocious puberty. http://www.medicines.org.uk/emc/medicine/24154

Dymista (fluticasone propionate/azelastine hydrochloride) nasal spray Section 4.4 now advises that visual disturbance may be reported with systemic and topical corticosteroid use (symptoms include blurred vision or other visual disturbances; possible causes include cataract, glaucoma or rare diseases such as central serous chorioretinopathy. http://www.medicines.org.uk/emc/medicine/27579

Entocort (budesonide) CR 3mg Capsules Entocort CR capsules are now licensed for the treatment of active microscopic colitis. The recommended dose is 9 mg once daily in the morning (corresponding to 3 capsules). http://www.medicines.org.uk/emc/medicine/172

Epanutin (phenytoin) preparations Section 4.8 has been updated to include “thyroid function test abnormal” as an adverse drug reaction. http://www.medicines.org.uk/emc/medicine/13289

Eperzan (albiglutide) 30 mg and 50 mg powder and solvent for solution for injection Angioedema, as an adverse allergic reaction, is now listed in section 4.8. http://www.medicines.org.uk/emc/medicine/31399

Epilim (sodium valproate) and Depakote (valproate semisodium) preparations In patients concomitantly treated with sodium valproate and nimodipine, the exposure to nimodipine can be increased by 50%. The nimodipine dose should, therefore, be decreased in case of hypotension. http://www.medicines.org.uk/emc/medicine/25929

EpiPen Adrenaline (Epinephrine) Auto-Injectors Various changes have been made to the SPC. This includes the addition of the following statement: “rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene) are known from post-marketing experience”. http://www.medicines.org.uk/emc/medicine/26974

Exjade (deferasirox) film-coated tablets Drug reaction with eosinophilia and systemic symptoms (DRESS) has been added as a rare adverse effect of treatment. If any severe cutaneous adverse reaction is suspected deferasirox should be discontinued immediately and not reintroduced. http://www.medicines.org.uk/emc/medicine/32428 EpiPen Adrenaline (Epinephrine) Auto-Injectors Various changes have been made to the SPC. This includes the addition of the following statement: “rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene) are known from post-marketing experience”. http://www.medicines.org.uk/emc/medicine/26974

Famvir (famciclovir) tablets (all strengths) The following adverse effects have been added: seizure (frequency not known), anaphylactic shock and anaphylactic reaction (frequency not known). http://www.medicines.org.uk/emc/medicine/6651

Faverin (fluvoxamine) 100 mg film-coated tablets Owing to fluvoxamine being a CYP2C19 inhibitor, the SPC now advises that concomitant use of fluvoxamine and clopidogrel is discouraged. Clopidogrel is metabolised to its active form by CYP2C19. http://www.medicines.org.uk/emc/medicine/22124

Fultium-D3 (colecalciferol; cholecalciferol) 3,200IU capsules SPC has been updated to reflect licence extension for the treatment of vitamin D deficiency in adolescents and also to advise that Fultium-D3 should not be used in children under the age of 12. http://www.medicines.org.uk/emc/medicine/28806

Humira (adalimumab) preparations Various sections of the SPC have been updated to reflect the approval of its use in the treatment of paediatric uveitis. http://www.medicines.org.uk/emc/medicine/31860

IntronA (interferon alfa-2b) preparations SPC warns that cases of hepatitis B re-activation have been reported in patients co-infected with hepatitis B and C viruses treated with interferon, and advises that all patients be screened for hepatitis B before starting treatment. Pericarditis has been added as a side-effect. http://www.medicines.org.uk/emc/medicine/20382

Invega (paliperidone) 3 mg, 6mg, 9 mg and 12mg prolonged-release tablets The recommended initial dose in moderate to severe renal impairment (CrCl 10-50ml/min) is now 3mg every other day (previously recommended 1.5mg every other day as the initial dose in these patients). The dose may be increased to 3mg once daily after clinical assessment. http://www.medicines.org.uk/emc/medicine/30349

Kaletra (100mg lopinavir /25mg ritonavir) film-coated tablets New contraindications and interaction information with venetoclax, with elbasvir/grazoprevir and with ombitasvir/paritaprevir/ritonavir with or without dasabuvir have been added to SPC. http://www.medicines.org.uk/emc/medicine/20855 Invega (paliperidone) 3 mg, 6mg, 9 mg and 12mg prolonged-release tablets The recommended initial dose in moderate to severe renal impairment (CrCl 10-50ml/min) is now 3mg every other day (previously recommended 1.5mg every other day as the initial dose in these patients). The dose may be increased to 3mg once daily after clinical assessment. http://www.medicines.org.uk/emc/medicine/30349

Ketoconazole HRA 200mg Tablets Drug interactions with edoxaban and isavuconazole have been added. Ketoconazole significantly increased the AUC of isavuconazole, and concomitant use is not recommended. Dose reductions of edoxaban are recommended with concomitant use (refer to edoxaban SPC). http://www.medicines.org.uk/emc/medicine/30077

Mekinist (trametinib) film-coated tablets Photosensitivity has been added as a common adverse effect of treatment. http://www.medicines.org.uk/emc/medicine/31241

Mavenclad (cladribine) 10mg tablets: Prescribers guide and patients’ guide The prescribers guide provides information on the most important risks associated with MAVENCLAD® and monitoring required to minimise these risks. http://www.medicines.org.uk/emc/RMM.1034.pdf

Neurontin (gabapentin) preparations SPC now advises that gabapentin has been associated with severe respiratory depression. Patients with respiratory disease, renal impairment, concomitant use of CNS depressants and the elderly might be at higher risk and dose adjustments might be necessary for these patients. http://www.medicines.org.uk/emc/medicine/27900

Norvir (ritonavir) products Contraindication regarding the interaction between ritonavir and venetoclax has been added to SPC. http://www.medicines.org.uk/emc/medicine/22952

Orkambi (lumacaftor and ivacaftor) 200 mg/125 mg film-coated tablets SPC has been updated to note serious respiratory events were seen more frequently in patients with percent predicted FEV1 <40, to describe the risk of potential fatal decompensation in patients with cirrhosis and portal hypertension, and to add cataracts as a side-effect. http://www.medicines.org.uk/emc/medicine/31534

Prolia (denosumab) Cataracts as an adverse drug reaction of denosumab has been removed from the SPC. http://www.medicines.org.uk/emc/medicine/23127 Orkambi (lumacaftor and ivacaftor) 200 mg/125 mg film-coated tablets SPC has been updated to note serious respiratory events were seen more frequently in patients with percent predicted FEV1 <40, to describe the risk of potential fatal decompensation in patients with cirrhosis and portal hypertension, and to add cataracts as a side-effect. http://www.medicines.org.uk/emc/medicine/31534

Prolia (denosumab) Cataracts as an adverse drug reaction of denosumab has been removed from the SPC. http://www.medicines.org.uk/emc/medicine/23127

Proscar (finasteride) 5mg film-coated Tablets SPC now warns that cases of depression, mood alterations and suicidal ideation have been reported. http://www.medicines.org.uk/emc/medicine/1190

Reyataz (atazanavir) Capsules Sections 4.4 and 4.8 have been updated with post-marketing reports of chronic kidney disease (frequency uncommon). Regular monitoring of renal function is advised throughout the treatment duration. http://www.medicines.org.uk/emc/medicine/14145

Siklos (hydroxycarbamide) 1000mg Film-Coated Tablets Educational materials for physicians contain important information on minimising the risk of serious adverse events and monitoring requirements. A booklet for patients contains safety information that they need to be aware of before, during and after treatment with Siklos. http://www.medicines.org.uk/emc/medicine/26268#rmm

Sovaldi (sofosbuvir) 400 mg film-coated tablets SPC has been updated with an extension of indication to include treatment of chronic hepatitis C in adolescents aged 12 to < 18 years. http://www.medicines.org.uk/emc/medicine/28539

Stivarga (regorafenib) 40 mg film-coated tablets Regorafenib is now licensed for the treatment of adults with hepatocellular carcinoma who have been previously treated with sorafenib. Changes relating to this new indication have been made throughout the SPC. http://www.medicines.org.uk/emc/medicine/28270

Tafinlar (dabrafenib) 50 mg & 75 mg hard capsules Data from an interaction study with rabeprazole has been added; the SPC now notes that medicines that alter the pH of the upper gastrointestinal tract are not expected to reduce the bioavailability of dabrafenib. Data from an interaction study with rifampin has also been added. http://www.medicines.org.uk/emc/medicine/28432

Tobradex (tobramycin and dexamethasone) Eye Drops Additions include anaphylactic reaction and erythema multiforme (adverse effects); untreated parasitic eye infections (contraindication); and a paragraph on interaction with inhibitors of CYP3A4. Sections on pregnancy and breastfeeding have been completely updated. http://www.medicines.org.uk/emc/medicine/4670 Tafinlar (dabrafenib) 50 mg & 75 mg hard capsules Data from an interaction study with rabeprazole has been added; the SPC now notes that medicines that alter the pH of the upper gastrointestinal tract are not expected to reduce the bioavailability of dabrafenib. Data from an interaction study with rifampin has also been added. http://www.medicines.org.uk/emc/medicine/28432

Topamax (topiramate) all strengths Section 4.4 now advises the risk for hyperammonemia with topiramate appears dose-related and has been reported more frequently when topiramate is used concomitantly with valproic acid and provides advice on management. Sections 4.5 and 4.8 have also been updated accordingly. http://www.medicines.org.uk/emc/medicine/31483

Vargatef (nintedanib) 100 mg and 150 mg soft capsules Information regarding post-marketing cases of diarrhoea (serious) and bleeding (serious and non-serious) has been added, as has information regarding the possible requirement for interruption, dose reduction and discontinuation of therapy in an event of dehydration. http://www.medicines.org.uk/emc/medicine/29790

Varilrix (live attenuated varicella-zoster virus - Oka strain) vaccine Varilrix is now licensed for active immunisation against varicella of healthy subjects from the age of 9 months. Other sections have been revised to reflect this indication. Additionally, information about interchangeability with other varicella-containing vaccines has been added http://www.medicines.org.uk/emc/medicine/9787 Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright © Midlands and Lancashire Commissioning Support Unit Medicines Safety Assurance Tool August 2017 To request this safety tool, or for more information about this tool, to make a comment, or share a safety issue please contact [email protected]

Prescribing regular drugs to prevent febrile convulsions risks more harm than benefit Proposed action National Institute for Health Research | 01-August-2017 Newsletter Optimise Rx/ScriptSwitch l Expert commentary is provided for a systematic review which found that intermittent diazepam, but not other Practice audit/search Other treatments, reduced the risk of recurrent febrile convulsions. Prophylactic treatment can have adverse effects, and although scary, recurrent febrile convulsions are benign. https://discover.dc.nihr.ac.uk/portal/article/4000735/prescribing-regular-drugs-to-prevent-febrile- convulsions-risks-more-harm-than-benefit Action taken

Status 1 Date completed

Shortage of Adult Hepatitis B Vaccine Proposed action Central Alerting System | 07-August-2017 Newsletter Optimise Rx/ScriptSwitch l There is a global shortage of hepatitis B vaccine which is currently impacting severely on the UK supply. The Practice audit/search Other situation is particularly critical during August but there is likely to still be some limitations on supply until early 2018. PHE have developed temporary recommendations to support clinicians undertaking an individual risk assessment to ensure that stock is available for those individuals at highest and most immediate risk of exposure to hepatitis B. Action taken https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102818

Status 1 Date completed Adrenaline auto-injectors: updated advice after European review Proposed action Medicines and Healthcare products Regulatory Agency | 15-August 2017 Newsletter Optimise Rx/ScriptSwitch l It is recommended that 2 adrenaline auto-injectors are prescribed, which patients should carry at all times. Practice audit/search Other https://www.gov.uk/drug-safety-update/adrenaline-auto-injectors-updated-advice-after-european-review

Action taken

Status 1 Date completed

Corticosteroids: rare risk of central serous chorioretinopathy with local as well as systemic administration Proposed action Medicines and Healthcare products Regulatory Agency | 15-August 2017 Newsletter Optimise Rx/ScriptSwitch l Central serous chorioretinopathy is a retinal disorder that has been linked to the systemic use of Practice audit/search Other corticosteroids. Recently, it has also been reported after local administration of corticosteroids via inhaled and intranasal, epidural, intra-articular, topical dermal, and periocular routes. https://www.gov.uk/drug-safety-update/corticosteroids-rare-risk-of-central-serous-chorioretinopathy-with- local-as-well-as-systemic-administration Action taken

Status 1 Date completed Insulin pens: NovoPen Echo and NovoPen 5 (certain batches) - risk of hyperglycaemia due to cartridge holder weakening when exposed to certain household chemicals Proposed action Medicines and Healthcare products Regulatory Agency | 24-August 2017 Newsletter Optimise Rx/ScriptSwitch l Manufactured by Novo Nordisk - recall and replacement of specific batches of cartridge holder Practice audit/search Other https://www.gov.uk/drug-device-alerts/insulin-pens-novopen-echo-and-novopen-5-certain-batches-risk-of- hyperglycaemia-due-to-cartridge-holder-weakening-when-exposed-to-certain-household-chemicals

Action taken

Status 1 Date completed

Differentiation of Mirena, Jaydess and Kyleena levonorgestrel intrauterine delivery systems Proposed action Bayer | 03-August-2017 Newsletter Optimise Rx/ScriptSwitch l Kyleena is a newly licensed levonorgestrel intrauterine delivery system (IUS), providing contraception for up to Practice audit/search Other five years. This education pack highlights the differences between this and the other two Bayer IUS currently available in the UK (Jaydess and Mirena). http://www.medicines.org.uk/emc/RMM.1018.pdf Action taken

Status 1 Date completed Summary of Product Characteristics Update Proposed action electronic Medicines Compendium | August 2017 Newsletter Optimise Rx/ScriptSwitch l Practice audit/search Other Aidulan (ethinylestradiol 20microg/ gestodene 75microg) film-coated tablets SPC has been updated with contraindication for concomitant use with ombitasvir/paritaprevir/ritonavir and dasabuvir as ALT elevations higher than 5 times upper limit of normal have been reported in women using ethinylestradiol-containing medication with these drugs. http://www.medicines.org.uk/emc/medicine/31258 Action taken

Arava (leflunomide) 100mg Tablets SPC now warns measurement of ionised calcium levels might show falsely decreased values with leflunomide and/or teriflunomide depending on type of ionised calcium analyser used. In case of doubtful measurements, total albumin adjusted serum calcium should be measured. Status 1 http://www.medicines.org.uk/emc/medicine/26343 Date completed

Arava (leflulnomide) tablets Measurement of ionised calcium levels might show falsely decreased values in patients on leflunomide. In case of doubtful measurements, it is recommended to determine the total albumin adjusted serum calcium concentration. http://www.medicines.org.uk/emc/medicine/26344

Calcichew Forte (calcium carbonate) Chewable Tablets The tablets no longer contain aspartame (E951) or sorbitol (E420). The warning about the use of this product in patients with phenylketonuria has been removed. http://www.medicines.org.uk/emc/medicine/28503

Cosopt Preservative-Free 20 mg/ml + 5 mg/ml, eye drops, solution in single-dose container The shelf life has been increased to 30 months and the product should not be stored above 25’C. http://www.medicines.org.uk/emc/medicine/31335

Cubicin (daptomycin) powder for concentrate for solution for injection or infusion The SPC now notes that the adverse effect eosinophilic pneumonia occasionally presents as organising pneumonia [defined pathologically by the presence in the distal air spaces of buds of granulation tissue] (frequency unknown). http://www.medicines.org.uk/emc/medicine/17341

Cuvitru (Human normal immunoglobulin) solution for subcutaneous injection The manufacturers now highlight that that if the preparation remains in siliconized syringes for more than two hours, visible particles may form. It states that the infusion must be started immediately upon transfer into the syringe to prevent particulate formation. http://www.medicines.org.uk/emc/medicine/33220 Cuvitru (Human normal immunoglobulin) solution for subcutaneous injection The manufacturers now highlight that that if the preparation remains in siliconized syringes for more than two hours, visible particles may form. It states that the infusion must be started immediately upon transfer into the syringe to prevent particulate formation. http://www.medicines.org.uk/emc/medicine/33220

Daktarin (miconazole) Sugar Free 2% Oral Gel The SPC now details the interaction with warfarin, and the product packaging has been updated to state that patients should not use if they are taking warfarin. Concomitant use can substantially increase INR, and fatal outcomes (due to bleeding) have been reported. http://www.medicines.org.uk/emc/medicine/22032

Darzalex (daratumumab) 20 mg/mL concentrate for solution for infusion Section 6.3 now advises that the unopened vials have a shelf life of 24 months (previously 18 months). http://www.medicines.org.uk/emc/medicine/32088

Eumovate Ointment (0.05% w/w clobetasone butyrate) Sections 4.4 and 4.8 have been updated to align to the PRAC recommendation with regard to blurred vision and central serous chorioretinopathy. Section 4.4 also now contains a statement relating to fire hazard in contact with dressings, clothing and bedding. http://www.medicines.org.uk/emc/medicine/2607

Epanutin (phenytoin) Ready Mixed Parenteral Sections 4.4 and 4.8 now include warnings about cardiovascular adverse effects, with asystole/cardiac arrest and bradycardia listed as possible adverse effects. http://www.medicines.org.uk/emc/medicine/14232

Giotrif (afatinib) 20 mg/30 mg/40 mg/50 mg film-coated tablets Nail disorder has been added to SPC as adverse effect of common frequency. http://www.medicines.org.uk/emc/medicine/28353

Harvoni 90 mg/400 mg (ledipasvir and sofosbuvir) film-coated tablets The indication has been extended to include treatment of chronic hepatitis C in adolescents aged 12 to < 18 years. Various other sections of the SPC have also been updated as a consequence. http://www.medicines.org.uk/emc/medicine/29471

Januvia (sitagliptin) and Janumet (sitagliptin/metformin) tablets SPC now highlights that there have been post-marketing reports of bullous pemphigoid in patients taking DPP- 4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, sitagliptin treatment should be discontinued. http://www.medicines.org.uk/emc/medicine/19609 Harvoni 90 mg/400 mg (ledipasvir and sofosbuvir) film-coated tablets The indication has been extended to include treatment of chronic hepatitis C in adolescents aged 12 to < 18 years. Various other sections of the SPC have also been updated as a consequence. http://www.medicines.org.uk/emc/medicine/29471

Keytruda (pembrolizumab) solution for infusion Sections 4.2, 4.4 and 4.8 have been updated with information on immune-related skin adverse reactions including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, some with fatal outcome. Depending on severity, treatment should be withheld or discontinued. http://www.medicines.org.uk/emc/medicine/33162

Loceryl Curanail (amorolfine) 5% w/v Medicated Nail Lacquer Following post-marketing experience, systemic hypersensitivity has been added as a potential adverse effect of treatment (frequency unknown). http://www.medicines.org.uk/emc/medicine/17637

Loceryl (amorolfine) Nail Lacquer 5% SPC now highlights that after application, an interval of at least 10 min should be respected before application of any cosmetic nail lacquer. Before repeat application, the cosmetic nail lacquer should be removed carefully. http://www.medicines.org.uk/emc/medicine/6408

Lynparza (olaparib) 50 mg hard capsules Rash, hypersensitivity and dermatitis have been added to SPC as adverse events. http://www.medicines.org.uk/emc/medicine/30359

Maxitrol (dexamethasone, polymyxin and neomycin) Ointment SPC has been updated to warn that Cushing's syndrome and/or adrenal suppression linked to systemic absorption of ocular dexamethasone may occur after intensive or long-term continuous therapy. Also visual disturbance may be reported with systemic and topical corticosteroid use. http://www.medicines.org.uk/emc/medicine/70

Moviprep, powder for oral solution The details on the procedure for use is now separated into different sections for procedures under general anaesthesia and procedures without general anaesthesia. http://www.medicines.org.uk/emc/medicine/19285 Maxitrol (dexamethasone, polymyxin and neomycin) Ointment SPC has been updated to warn that Cushing's syndrome and/or adrenal suppression linked to systemic absorption of ocular dexamethasone may occur after intensive or long-term continuous therapy. Also visual disturbance may be reported with systemic and topical corticosteroid use. http://www.medicines.org.uk/emc/medicine/70

Munalea 150/30 (desogestrel/ethinylestradiol) micrograms Film-coated Tablets Sections 4.3, 4.4 and 4.5 warns that Munalea should not be used by patients with hepatitis C taking ombitasvir/paritaprevir/ritonavir and dasabuvir. Concomitant use may increase the risk of ALT elevations; an alternative method of contraception must be considered. http://www.medicines.org.uk/emc/medicine/31009

Olumiant (baricitinib) 2 mg and 4 mg Film-Coated Tablets Section 4.4 now warns that events of DVT and PE have been reported in patients receiving baricitinib. It should be used with caution in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery and immobilisation http://www.medicines.org.uk/emc/medicine/32997

ORENCIA (abatacept) 250 mg powder for concentrate for solution for infusion Abatacept is now licensed, alone or with methotrexate (MTX), for the treatment of active psoriatic arthritis in adults when the response to previous DMARD, including MTX has been inadequate, and for whom additional systemic therapy for psoriatic skin lesions is not required. http://www.medicines.org.uk/emc/medicine/19714

Oruvail (ketoprofen) 100mg capsules Section 4.5 has been updated to include interactions with: heparin, vit K antagonists (e.g. warfarin), platelet aggregation inhibitors (e.g. ticlopidine, clopidogrel), thrombin inhibitors (e.g. dabigatran) and direct factor Xa inhibitors (e.g. apixaban, rivaroxaban, edoxaban). http://www.medicines.org.uk/emc/medicine/25505

Otomize (neomycin/ dexamethasone) SPC has been updated to warn visual disturbance may be reported with systemic/topical corticosteroid use. Patients with these ADRs should be considered for referral to ophthalmologist as causes may include cataract, glaucoma or rare diseases e.g. central serous chorioretinopathy. http://www.medicines.org.uk/emc/medicine/13699

Perjeta (pertuzumab) 420 mg Concentrate for Solution for Infusion Section 4.2 now advises that the infusion should be discontinued immediately and permanently if the patient experiences a NCI-CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome. http://www.medicines.org.uk/emc/medicine/27473 Otomize (neomycin/ dexamethasone) SPC has been updated to warn visual disturbance may be reported with systemic/topical corticosteroid use. Patients with these ADRs should be considered for referral to ophthalmologist as causes may include cataract, glaucoma or rare diseases e.g. central serous chorioretinopathy. http://www.medicines.org.uk/emc/medicine/13699

Praxbind (idarucizumab) 2.5 g/50 mL solution for injection/infusion Sections 6.3 (Shelf life) and 6.4 (Special precautions for storage) of the SPC have been updated to reflect room temperature now defined as 30 degrees (previously 25 degrees). http://www.medicines.org.uk/emc/medicine/31243

Qvar (beclomethasone) inhalers (all products) SPCs revised to warn of possible systemic effects with concomitant use of strong CYP3A inhibitors (e.g. ritonavir, cobicistat). Appropriate monitoring is advised with use of such agents, though beclomethasone is less dependent on CYP3A metabolism than other steroids http://www.medicines.org.uk/emc/medicine/23274

Seebri (glycopyrronium) Breezhaler Inhalation Powder Nausea, vomiting (both uncommon) and musculoskeletal pain (common) have been added as potential adverse reactions to treatment. http://www.medicines.org.uk/emc/medicine/27138

Sirturo (bedaquiline fumarate) 100 mg tablets Section 4.4 now advises that when bedaquiline is co administered with other medicinal products that prolong QTc interval (including delamanid and levofloxacin), an additive or synergistic effect on QT prolongation cannot be excluded. Caution is recommended. http://www.medicines.org.uk/emc/medicine/29644

Soliris (eculizumab) The indication has been updated to include treatment of adults with refractory generalized myasthenia gravis who are anti-acetylcholine receptor antibody-positive (information relating to this new indication has been added to various sections of the SPC). http://www.medicines.org.uk/emc/medicine/19966

Temomedac (temozolomide) 140mg hard capsules Following PRAC Recommendation, SPC has been updated with warning that post marketing cases of meningoencephalitis herpetic (including fatalities) has been observed in patients on temozolomide in combination with radiotherapy, including cases on concomitant steroids. http://www.medicines.org.uk/emc/medicine/23338 Soliris (eculizumab) The indication has been updated to include treatment of adults with refractory generalized myasthenia gravis who are anti-acetylcholine receptor antibody-positive (information relating to this new indication has been added to various sections of the SPC). http://www.medicines.org.uk/emc/medicine/19966

Temomedac (temozolomide) 250mg hard capsules Sections 4.4 and 4.8 note that post marketing cases of herpetic meningoencephalitis (including fatal cases) have been reported (frequency uncommon) in patients receiving temozolomide in combination with radiotherapy, including cases of concomitant steroid administration. http://www.medicines.org.uk/emc/medicine/23336

TicoVac (tick-borne encephalitis vaccine) Junior 0.25 ml Suspension for injection in a pre-filled syringe Guillain-Barré syndrome has been added to SPC as rare adverse effect. http://www.medicines.org.uk/emc/medicine/30334

Toctino (alitretinoin) 10mg and 30mg soft capsules Section 4.8 now lists photosensitivity reactions and nail disorders as new post marketing adverse reactions. http://www.medicines.org.uk/emc/medicine/21177

Tyverb (lapatinib) Stevens-Johnson syndrome and toxic epidermal necrolysis have been added to SPC as adverse effects of unknown frequency. http://www.medicines.org.uk/emc/medicine/20929

Xalkori (crizotinib) 200mg and 250mg hard capsule Section 4.1 now clarifies that crizotinib is to be used as monotherapy only, for anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer. http://www.medicines.org.uk/emc/medicine/27168 Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright © Midlands and Lancashire Commissioning Support Unit Medicines Safety Assurance Tool July 2017 To request this safety tool, or for more information about this tool, to make a comment, or share a safety issue please contact [email protected]

Risk of death and severe harm from ingestion of superabsorbent polymer gel granules Proposed action Central Alerting System | 05-July-2017 Newsletter Optimise Rx/ScriptSwitch l Superabsorbent polymer gel granules are widely used in health and social care, typically as small sachets Practice audit/search Other placed in urine and vomit bowls. If the gel granules are put in the mouth they expand on contact with saliva risking airway obstruction. This has happened where patients have mistaken the sachets for sweets, or sugar or salt packets, but some incident reports also describe attempts of deliberate self-harm. Healthcare providers are asked to review their overall approach to using these products. Action taken https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102798

Status 1 Date completed

Important safety information for people with diabetes using NovoPen® Echo® or NovoPen® 5 Proposed action Novo Nordisk | 05-July-2017 Newsletter Optimise Rx/ScriptSwitch l The insulin cartridge holder used in some batches of NovoPen Echo and NovoPen 5 may crack or break if Practice audit/search Other exposed to certain chemicals (e.g. household cleaning agents). Patients should check their device and contact the manufacturer for replacement if it belongs to an affected batch. http://offlinehbpl.hbpl.co.uk/NewsAttachments/2MM/170705-Important-safety-information-for-people-with- diabetes-using-NovoPen-Echo-or-NovoPen-5.pdf Action taken

Status 1 Date completed

Clexane (enoxaparin sodium) Proposed action Sanofi |June-2017 Newsletter Optimise Rx/ScriptSwitch l Updates to strength expression, dose regimens in DVT/PE, use in patients with severe renal impairment Practice audit/search Other https://assets.publishing.service.gov.uk/media/596f669a40f0b60a400001ba/Clexane_DHPC_300617.pdf Updates to strength expression, dose regimens in DVT/PE, use in patients with severe renal impairment Practice audit/search https://assets.publishing.service.gov.uk/media/596f669a40f0b60a400001ba/Clexane_DHPC_300617.pdf

Action taken

Status 1 Date completed

The safer management of controlled drugs Proposed action Care Quality Commission | 27-July-2017 Newsletter Optimise Rx/ScriptSwitch l Prescribers must make sure that they review patients regularly, depending on their clinical need. This is to Practice audit/search Other ensure that the prescribed controlled drugs and length of treatment continues to be the most appropriate for their condition and to reduce opportunities for over prescribing and diversion. http://www.cqc.org.uk/sites/default/files/20170718_controlleddrugs2016_report.pdf Action taken

Status 1 Date completed Epilim (sodium valproate) risk management material Proposed action Sanofi UK | July-2017 Newsletter Optimise Rx/ScriptSwitch l This poster, to be displayed in dispensaries of pharmacies warns that valproate should only be used in girls, Practice audit/search Other women of child bearing age and those who are pregnant or planning pregnancy, when other treatments are ineffective or not tolerated. http://www.medicines.org.uk/emc/RMM.1002.pdf

Sanofi has issued letters for specialists and specialist nurses/midwives, GPs and pharmacists advising that Action taken valproate medicines should be used only when no other treatment is effective or tolerated in girls, women of childbearing age, and women who are pregnant/planning pregnancy. http://www.medicines.org.uk/emc/medicine/23020#rmm

Status 1 Date completed

Glucose content of Lucozade Energy drinks reduced by 50% from April 2017 Proposed action Royal Pharmaceutical Society of Great Britain | 30-March-2017 Newsletter Optimise Rx/ScriptSwitch l People with diabetes who consume Lucozade Energy Original for the treatment of hypoglycaemia should be Practice audit/search Other advised to check the label of any product purchased to ensure that they are aware of the correct quantity to consume. http://www.medicinesresources.nhs.uk/en/Medicines-Awareness/Safety-Alerts/Safety-alerts/Glucose- content-of-Lucozade-Energy-drinks-to-be-reduced-by-50-from-April-2017/ Action taken

Status 1 Date completed Summary of Product Characteristics Update Proposed action July-2017 Newsletter Optimise Rx/ScriptSwitch l Practice audit/search Other Alecensa (alectinib) 150 mg Hard Capsules SPC updated with information about reports of increased alkaline phosphatase in the post-marketing period. Cases were also reported in pivotal Phase II clinical trials NP28761 and NP28673. This has been added to SPC as a common adverse effect. http://www.medicines.org.uk/emc/medicine/33005 Action taken

Alprolix (eftrenonacog alfa) powder and solvent for solution for injection The SPC now states that some patients who are well-controlled on a once every 10 days regimen might be treated on an interval of 14 days or longer. Side-effects of FIX inhibitor development and hypersensitivity (observed in post-marketing experience) have been added. Status 1 http://www.medicines.org.uk/emc/medicine/32153 Date completed

Anoro Ellipta (55 micrograms umeclidinium /22 micrograms vilanterol) inhalation powder, pre-dispensed Dysphonia (voice disorder) has been added to SPC as adverse reaction of uncommon frequency. http://www.medicines.org.uk/emc/medicine/28949

Atriance (nelarabine) 5 mg/ml solution for infusion SPC updated to warn that patients treated with nelarabine are potentially at risk of suffering from somnolence during and for several days after treatment therefore they should be warned that somnolence can affect performance of skilled tasks, such as driving. http://www.medicines.org.uk/emc/medicine/20045

Aubagio (teriflunomide) 14 mg film-coated tablets SPC now warns measurement of ionised calcium (IC) levels might show falsely decreased values under treatment with leflunomide and/or teriflunomide (metabolite) depending on type of IC analyser used. In case of doubt, total albumin adjusted serum calcium level should be measured. http://www.medicines.org.uk/emc/medicine/28533

Bexsero Meningococcal Group B vaccine for injection in pre-filled syringe The SPC now notes that reported injection site reactions include extensive swelling of the vaccinated limb and injection site nodule. http://www.medicines.org.uk/emc/medicine/28407

Canesten products containing fluconazole SPCs for fluconazole products have been updated with data from study suggesting increased risk of spontaneous abortion in women treated with it in 1st trimester. It should not be used during pregnancy/in women of childbearing potential unless adequate contraception is used. http://www.medicines.org.uk/emc/medicine/13959 Canesten products containing fluconazole SPCs for fluconazole products have been updated with data from study suggesting increased risk of spontaneous abortion in women treated with it in 1st trimester. It should not be used during pregnancy/in women of childbearing potential unless adequate contraception is used. http://www.medicines.org.uk/emc/medicine/13959

Copaxone (glatiramer acetate) Injection, Pre-filled Syringe Glatiramer is no longer contraindicated in pregnancy. Current data indicate no malformative or feto/neonatal toxicity, however no relevant epidemiological data are available. It is preferable to avoid the use during pregnancy unless the benefit to the mother outweighs the risk to http://www.medicines.org.uk/emc/medicine/30795

Daktarin (miconazole) Oral Gel SPC has been updated to advise increases in INR and bleeding events have been reported in patients on oral anticoagulants and miconazole (MC) oral gel. MC is systemically absorbed and is known to inhibit CYP2C9 and CYP3A4 which can lead to prolonged effects of warfarin. http://www.medicines.org.uk/emc/medicine/7301

Desferal (desferrioxamine mesilate) vials Shelf life has increased from 18 to 36 months and storage conditions have changed from above 30ºC to above 25ºC. http://www.medicines.org.uk/emc/medicine/2666

Dysport (botulinum type A toxin) 300U and 500U SPC has been updated with new indication of axillary hyperhidrosis. http://www.medicines.org.uk/emc/medicine/32114

Eperzan (albiglutide) 30 mg and 50 mg powder and solvent for solution for injection SPC now notes dehydration, sometimes leading to renal impairment and acute renal failure, has been reported and has occurred in patients without gastrointestinal side effects. Patients should be advised of this potential risk and take precautions to avoid fluid depletion. http://www.medicines.org.uk/emc/medicine/31399

Evorel (estradiol) 25, 50, 75 & 100 patches Section 4.2 advises on the addition of approved oral progestogens (eg oral norethisterone, 1mg/day or medroxyprogesterone acetate, 2.5mg/day), either on a cyclical or continuous basis for women with an intact uterus for the prevention of adverse endometrial effects. http://www.medicines.org.uk/emc/medicine/7235 Eperzan (albiglutide) 30 mg and 50 mg powder and solvent for solution for injection SPC now notes dehydration, sometimes leading to renal impairment and acute renal failure, has been reported and has occurred in patients without gastrointestinal side effects. Patients should be advised of this potential risk and take precautions to avoid fluid depletion. http://www.medicines.org.uk/emc/medicine/31399

Evra (norelgestromin/ ethinyl estradiol) transdermal patch Sections 4.3, 4.4 and 4.5 include a contraindication for patients receiving drug combinations with ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin. Concomitant use may increase the risk of ALT elevations. http://www.medicines.org.uk/emc/medicine/12124

Foscavir (foscarnet) 24 mg/ml Solution for Infusion Number of adverse events added, including hypersensitivity, dehydration, tachycardia, gastrointestinal haemorrhage, urticaria, angioedema, proteinuria, haematuria, erythema multiforme, toxic epidermal necrolysis, Stevens Johnson syndrome, glomerulonephritis and nephrotic syndrome http://www.medicines.org.uk/emc/medicine/174

Gilenya (fingolimod) 0.5mg hard capsules Before initiation of fingolimod, in women of childbearing potential, a negative pregnancy test result needs to be available. Counsellingshould be provided regarding the potential for serious risk to the foetus and the need for effective contraception during treatment. http://www.medicines.org.uk/emc/medicine/24443

Imodium (loperamide) 1 mg/5 ml oral solution SPC has been updated to warn that cardiac events including QT prolongation and torsades de pointes have been reported in association with overdose. Some cases had a fatal outcome. Patients should not exceed recommended dose and/or recommended duration of treatment. http://www.medicines.org.uk/emc/medicine/17607

Incruse (umeclidinium) 55 micrograms inhalation powder, pre-dispensed Eye pain (rare frequency) and increased intraocular pressure (unknown frequency) have been added to SPC as adverse effects. http://www.medicines.org.uk/emc/medicine/29394

Komboglyze (saxagliptin, metformin) 2.5mg-850mg & 2.5mg-1000mg Tablets Information on ‘saxagliptin add on to dapagliflozin plus metformin therapy’ and ‘saxagliptin and dapagliflozin add on to metformin therapy’ has been added to section 5.1 and the indication rewritten to incorporate this updated information. http://www.medicines.org.uk/emc/medicine/27311 Incruse (umeclidinium) 55 micrograms inhalation powder, pre-dispensed Eye pain (rare frequency) and increased intraocular pressure (unknown frequency) have been added to SPC as adverse effects. http://www.medicines.org.uk/emc/medicine/29394

Lioresal (baclofen) – all formulations Sections 4.4, 4.6 and 4.8 include additional information on drug withdrawal symptoms in neonates exposed to intrauterine levels of baclofen. Onset of scoliosis or worsening of pre-existing scoliosis has been reported in patients treated specifically with Lioresal Intrathecal. http://www.medicines.org.uk/emc/medicine/4113

Lyrica (pregabalin) capsules Hepatobiliary disorders have been added to section 4.8. Adverse effects include elevated liver enzymes (uncommon), jaundice (rare) and hepatic failure/hepatitis (very rare). http://www.medicines.org.uk/emc/medicine/14651

Mirvaso (brimonidine) 3mg/g Gel SPC now highlights that brimonidine gel should not be applied to irritated skin after laser surgery. Bradycardia (rare) and dizziness (uncommon) have been added as potential adverse effects of treatment. http://www.medicines.org.uk/emc/medicine/28682

MST (morphine sulphate) Continus tablets 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg Pneumonia aspiration has been added to the list of symptoms of overdose. http://www.medicines.org.uk/emc/medicine/1223

One-Alpha Drops (alfacalcidol) In section 6.1 (List of excipients), dl-a-tocopherol is renamed to All-rac-a-tocopherol. The in use shelf life of the product has been changed from 28 days to 4 months. http://www.medicines.org.uk/emc/medicine/3352

Onglyza (saxagliptin) 2.5mg & 5mg film-coated tablets Information has been added to section 5.1 on ‘saxagliptin add on to dapagliflozin plus metformin therapy’ and on ‘saxagliptin and dapagliflozin added on to metformin therapy’. http://www.medicines.org.uk/emc/medicine/22315

ORENCIA (abatacept) 125 mg solution for injection (pre-filled syringe) ORENCIA, alone or in combination with methotrexate (MTX), is licensed for the treatment of active psoriatic arthritis in adults when the response to previous DMARD therapy including MTX has been inadequate, and for whom additional systemic therapy is not required. http://www.medicines.org.uk/emc/medicine/27216 ORENCIA (abatacept) 125 mg solution for injection (pre-filled syringe) ORENCIA, alone or in combination with methotrexate (MTX), is licensed for the treatment of active psoriatic arthritis in adults when the response to previous DMARD therapy including MTX has been inadequate, and for whom additional systemic therapy is not required. http://www.medicines.org.uk/emc/medicine/27216

Prolia (denosumab) Osteonecrosis of the external auditory canal (frequency unknown) has been reported with denosumab. Possible risk factors include steroid use and chemotherapy and/or local risk factors such as infection or trauma. SPC has been updated with information relating to when to re-evalaute patients after long term treatment and risk of adverse outcomes such as osteonecrosis of the jaw and atypical femur fractures. SPC has been updated to include advice about long-term use: Optimal total duration of antiresorptive treatment for osteoporosis (incl both denosumab and bisphosphonates) has not been established. The need for continued treatment should be re-evaluated particularly after >5 yrs. http://www.medicines.org.uk/emc/medicine/23127

Propecia (finasteride) 1mg tablets Section 4.4 includes a new warning statement under a new sub-heading of ‘Mood alterations and depression’ to reflect that cases of depression, mood alterations and suicidal ideation have been reported. Section 4.8 has also been updated to include this information. http://www.medicines.org.uk/emc/medicine/3680

Renvela (Sevelamer carbonate) powder for oral suspension The SPC has been updated to highlight the licence extension for use in children and adolescents (>6 years of age and a body surface area (BSA) of ≥0.75m2). http://www.medicines.org.uk/emc/medicine/22782

Revestive (teduglutide) SPC highlights that a 1.25 mg strength vial is available for paediatric use (patients with a body weight <20 kg). Also, it is strongly recommended that the name and lot number of the product are recorded on each administration. http://www.medicines.org.uk/emc/medicine/29315

Sebivo (telbivudine) 600mg film-coated tablets Rare post-marketing cases of lactic acidosis (LA) have been reported with telbivudine; more often secondary to other serious conditions. Treatment should be discontinued when metabolic/LA of unknown aetiology occurs. Benign digestive symptoms may be indicative of LA development. http://www.medicines.org.uk/emc/medicine/19740 Revestive (teduglutide) SPC highlights that a 1.25 mg strength vial is available for paediatric use (patients with a body weight <20 kg). Also, it is strongly recommended that the name and lot number of the product are recorded on each administration. http://www.medicines.org.uk/emc/medicine/29315

Selincro (nalmefene) 18mg film-coated tablets Section 4.7 has been amended and now notes that due to the possible occurrence of a number of adverse effects, nalmefene may have minor to moderate influence on the ability to drive and use machines and patients should exercise caution particular when starting treatment. http://www.medicines.org.uk/emc/medicine/27609

Silkis (calcitriol) 3 micrograms per g ointment The SPC now advises that caution must be used in patients receiving medications known to increase the serum calcium level, e.g. thiazide diuretics, or medications with pharmacological effects impacted by a change in calcium levels such as digoxin. http://www.medicines.org.uk/emc/medicine/8621

Strensiq (asfotase) injection SPC now highlights that treating physicians should inform a testing lab that a patient is being treated with asfotase when ordering samples. Alkaline Phosphatase is a detection reagent in many assays, and if asfotase alfa is present aberrant values could be reported http://www.medicines.org.uk/emc/medicine/30861

Tivicay (dolutegravir) film-coated tablets The shelf-life of Tivicay 10mg, 25mg, and 50mg tablets has been extended from 3 to 5 years, from 3 to 4 years and from 2 to 5 years respectively. http://www.medicines.org.uk/emc/medicine/28545

Uptravi (selexipag) Sections 4.3, 4.4 and 4.5 have been updated with information on the concomitant use of strong inhibitors of CYP2C8. http://www.medicines.org.uk/emc/medicine/31963

Xagrid (anagrelide) 0.5mg hard capsule SPC now warns that cases of pulmonary hypertension have been reported in patients treated with anagrelide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during anagrelide therapy. http://www.medicines.org.uk/emc/medicine/15737 Uptravi (selexipag) Sections 4.3, 4.4 and 4.5 have been updated with information on the concomitant use of strong inhibitors of CYP2C8. http://www.medicines.org.uk/emc/medicine/31963

Xarelto (rivaroxaban) film coated tablets (all strengths) Serious skin reactions, including Stevens-Johnson syndrome/Toxic Epidermal Necrolysis, have been reported. The highest risk appears to be early in the course of therapy. Treatment should be discontinued at the first appearance of a severe skin rash http://www.medicines.org.uk/emc/medicine/21265

Xtandi (enzalutamide) 40mg capsules Addition of seizure related information to sections 4.4/4.8. Caution should be used in patients with a history of seizures or other predisposing factors. Risk of seizure may be increased in patients receiving concomitant medicines that lower seizure threshold. http://www.medicines.org.uk/emc/medicine/27912

Xultophy 100 units/ml insulin degludec + 3.6 mg/mL liraglutide solution for injection in a pre-filled pen Use in hepatic impairment (HI) has been revised to state that Xultophy can be used in mild or moderate HI and glucose monitoring is to be intensified and dose adjusted on individual basis. Due to liraglutide component, it is not recommended for use in severe HI. http://www.medicines.org.uk/emc/medicine/29493

Zometa (zoledronic acid) 4mg/100ml Solution for Infusion Section 4.4 and 4.8 have been updated with new information on osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction, frequency, very rare) and other anatomical sites including femur and hip (frequency, very rare). http://www.medicines.org.uk/emc/medicine/25058

Zometa (zoledronic acid) 4mg/5ml Concentrate for Solution for Infusion SPC revised to warn osteonecrosis (ON) of external auditory canal has been reported with bisphosphonates, mainly linked to long-term therapy. There have also been sporadic reports of ON of other sites, including hip/femur, mainly in adult cancer patients treated with Zometa. http://www.medicines.org.uk/emc/medicine/14062 Zometa (zoledronic acid) 4mg/100ml Solution for Infusion Section 4.4 and 4.8 have been updated with new information on osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction, frequency, very rare) and other anatomical sites including femur and hip (frequency, very rare). http://www.medicines.org.uk/emc/medicine/25058

Zometa (zoledronic acid) 4mg/5ml Concentrate for Solution for Infusion SPC revised to warn osteonecrosis (ON) of external auditory canal has been reported with bisphosphonates, mainly linked to long-term therapy. There have also been sporadic reports of ON of other sites, including hip/femur, mainly in adult cancer patients treated with Zometa. http://www.medicines.org.uk/emc/medicine/14062 Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright © Midlands and Lancashire Commissioning Support Unit Medicines Safety Assurance Tool June 2017 To request this safety tool, or for more information about this tool, to make a comment, or share a safety issue please contact [email protected]

Brimonidine gel (Mirvaso): risk of systemic cardiovascular effects; not to be applied to damaged skin Proposed action MHRA | 21-June-2017 Newsletter Optimise Rx/ScriptSwitch • cases of bradycardia, hypotension (including orthostatic hypotension), and dizziness after application Practice audit/search Other of brimonidine gel have been reported, some of which required hospitalisation • some cases were associated with application of brimonidine gel after laser procedures to the skin, which possibly caused increased absorption of the gel • warn patients not to apply brimonidine gel to irritated or damaged skin, including after laser therapy Action taken to the skin

Status https://www.gov.uk/drug-safety-update/brimonidine-gel-mirvaso-risk-of-systemic-cardiovascular-effects-not-to-be-applied-to-damaged-skin Date completed

Denosumab (Prolia, Xgeva▼): reports of osteonecrosis of the external auditory canal Proposed action MHRA | 21-June-2017 Newsletter Optimise Rx/ScriptSwitch • the possibility of osteonecrosis of the external auditory canal should be considered in patients Practice audit/search Other receiving denosumab who present with ear symptoms including chronic ear infections or in those with suspected cholesteatoma • possible risk factors include steroid use and chemotherapy, with or without local risk factors such as infection or trauma Action taken • advise patients to report any ear pain, discharge from the ear, or an ear infection during denosumab treatment • report cases of osteonecrosis of any bone suspected to be associated with denosumab or any other medicine on a Yellow Card • the possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections or in those with suspected cholesteatoma • possible risk factors include steroid use and chemotherapy, with or without local risk factors such as infection or trauma • advise patients to report any ear pain, discharge from the ear, or an ear infection during denosumab treatment • report cases of osteonecrosis of any bone suspected to be associated with denosumab or any other medicine on a Yellow Card

Status https://www.gov.uk/drug-safety-update/denosumab-prolia-xgeva-reports-of-osteonecrosis-of-the-external-auditory-canal Date completed

e-cigarettes and refill containers (e-liquids): report suspected side effects and safety concerns Proposed action MHRA | 21-June-2017 Newsletter Optimise Rx/ScriptSwitch Members of the public and healthcare professionals can use the Yellow Card Scheme website to report any Practice audit/search Other suspected side effects or safety concerns with e-cigarettes and the e-liquids used for vaping. These issues could include:

• suspected side-effects that occurred after the use of e-cigarettes and e-liquids • harm to children or non-users, including accidental poisoning Action taken • safety issues or defects with e-cigarette devices

Status https://www.gov.uk/drug-safety-update/e-cigarettes-and-refill-containers-e-liquids-report-suspected-side-effects-and-safety-concerns Date completed

Influenza Season 2016/17: Use of Antiviral Medicines Proposed action CAS | 12-Jun-2017 Newsletter Optimise Rx/ScriptSwitch Prescribers working in primary care and community pharmacists should no longer prescribe or supply Practice audit/search Other antiviral medicines for the prophylaxis and treatment of influenza on an FP10 prescription form

Action taken

Status https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102782 Date completed Risk minimisation materials: Physician prescribing checklist for Mysimba (8mg naltrexone /90mg bupropion) prolonged-release tablets Proposed action electronic Medicines Compendium | 14-Jun-2017 Newsletter Optimise Rx/ScriptSwitch This checklist ensures the appropriate contraindications and special warnings/precautions are considered Practice audit/search Other when prescribing Mysimba prolonged-release tablets.

Action taken

Status http://www.medicines.org.uk/emc/RMM.886.pdf Date completed

Risk management materials for Valdoxan® (agomelatine) - liver function monitoring and drug interactions Proposed action electronic Medicines Compendium | 19-Jun-2017 Newsletter Optimise Rx/ScriptSwitch New guidance for healthcare professionals has been provided for monitoring liver function in patients before Practice audit/search Other and during treatment with Valdoxan. Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) is also contraindicated with Valdoxan.

Action taken

Status http://www.medicines.org.uk/emc/RMM.64.pdf Date completed Educational Risk Minimisation Materials: Prescribers' Administration Guide for Qutenza® Proposed action electronic Medicines Compendium | 22-Jun-2017 Newsletter Optimise Rx/ScriptSwitch Prescribers should refer to this administration guide before administering Qutenza. It covers warnings and Practice audit/search Other precautions for use, practice precautions, briefing the patient, correct application of patch, managing treatment-associated discomfort, and patient follow-up.

Action taken

Status http://www.medicines.org.uk/emc/RMM.558.pdf Date completed

Summary of Product Characteristics Updates Proposed action electronic Medicines Compendium | Jun-2017 Newsletter Optimise Rx/ScriptSwitch Practice audit/search Other Revised SPC: Ganfort® (bimatoprost and timolol) preparations The adverse events of asthma exacerbation and chronic obstructive pulmonary disease (COPD) exacerbation have been added to section 4.8. http://www.medicines.org.uk/emc/medicine/28209 Action taken

Revised SPC: Zocor® (simvastatin) tablets Simvastatin should now not be used within 7 days of stopping fusidic acid as well as avoiding concomitant administration. Also, simvastatin dose adjustments should be considered in concomitant administration of Breast Cancer Resistant Protein inhibitors (eg elbasvir, grazoprevir) http://www.medicines.org.uk/emc/medicine/1201 Status Date completed

Revised SPC: Reminyl® (galantamine) – all presentations Complete atrioventricular block is now listed as a rare adverse reaction. http://www.medicines.org.uk/emc/medicine/10335

Revised SPC: Simvastatin Rosemont 20mg/5ml and 40mg/5ml Oral Suspension Section 4.2 now advises that simvastatin Rosemont oral suspension is suitable for administration via nasogastric or percutaneous endoscopic gastrostomy tubes. http://www.medicines.org.uk/emc/medicine/32577 Revised SPC: Simvastatin Rosemont 20mg/5ml and 40mg/5ml Oral Suspension Section 4.2 now advises that simvastatin Rosemont oral suspension is suitable for administration via nasogastric or percutaneous endoscopic gastrostomy tubes. http://www.medicines.org.uk/emc/medicine/32577

Revised SPC: Actiq® (fentanyl) Lozenges The SPC now states use in those aged <16 years is not recommended. Additional side-effects listed/discussed include adrenal insufficiency, androgen deficiency, neonatal withdrawal syndrome and anaphylaxis and hypersensitivity. http://www.medicines.org.uk/emc/medicine/30554

Revised SPC: Losec® (omeprazole) – all formulations Section 4.8 has been updated with a new adverse effect - benign fundic gland polyps (frequency common). http://www.medicines.org.uk/emc/medicine/7275

Revised SPC: Neoclarityn® (desloratadine) – all formulations Section 4.4 contains information on administration in patients with medical/familial history of seizure and discontinuation in patients who experience a seizure. Section 4.8 has been updated with abnormal behaviour and aggression as potential adverse events (frequency unknown). http://www.medicines.org.uk/emc/medicine/9290

Revised SPCs: Solu-Medrone® (methylprednisolone) preparations Sections 4.4 and 4.5 have been revised to include warnings concerning co-treatment with CYP3A inhibitors (including cobicistat-containing products), which is expected to increase the risk of systemic side-effects. The combination should be avoided unless benefit outweighs risk. http://www.medicines.org.uk/emc/medicine/27656

Revised SPC: Pevanti® (prednisolone) tablets SPC highlights that visual disturbance may occur with corticosteroids. If blurred vision or other visual disturbances occur, the patient should be considered for referral to an ophthalmologist. Possible causes may include cataract, glaucoma or central serous chorioretinopathy. http://www.medicines.org.uk/emc/medicine/30012

Revised SPC: DuoResp Spiromax® (budesonide/formoterol) inhalation powder Sections 4.4 and 4.8 note that visual disturbance may occur with corticosteroids.If blurred vision or other visual disturbances occur, the patient should be considered for referral to an ophthalmologist Possible causes may include cataract, glaucoma or central serous chorioretino http://www.medicines.org.uk/emc/medicine/29187 Revised SPC: DuoResp Spiromax® (budesonide/formoterol) inhalation powder Sections 4.4 and 4.8 note that visual disturbance may occur with corticosteroids.If blurred vision or other visual disturbances occur, the patient should be considered for referral to an ophthalmologist Possible causes may include cataract, glaucoma or central serous chorioretino http://www.medicines.org.uk/emc/medicine/29187

Revised SPC: Brevinor® (norethisterone/ethinylestradiol) Tablets SPC has been updated with information on interaction between combined hormonal contraceptives containing ethinylestradiol with products containing ombitasvir/paritaprevir/ritonavir (Viekirax) and dasabuvir with or without ribavirin, which may increase risk of ALT elevations. http://www.medicines.org.uk/emc/medicine/1899

Revised SPC: Symbicort® (budesonide/formoterol) Turbohaler Inhalation powder (all strengths) The storage restriction has been removed from SPC. Previously it had advised that device should not be stored at temperatures above 30 degrees and that the container should be kept tightly closed to guard against development of moisture. http://www.medicines.org.uk/emc/medicine/4820

Revised SPC: Nexium® (esomeprazole) preparations Fundic gland polyps (benign) has been added as an undesirable effect. http://www.medicines.org.uk/emc/medicine/24695

Revised SPC: Qtern® (saxagliptin and dapagliflozin) 5 mg/10 mg film-coated tablets Section 4.4 now notes that an increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing long-term, clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. http://www.medicines.org.uk/emc/medicine/32750

Revised SPC: Avodart® (dutasteride) 0.5mg soft capsules Sections 4.4 and 5.1 of SPC have been updated with data from trials or reports during post-marketing period, about the risk of prostate and male breast cancer, and heart failure. http://www.medicines.org.uk/emc/medicine/11618

Revised SPC: Eperzan® (albiglutide) powder and solvent for solution for injection This SPC now advises that dehydration, sometimes leading to renal impairment and acute renal failure, has been reported in patients treated with albiglutide. Patients should be advised of this risk and advised to take precautions to avoid fluid depletion http://www.medicines.org.uk/emc/medicine/31399 Revised SPC: Eperzan® (albiglutide) powder and solvent for solution for injection This SPC now advises that dehydration, sometimes leading to renal impairment and acute renal failure, has been reported in patients treated with albiglutide. Patients should be advised of this risk and advised to take precautions to avoid fluid depletion http://www.medicines.org.uk/emc/medicine/31399

Revised SPC: Lumigan® (bimatoprost) 0.1mg/ml Eye discharge, increased lacrimation, eye oedema and foreign body sensation in the eyes have been added as potential adverse effects of treatment (frequency unknown) http://www.medicines.org.uk/emc/medicine/22807

Revised SPC: Trulicity® (dulaglutide) solution for injection Angioedema has been added as a rare potential adverse effect of treatment. http://www.medicines.org.uk/emc/medicine/29747

Revised SPC: Combodart (0.5 mg dutasteride/0.4 mg tamsulosin) hard capsules Sections 4.4 and 5.1 of SPC have been updated with data from trials or reports during post-marketing period, about the risk of prostate and male breast cancer, and heart failure with dutasteride. http://www.medicines.org.uk/emc/medicine/22943

Revised SPC: Intuniv (guanfacine) 1 mg, 2 mg, 3 mg, 4 mg prolonged-release tablets Erectile dysfunction has been added to SPC as an undesirable effect of unknown frequency. http://www.medicines.org.uk/emc/medicine/31294

Revised SPC: Xgeva® (denosumab) SPC updated to warn osteonecrosis of external auditory canal has been reported with denosumab. This should be considered in patients with ear symptoms including chronic ear infections. Risk factors include steroids and chemotherapy and/or local risk factors, e.g. infection/trauma http://www.medicines.org.uk/emc/medicine/24755

Revised SPC: NovoRapid 100 units/ml in a vial, NovoRapid Penfill 100 units/ml, NovoRapid FlexPen 100 units/ml, The storage information for NovoRapid FlexPen/NovoRapid FlexTouch has been updated to say that it can be stored in a refrigerator (previously stated that it should not be refrigerated). [Information for NovoRapid vial/NovoRapid Penfill and NovoRapid PumpCart remains unchanged]. http://www.medicines.org.uk/emc/medicine/25033 Revised SPC: NovoRapid 100 units/ml in a vial, NovoRapid Penfill 100 units/ml, NovoRapid FlexPen 100 units/ml, The storage information for NovoRapid FlexPen/NovoRapid FlexTouch has been updated to say that it can be stored in a refrigerator (previously stated that it should not be refrigerated). [Information for NovoRapid vial/NovoRapid Penfill and NovoRapid PumpCart remains unchanged]. http://www.medicines.org.uk/emc/medicine/25033

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1 Date completed Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright © Midlands and Lancashire Commissioning Support Unit Medicines Safety Assurance Tool May 2017 To request this safety tool, or for more information about this tool, to make a comment, or share a safety issue please contact [email protected]

Educational Risk Minimisation Materials for Clexane (enoxaparin sodium) Proposed action NICE | 15-May-2017 Newsletter Optimise Rx/ScriptSwitch l Dear Healthcare Professional” letter notes that enoxaparin is expressed both in international units (IU) of anti- Practice audit/search Other Xa activity and in milligrams (mg); and that its use in severe renal impairment is not recommended. There is also further clarification on dose regimens for DVT/PE. http://www.medicines.org.uk/emc/RMM.825.pdf Action taken

Status 1 Date completed

Educational Risk Minimisation Materials for Levetiracetam 100mg/ml oral solution Proposed action NICE | 12-May-2017 Newsletter Optimise Rx/ScriptSwitch l ‘Dear Healthcare Professional’ letter covers overdose due to medication errors and how to reduce risk. Where Practice audit/search Other cause of reported accidental overdosing was known, it was either due to use of inappropriate syringe or misunderstanding of caregiver about how to properly measure dose. http://www.medicines.org.uk/emc/RMM.823.pdf Action taken

Status 1 Date completed Risk management materials for Daxas (roflumilast) 500 micrograms film-coated tablets: Proposed action Information for prescribers and patients Newsletter Optimise Rx/ScriptSwitch NICE | 09-May-2017 l Practice audit/search Other This document contains information for healthcare professionals describing key prescribing and monitoring information (especially monitoring weight) to consider when prescribing roflumilast. http://www.medicines.org.uk/emc/RMM.817.pdf Action taken

Status 1 Date completed Finasteride: rare reports of depression and suicidal thoughts Proposed action NICE | 26-May-2017 Newsletter Optimise Rx/ScriptSwitch l We have received reports of depression and, in rare cases, suicidal thoughts in men taking finasteride 1 mg Practice audit/search Other (Propecia) for male pattern hair loss. Be aware that depression is also associated with finasteride 5 mg (Proscar). Advice for healthcare professionals: • Since finasteride has been marketed there have been a number of spontaneous adverse drug reaction Action taken reports suggesting a possible link to depression, and in rare cases, suicidal thoughts • Advise patients to stop finasteride 1 mg (Propecia) immediately if they develop depression and inform a healthcare professional • Be aware that the product information for finasteride 5 mg (Proscar) already lists depression as a possible adverse reaction Status 1 Date completed https://www.gov.uk/drug-safety-update/finasteride-rare-reports-of-depression-and-suicidal-thoughts

Accu-Chek® Insight insulin pumps - updated information for battery management Proposed action MHRA | 02-May-2017 Newsletter Optimise Rx/ScriptSwitch l Manufactured by Roche Diabetes Care – Replacement and update to MDA/2015/029 with new instructions to Practice audit/search Other improve battery lifetime and prevent unexpected pump shut down or rapid battery depletion. Action • Identify all users of Accu-Chek Insight insulin pumps. • Ensure that all patients and carers: Action taken o Receive the manufacturer’s Field Safety Notice (FSN) o Understand the instructions detailed in the FSN and follow the advice given by the manufacturer o Use Energizer® Ultimate lithium batteries (1.5V AAA / FR03) provided by the manufacturer and follow the steps described in the handling instructions in the FSN Status 1 • Contact Roche if you experience unexpected pump shut down or rapid battery depletion. • Return the FSN acknowledgment form to Roche as currently the manufacturer hasn’t received Date completed enough responses. https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102722 Class 2 Medicines Recall: Sodium Cromoglicate 2% w/v 13.5 mL Eye Drops Proposed action CAS | 18-May-2017 Newsletter Optimise Rx/ScriptSwitch l FDC International Ltd is recalling the batches listed as a precautionary measure due to a precipitate observed Practice audit/search Other in the bottles. https://assets.publishing.service.gov.uk/media/591eb86be5274a5e5100005a/Sodium_Cromoglicate_13.5_mL_Eye_Drops.pdf Action taken

Status 1 Date completed

Medical Device Alert: All LIFEPAK 1000 automatic external defibrillators (AEDs) - risk of device shutting down unexpectedly during patient treatment and possible failure to deliver therapy Proposed action CAS | 18-May-2017 Newsletter Optimise Rx/ScriptSwitch l 1. Identify all LIFEPAK 1000 defibrillators in your possession. Practice audit/search Other 2. Ensure that all those responsible for the AED follow the instructions in the manufacturer’s Field Safety Notice (FSN). 3. If you have already acted on this FSN, no further action is required. Action taken https://assets.publishing.service.gov.uk/media/591da3bd40f0b63e0b00005f/MDA_-_2017-013_Final.pdf

Status 1 Date completed Public Health England: Management of infection guidance for primary care for consultation and Proposed action local adaptation: Update Newsletter Optimise Rx/ScriptSwitch PHE | 10-May-2017 Practice audit/search Other l Following a review of new evidence detailing increased risk of spontaneous abortion with azithromycin, clarithromycin, metronidazole, tetracyclines, quinolones and sulphonamides PHE guidance has been updated on antibiotic use pregnancy. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/612743/Managing_common_infections.pdfAction taken

Status 1 Date completed

Trimethoprim and Methotrexate: never co-prescribe Proposed action CCG | 31-May-2017 Newsletter Optimise Rx/ScriptSwitch l The BNF states that there is an increased risk of haematological toxicity when methotrexate is given with Practice audit/search Other trimethoprim (also with co-trimoxazole). Several cases of severe bone marrow depression (some of which were fatal) have been reported in patients given low-dose methotrexate and trimethoprim or co-trimoxazole (sulfamethoxazole with trimethoprim). This potentially fatal interaction can occur even with short courses or low doses of trimethoprim. Action taken Pancytopenia has also been reported in a few patients given co-trimoxazole shortly after stopping methotrexate. Bone marrow suppression can occur abruptly, leading to: • Life threatening infections, as the body cannot produce leukocytes in response to invading bacteria and viruses. • Anaemia due to a lack of red blood cells. Status 1 • Spontaneous severe bleeding due to a deficiency of platelets. Date completed Prescribers should be aware that some information sources do not stress the importance of this interaction. EMIS Web highlights this drug interaction with a high severity warning.

SPC updates Proposed action NICE | 30-May-2017 Newsletter Optimise Rx/ScriptSwitch l Practice audit/search Other Revised SPC: Anusol HC (bismuth, zinc oxide and hydrocortisone) preparations SPC now highlights that visual disturbance has been reported with systemic and topical corticosteroid use. Patients with such symptoms should be considered for ophthalmology referral. http://www.medicines.org.uk/emc/medicine/10493 Action taken Revised SPC: Avelox (moxifloxacin) preparations Sections 4.4 (special warnings and precautions) and 4.8 (undesirable effects) have been updated to include the adverse reaction vasculitis with a frequency very rare and to modify the warnings on hypersensitivity reactions and peripheral neuropathy. http://www.medicines.org.uk/emc/medicine/22827 Status 1 Revised SPC: Briviact (brivaracetam) – all formulations Date completed Section 4.8 warns reactions suggestive of immediate (Type I) hypersensitivity have been reported in a small number of brivaracetam patients during clinical development. https://www.medicines.org.uk/emc/medicine/31452 Revised SPC: Budenofalk (budesonide) preparations Various additions, including side-effects (blurred vision, aggression, psychomotor hyperactivity and anxiety). Interaction with CYP3A inhibitors (increased risk of systemic side-effects) and further detail in the pregnancy and breast-feeding sections. http://www.medicines.org.uk/emc/medicine/18725 Revised SPC: Dalacin C (clindamycin) capsules Dose modification is not necessary in renal or hepatic insufficiency (4.2). Amended warnings made on hypersensitivity and severe skin reactions (4.4). C. difficile colitis, anaphylactic shock, anaphylactic reaction, hypersensitivity and angioedema have been added as adverse events (4.8) http://www.medicines.org.uk/emc/medicine/12425 Revised SPC: Diflucan (fluconazole) all formulations Section 4.4 updated with information on QT prolongation, reported during post-marketing surveillance. Section 4.5 notes that administration of fluconazole with amiodarone may increase QT prolongation; caution therefore advised, notably with high dose fluconazole (800 mg). http://www.medicines.org.uk/emc/medicine/25675 Revised SPC: Epanutin (phenytoin) – various presentations Information regarding the potential need for dose modification in elderly patients, and dose modification and/or measurement of unbound phenytoin levels in patients with renal or hepatic diseases, hypoalbuminemia, and/or hyperbilirubinemia has been added. http://www.medicines.org.uk/emc/medicine/13289 Revised SPC: Epanutin (phenytoin) – various presentations Information regarding the potential need for dose modification in elderly patients, and dose modification and/or measurement of unbound phenytoin levels in patients with renal or hepatic diseases, hypoalbuminemia, and/or hyperbilirubinemia has been added. http://www.medicines.org.uk/emc/medicine/13289 Revised SPC: Epanutin (phenytoin) Infatabs Sections 4.2 and 4.4 now includes information regarding the potential need for dose modification and/or measurement of unbound phenytoin due to potential for elevated concentration of unbound phenytoin in patients with renal or hepatic diseases, and hypo/hyperalbuminaemia http://www.medicines.org.uk/emc/medicine/13303 Revised SPC: Firmagon (degarelix) 120mg Injection SPC updated to warn that serious injection site reactions were very rarely reported such as injection site infection, injection site abscess or injection site necrosis that could require surgical treatment/drainage. http://www.medicines.org.uk/emc/medicine/21701 Revised SPC: Forxiga (dapagliflozin propanediol monohydrate) 5 mg & 10 mg film coated tablets Section 4.4 advises of an increase in cases of lower limb amputation (primarily of the toe) reported in ongoing long-term, clinical studies with another SGLT2 inhibitor, but it is unknown whether this constitutes a class effect. Counsel patients on routine preventative foot care. http://www.medicines.org.uk/emc/medicine/27188 Revised SPC: Heminevrin (clomethiazole) 192 mg Capsules Section 4.5 now warns of possible interactions with CYP2E1-substrates. http://www.medicines.org.uk/emc/medicine/33156 Revised SPC: Invokana (canagliflozin) 100 mg and 300 mg film-coated tablets Section 4.4 has been revised to include class labelling text on diabetic ketoacidosis - Rare cases of diabetic ketoacidosis, including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including canagliflozin. http://www.medicines.org.uk/emc/medicine/28400 Revised SPC: Jardiance (empagliflozin) 10 mg and 25 mg film-coated tablets The SPC now notes (section 4.4) that an increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing long-term clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. http://www.medicines.org.uk/emc/medicine/28973 Revised SPC: Nasonex (mometasone furoate monohydrate) 50 micrograms/actuation Nasal Spray, Suspension Section 4.5 now includes information regarding the expected increased risk of systemic side effects after co- treatment with CYP3A inhibitors, including cobicistat-containing products. The combination should be avoided. http://www.medicines.org.uk/emc/medicine/9748 Revised SPC: Nasonex (mometasone furoate monohydrate) 50 micrograms/actuation Nasal Spray, Suspension Section 4.5 now includes information regarding the expected increased risk of systemic side effects after co- treatment with CYP3A inhibitors, including cobicistat-containing products. The combination should be avoided. http://www.medicines.org.uk/emc/medicine/9748 Revised SPC: Nuvaring (etonogestrel and ethinylestradiol) vaginal delivery system Sections 4.3, 4.4 and 4.5 contraindicate the co-administration of ombitasvir/paritaprevir/ritonavir and dasabuvir with ethinyloestradiol because of the increased risk of elevated ALT. http://www.medicines.org.uk/emc/medicine/21419 Revised SPC: Octasa (mesalazine) 400mg MR Tablets Pleurisy has been added as a potential adverse effect from treatment (frequency unknown). http://www.medicines.org.uk/emc/medicine/27094 Revised SPC: Pradaxa (dabigatran etexilate) hard capsules – all strengths The colour of Pradaxa caps have been changed according to dosage strength, as part of the worldwide harmonisation process. The 75mg cap is white, the 110mg cap is light blue and the 125mg cap is two-tone light blue/white. Sunset yellow colouring has been removed from the casing. http://www.medicines.org.uk/emc/medicine/20760 Revised SPC: Soolantra (ivermectin) 10mg/g Cream Contact dermatitis has been added as a potential adverse effect from treatment (frequency unknown). http://www.medicines.org.uk/emc/medicine/30353 Revised SPC: Tresiba (insulin degludec) 100 units/mL, 200 units/mL Pre filled (FlexTouch), 100 units/mL Cartridge (Penfill) Dosing information has been extensively revised: In patients with type 2 diabetes, dose reduction of 20% based on previous basal insulin dose followed by individual dosage adjustments should be considered when transferring from twice-daily basal insulin or from insulin glargine. http://www.medicines.org.uk/emc/medicine/27360 Revised SPC: Vokanamet (canagliflozin with metformin) 50 mg/850 mg, 50 mg/1000 mg, 150 mg/850 mg and 150 mg/1000 mg film coated tablets Section 4.4 has been revised to include class labelling text on diabetic ketoacidosis - Rare cases of diabetic ketoacidosis, including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including canagliflozin. http://www.medicines.org.uk/emc/medicine/29368 Revised SPC: Xigduo (dapagliflozin and metformin) film coated tablets Section 4.4 contains new clinical information on risk of lower limb amputations; patients should be counselled on routine preventative foot care. Rash has been added as a common adverse event (≥ 1/100 to < 1/10). http://www.medicines.org.uk/emc/medicine/28667 Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright © Midlands and Lancashire Commissioning Support Unit

Medicines Safety Assurance Tool April 2017

Valproate and developmental disorders: new alert asking for patient review and further consideration of risk minimisation measures Date of alert Status Date completed Medicines and Healthcare products Regulatory Agency 24-Apr-2017

Patient Safety Alerts have now been issued asking all organisations to undertake systematic Proposed action Newsletter Prescribing decision support Search/audit identification of women and girls taking valproate. Babies born to mothers who take valproate medicines (Epilim▼, Depakote▼) during pregnancy have a 30–40% risk of developmental disability and a 10% risk of birth defects.

Advice for healthcare professionals

• Do not prescribe valproate medicines for epilepsy or bipolar disorder in women and girls unless other treatments are ineffective or not tolerated; migraine is not a licensed indication. • Ensure women and girls taking valproate medicines understand the 30–40% risk of Action taken neurodevelopmental disorders and 10% risk of birth defects and are using effective contraception. • Valproate use in women and girls of childbearing potential must be initiated and supervised by specialists in the treatment of epilepsy or bipolar disorder.

https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAlert.aspx?AlertID=102582

https://www.gov.uk/drug-safety-update/valproate-and-developmental-disorders-new-alert-asking-for-patient- review-and-further-consideration-of-risk-minimisation-measures Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright © Midlands and Lancashire Commissioning Support Unit

Medicines Safety Assurance Tool April 2017

Mucodyne® Paediatric Syrup 250 mg/5 mL (carbocisteine oral liquid): new double- strength presentation - check dose volume to ensure appropriate dose is given Date of alert Status Date completed Medicines and Healthcare products Regulatory Agency 24-Apr-2017

Summary Proposed action Newsletter Prescribing decision support Search/audit Mucodyne Paediatric Syrup has been re-launched and has double the concentration of the active ingredient carbocisteine per millilitre compared with the previous formulation.

To reduce the risk of accidental overdose, dose volumes must be checked to ensure the appropriate dose is administered, especially if they have used Mucodyne Syrup in the past.

Action taken https://assets.publishing.service.gov.uk/media/58fa19a7ed915d06b00001a2/MucodynePaediatricReformulati on_October_2016.pdf Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright © Midlands and Lancashire Commissioning Support Unit

Medicines Safety Assurance Tool April 2017

Evidence of harm from fentanyl-contaminated heroin Date of alert Status Date completed Central Alerting System: CMO Messaging 27-Apr-2017

This alert advises of the availability of, and harms from, heroin that has been mixed with Proposed action Newsletter Prescribing decision support Search/audit fentanyl or carfentanyl, both unusually potent synthetic opioids.

There is significant evidence from a small number of post-mortem results of recent drug user deaths and from police seizures that some heroin may contain fentanyl or carfentanyl added by dealers. These are highly potent synthetic opioids and very small amounts can cause severe or even fatal toxicity.

Those of you in contact with heroin users should be alert to the increased possibility of overdose arising from heroin cut with these synthetic opioids, be able to recognise possible symptoms of overdose and respond appropriately. Action taken

https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAlert.aspx?AlertID=102588 Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright © Midlands and Lancashire Commissioning Support Unit

Medicines Safety Assurance Tool April 2017 Medicines Safety Assurance Tool (MASTER): March 2017

Date of Alert Title of Alert Source of Alert

SGLT2 inhibitors: updated advice on 22.03.2017 increased risk of lower- MHRA limb amputation (mainly toes)

Launch of pilot reporting scheme for harms associated with 22.03.2017 MHRA illicit drugs, particularly new psychoactive substances Pradaxa® capsule 27.03.2017 Manufacturer Letter colour change

Class 2 Medicines Recall: 29.03.2017 MHRA Diclo-SR 75 Tablets (Diclofenac Sodium)

Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Copyright ©Midlands and Lancashire CSU Medicines Safety Assurance Tool (MASTER): March 2017

Summary of Alert SGLT2 Inhibitors: updated advice on increased risk of lower-limb amputation (mainly toes)

Canagliflozin may increase the risk of lower-limb amputation (mainly toes) in patients with type 2 diabetes. Evidence does not show an increased risk for dapagliflozin and empagliflozin, but the risk may be a class effect. Preventive foot care is important for all patients with diabetes.

Advice to Healthcare Professionals: • carefully monitor patients receiving canagliflozin who have risk factors for amputation, such as poor control of diabetes and problems with the heart and blood vessels • consider stopping canagliflozin if patients develop foot complications such as infection, skin ulcers, osteomyelitis, or gangrene • advise patients receiving any sodium-glucose co-transporter 2 (SGLT2) inhibitor about the importance of routine preventive foot care and adequate hydration • continue to follow standard treatment guidelines (https://www.nice.org.uk/guidance/ng19) for routine preventive foot care for people with diabetes • report any suspected side effect with SGLT2 inhibitors or any other medicine on a Yellow Card For further information please click the title in the alert column.

Launch of pilot reporting scheme for harm associated with illicit drugs, particularly new psychoactive substances

The MHRA are launching a pilot scheme for healthcare professionals in the UK to report suspected adverse reactions to illicit drugs, particularly new psychoactive substances.

A pilot reporting website, the Report Illicit Drug Reaction form (https://report-illicit-drug-reaction.phe.gov.uk/), will be available for 1 year for healthcare professionals across the UK who come into contact with patients experiencing harm associated with use of illicit drugs, particularly new psychoactive substances. The pilot aims to better collect data on harms from illicit drug use, to support provision of clinical guidance to professionals. For further information please click the title in the alert column. Pradaxa® capsule colour change

The manufacturer of dabigatran (Pradaxa®) has written to healthcare professionals to advise that the colour of the capsule is being changed to improve patient safety.

Dabigatran is available in three strengths, 75mg, 110mg and 150mg. Previously the capsule shell was the same colour for all three strengths with a difference in size and imprint text. The new colour will see the 75mg capsule coloured white, the 110mg light blue and the 150mg two-tone white and light blue. The size and text imprint will remain the same. The changes have also removed sunset yellow as a colouring agent. For further information patient support materials are available from company representatives or direct from the company by emailing [email protected] or calling 01344 742 579.

Class 2 Medicines Recall: Diclo-SR 75 Tablets ® (Diclofenac Sodium)

Strides Pharma UK Ltd trading as Co-pharma is recalling the batches (7226423, 7226424, 7226425, 7227697, 7227698) as a precautionary measure due to high trending stability results obtained for the impurity test. All remaining packs of the listed batches should be quarantined and returned to your supplier. For further information please click the titile in the alert column. Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Proposed actions Actions taken Date completed Status

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The information displayed on the left hand side is in order of risk (top indicating highest risk) Medicines Safety Assurance Tool (MASTER): Feb 2017

Date of Alert Title of Alert Source of Alert

Alka-Seltzer Original & Alka-Seltzer XS - recall 01.02.2017 of some batches due to MHRA an issue with the blister foil

06.03.2017 SPC Updates NICE

Precautionary recall of 16.02.2017 MHRA Ergometrine Injections Hyoscine butylbromide (Buscopan) injection: risk of serious adverse 21.02.2017 MHRA effects in patients with underlying cardiac disease

Precautionary recall of 23.02.2017 Viridal Duo Powder and MHRA Solvent for Injection

Oxylog 3000 And Oxylog 3000 Plus 08.02.2017 MHRA Ventilator - Risk Of Failure

Summary of Alert Bayer plc is voluntarily recalling batches due to an issue with the blister foil. A problem with the blistering process has resulted in the potential for small holes or cracks being present in the aluminum layer of the tablet blister material, which are not visible to the consumer. This could result in compromise of the moisture barrier provided by the aluminum layer. Bayer has assessed this defect as unlikely to pose a safety risk for consumers; therefore affected batches are not being recalled to patient level.

Action for healthcare professionals: All remaining units of the affected batches should immediately be quarantined. Bayer is contacting potentially affected customers by letter and will arrange uplift of affected stock following receipt of a form listing affected stock in hand.

For further information please click the title in the alert column.

SPC Updates (Primary Care)

Revised SPC: Exviera (dasabuvir) 250 mg film-coated tablets SPC has been updated with warning that cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment.

Revised SPC: Olysio (simeprevir) 150mg hard capsules SPC has been updated with warning that cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment.

Revised SPC: Viekirax (12.5 mg ombitasvir/75mg paritaprevir /50 mg ritonavir) film-coated tablets SPC has been updated with warning that cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment.

Recall of Ergometrine Injections by hameln pharmaceuticals limited, because the contents of some ampoules may not comply with the required specification.

For further information please click the title in the alert column. Prescribing information has been updated to help to minimise the risk of serious adverse reactions in patients with cardiac disease. Advice for healthcare professionals: • hyoscine butylbromide injection can cause serious adverse effects including tachycardia, hypotension, and anaphylaxis • these adverse effects can result in a fatal outcome in patients with underlying cardiac disease, such as those with heart failure, coronary heart disease, cardiac arrhythmia, or hypertension • hyoscine butylbromide injection should be used with caution in patients with cardiac disease • monitor these patients, and ensure that resuscitation equipment, and personnel who are trained how to use this equipment, are readily available • hyoscine butylbromide injection remains contraindicated in patients with tachycardia

For further information please click the title in the alert column.

UCB Pharma Limited is voluntarily recalling the Viridal Duo Powder and Solvent for Injection (10mcg/ml and 40mcg/ml) above batches as a precautionary measure due to a possible issue with the integrity of the cap seal which may result in a lack of sterility assurance. The company has received no relevant reports of adverse reactions or product complaints associated with any UK batches to date. Remaining stock of the listed batches should be quarantined and returned to the original supplier for credit. Patients are asked to return packs from affected batches to their community pharmacist. Limited replacement stock is available through wholesalers.

For further information please click the title in the alert column.

Manufactured by Dräger – ventilator may stop working if oxide layers accumulate due to the infrequent use of the control knobs (potentiometers).

For further information please click the title in the alert column.

Please note that the information in this Safety log is correct at the time of publication. Clinicians should always refer to the most up to date information Proposed actions Actions taken Date completed Status

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The information displayed on the left hand side is in order of risk (top indicating highest risk) Medicines Safety Assurance Tool (MASTER): Jan 2017

Date of Alert Title of Alert Source of Alert

Class 4 Caution in Use: Arava 10mg film- 03.01.2017 coated tablets MHRA (Leflunomide) Medical safety alert - GOV.UK

03.01.2017 SPC Updates NICE Case Study: Over CQC National ordering of fentanyl 04.01.2017 Controlled Drugs patches via repeat prescriptions Vigilance Sub-Group

Drug Alert Class 4, Bayer Plc, Mirena 20 05.01.2017 mcg!/24 Hours CAS Intrauterine Delivery System

Direct-acting antivirals to treat chronic hepatitis C: risk of 20.01.2017 MHRA interaction with vitamin K antagonists and changes in INR Apremilast (Otezla ▼): 20.01.2017 risk of suicidal thoughts MHRA and behaviour

Summary of Alert Class 4 Caution in Use: Arava 10mg film-coated tablets (Leflunomide)

Sanofi has informed the MHRA that there is an error in the Braille in 1 in 5 cartons of Arava 10mg film-coated tablets specifically batch numbers: 5JK2A, 5JK3A, 5JK6G and 6EV2A. On affected cartons, the strength of the product reads ‘20mg’ instead of ‘10mg’ in Braille. The printed text is correct on all packaging.There is a risk to patients who have compromised eye-sight and who rely solely on Braille to determine their tablet strength.

Packs with the above batch numbers should not be dispensed to patients who rely solely on Braille. We understand that there is an alternative batch available, batch number 6GL5E, expiry Aug 2019

Further information is available from: https://www.gov.uk/drug-device-alerts/class-4-caution-in-use-arava- 10mg-film-coated-tablets-leflunomide.

SPC Updates (Primary Care)

Revised SPC: ZEPATIER® (elbasvir and grazoprevir) film coated tablets: Section 4.5 now includes advice on the interaction between Zepatier and vitamin K antagonists – INR should be monitored closely.

Revised SPC: Sustanon® 250, 250mg/ml solution for injection (testosterone propionate, testosterone phenylpropionate, testosterone isocaproate, testosterone decanoate): Section 4.4 now advises that testosterone should be used with caution in patients with thrombophilia, as there have been post-marketing studies and reports of thrombotic events in these patients during testosterone therapy.

Revised SPC: APO-go® (apomorphine) products: SPC has been updated with additional information related to domperidone usage prior to initiation of treatment, titration and discontinuation, and also on assessment of risk factors for QT interval prolongation prior to initiation of domperidone and apomorphine. Case Study for Shared Learning: Over-ordering of fentanyl patches via repeat prescriptions Patient A had a problem with his fentanyl patches falling off and was replacing them after1-2 days. This resulted in Patient A over-ordering fentanyl patches via repeat prescriptions. Even with changing a patch every 2 days, Patient A over a 12 month period was legitimately prescribed a 520 day supply of fentanyl patches. A teenage friend of Patient A’s son was found dead after ingesting a fentanyl patch. Patient A’s son had been stealing his father’s patches and had given one to his friend. Patient A had suspected his son of stealing his fentanyl patches. A full investigation was undertaken and it was noted there were various points at which the excessive amount of prescribed fentanyl patches could have been picked up: the staff printing off the repeat scripts; the doctors signing the repeat scripts and the pharmacy staff dispensing the prescriptions. For further information please click the title in the alert column

Drug Alert Class 4, Bayer Plc, Mirena 20 mcg/24 Hours Intrauterine Delivery System. PL 00010/0547 Bayer plc has informed the MHRA that they have received two complaints globally concerning Mirena inserters with an insertion tube which is mounted inversely to the handle. This has resulted in inversion of the insertion depth scale, which may lead to incorrect insertion depth and the possibility of a reduced efficacy or adverse events. A very small number of Mirena inserters may potentially be affected by this issue. An investigation has shown that both complaints involve one batch of inserters and Mirena batch TU01BPE has been manufactured using inserters from the same batch. Any stock on hand from the above batch should be inspected to ensure that the insertion tube is mounted correctly. This can be done without opening the blister. This alert is for pharmacy level communication but patients may ask general practice for advice. Further information is available from: https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAlert.aspx?AlertID=102565

Direct-acting antivirals to treat chronic hepatitis C: risk of interaction with vitamin K antagonists and changes in INR. INR should be monitored closely during treatment of chronic hepatitis C with direct-acting antivirals in patients also receiving vitamin K antagonists (e.g. warfarin), because of possible changes in liver function during treatment. Direct-acting antivirals for the treatment of chronic hepatitis C infection include: boceprevir (Victrelis); daclatasvir (Daklinza▼); dasabuvir (Exviera▼); ombitasvir, paritaprevir, ritonavir (Viekirax▼); sofosbuvir (Sovaldi▼); ledipasvir with sofosbuvir (Harvoni▼); and simeprevir (Olysio▼). Vitamin K antagonists are used as anticoagulant medicines, and include warfarin and acenocoumarol. Healthcare professionals are advised to: be aware that changes in liver function due to treatment with direct-acting antivirals for chronic hepatitis C infection may result in fluctuations of INR values in patients taking vitamin K antagonists. In these patients, INR should be monitored closely and, if necessary, anticoagulant therapy adjusted. Further information is available from: https://www.gov.uk/drug-safety-update/direct-acting-antivirals-to-treat-chronic- hepatitis-c-risk-of-interaction-with-vitamin-k-antagonists-and-changes-in-inr Apremilast (Otezla ▼): risk of suicidal thoughts and behaviour. There is an increased risk that some patients may experience psychiatric symptoms with apremilast, including depression and suicidal thoughts. Stop treatment if patients have new psychiatric symptoms or if existing symptoms worsen. Apremilast (Otezla▼) is a phosphodiesterase-type-4 inhibitor for the treatment of moderate to severe chronic plaque psoriasis or active psoriatic arthritis in adults who have not responded to other systemic treatments. Advice for healthcare professionals: • apremilast is associated with an increased risk of psychiatric symptoms, including depression, suicidal thoughts, and suicidal behaviours • suicidal thoughts and behaviour, including completed suicide, have been reported in patients with or without a history of depression • carefully assess the benefits and risks of starting or continuing treatment in patients with a history of psychiatric symptoms, or in those who are taking other medicines likely to cause psychiatric symptoms • stop treatment if patients experience new psychiatric symptoms or if existing symptoms get worse • advise patients to inform a healthcare professional if they notice changes in their mood Further information is available from: https://www.gov.uk/drug-safety-update/direct-acting-antiviral- interferon-free-regimens-to-treat-chronic-hepatitis-c-risk-of-hepatitis-b-reactivation.

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The information displayed on the left hand side is in order of risk (top indicating highest risk) Medicines Safety Assurance Tool (MASTER): Dec 2016

Date of Alert Title of Alert Source of Alert

Spironolactone and renin-angiotensin system drugs in heart 31.12.2016 failure: risk of MHRA potentially fatal hyperkalaemia—clarific ation, December 2016

Drug Alert Class 4 Caution In Use; Medreich; Amoxicillin Sugar Free Suspension 14.12.2016 CAS 250mg/5l And 125mg/5l; Pl 21880/0124 And Pl 21880/0123 Cobicistat, ritonavir and coadministration with a 31.12.2016 steroid: risk of systemic MHRA corticosteroid adverse effects

Central Alerting System: Influenza 19.12.2016 CAS Season 2016/17: Use Of Antiviral Medicines

December BNF/BNFC 31.12.2016 BNF eNewsletter 31.12.2016 SPC Updates NICE

31.12.2016 SPC Updates NICE

Summary of Alert Spironolactone and renin-angiotensin system drugs in heart failure: risk of potentially fatal hyperkalaemia—clarification, December 2016

In light of feedback, MHRA has clarified previous communication on this topic and advises concomitant use of spironolactone /eplerenone with ACEi or ARB increases risk of severe hyperkalaemia, particularly in patients with marked renal impairment, and should be used with caution.

For further information is published on the MHRA website: https://www.gov.uk/drug-safety- update/spironolactone-and-renin-angiotensin-system-drugs-in-heart-failure-risk-of-potentially-fatal- hyperkalaemia-clarification

Drug Alert Class 4 Caution In Use; Medreich; Amoxicillin Sugar Free Suspension 250mg/5l And 125mg/5l; Pl 21880/0124 And Pl 21880/0123 Medreich® has provided handling instructions following several complaints that the child-resistant caps are difficult to open. The complaints follow the introduction of a new child-resistant cap with a red tamper-evident ring earlier this year. A very small number of caps have an incompatibility between the cap and the bottle. Additionally, the new child-resistant caps with a red tamper-evident ring require more pressure to open for the first time compared to child-resistant caps with an induction seal.

This alert is for pharmacy level communication but patients may ask general practice for advice.

For further information is published on the MHRA website: https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102665 Cobicistat, ritonavir and coadministration with a steroid: risk of systemic corticosteroid adverse effects Coadministration of a corticosteroid with an HIV-treatment-boosting agent may increase the risk of adrenal suppression due to a pharmacokinetic interaction. Advice for healthcare professionals: • all clinicians who may prescribe or administer steroids to patients with HIV should be aware that concomitant use of a corticosteroid metabolised by cytochrome P450 3A (CYP3A) and a HIV-treatment-boosting agent may increase the risk of systemic corticosteroid-related adverse effects • although these reactions are rarely reported, there is potential for this interaction to occur even with non- systemically administered steroid formulations, including intranasal, inhaled, and intra-articular routes • coadministration of a HIV-treatment-boosting agent with a CYP3A-metabolised corticosteroid is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid-related reactions • if coadministration is necessary, use of beclomethasone should be considered where possible—particularly for long-term use. Beclomethasone is less dependent on CYP3A metabolism and, although the risk of an interaction leading to adverse corticosteroid effects may not be completely removed, it may be lower For further information is published on the MHRA website: https://www.gov.uk/drug-safety-update/cobicistat- ritonavir-and-coadminsitration-with-a-steroid-risk-of-systemic-corticosteroid-adverse-effects

Central Alerting System: Influenza Season 2016/17: Use Of Antiviral Medicines With surveillance data indicating an increase in influenza cases in the community. GPs and other prescribers working in primary care may now prescribe antiviral medicines for the prophylaxis and treatment of influenza at NHS expense. This is in accordance with NICE guidance, and Schedule 2 to the National Health Service (General Medical Services Contracts) (Prescription of drugs etc) Regulations 2004), commonly known as the Grey List or Selected List Scheme (SLS). Antiviral medicines may be prescribed for patients in "clinical at-risk groups" as well as any who are at risk of severe illness and/or complications from influenza if not treated.

Information on at risk groups and patients eligible for treatment in primary care at NHS expense with either oseltamivir (Tamiflu), or zanamivir (Relenza), is available at https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/563029/PHE_guidance_antivir als_influenza_2016_to_2017_FINAL.pdf

December BNF/BNFC eNewsletter This issue includes new monographs for brivaracetam, elvitegravir, lumacaftor/ivacaftor, panobinostat and ceritinib, as well as dose changes to metronidazole (for acute ulcerative gingivitis/acute oral infections), and etoricoxib (for rheumatoid arthritis/ankylosing spondylitis). For further information: http://pharmaceuticalpress.cmail20.com/t/ViewEmail/y/7BECD3B3FD06529B/7071F82C996F6C90FCACEB58A03 3025D SPC updates (Primary care):

Revised SPC: Cardura (doxazosin) preparations SPC now highlights that prostate cancer should be ruled out before initiating therapy. Priapism has been added as a rare adverse event. Gastrointestinal obstruction has also been added as a rare adverse effect for the modified release preparations only.

Revised SPC: Certican (everolimus) Tablets SPC now states that everolimus has a narrow therapeutic index which may require adjustments in dosing to maintain therapeutic response.

Revised SPC: Dantrium (dantrolene) 25mg Capsules Gastrointestinal bleeding, tachycardia, bradycardia and hepatitis have been added to SPC as adverse drug reactions.

Revised SPC: Edarbi (azilsartan medoxomil) tablets The following wording has been removed from SPC: “caution should be exercised in hypertensive patients with congestive heart failure as there is no experience of use of Edarbi in these patients.”

Revised SPCs: Epclusa (sofosbuvir and velpatasvir), Sovaldi (sofosbuvir) and Harvoni (sofosbuvir and ledipasvir) SPCs updated to highlight that as liver function may change during treatment, close monitoring of INR is recommended during treatment in patients taking concomitant vitamin K antagonists.

Revised SPC: Intuniv (guanfacine) 1 mg, 2 mg, 3 mg, 4 mg prolonged-release tablets SPC has been updated to include warning about risk of withdrawal blood pressure, increase/rebound hypertension and heart rate increase, and in very rare cases, hypertensive encephalopathy upon abrupt discontinuation of guanfacine (based on a single postmarketing case report).

Revised SPC: Lojuxta (lomitapide mesylate) hard capsules SPC has been updated to include a warning on dehydration, and to add dehydration, alopecia and myalgia as adverse effects of lomitapide.

Revised SPC: Plavix (clopidogrel) 75mg and 300mg tablets Kounis syndrome, a potentially life-threatening medical emergency consisting of both a severe allergic reaction and acute coronary syndrome, has been added to SPC as a very rare adverse effect.

Revised SPC: Tritace (Ramipril) tablets SPC updated to include increased risk of angioedema which has been reported as an interaction of ACE inhibitors in combination with racecadotril.

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The information displayed on the left hand side is in order of risk (top indicating highest risk)

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The information displayed on the left hand side is in order of risk (top indicating highest risk) Medicines Safety Assurance Tool (MASTER): Nov 2016

Date of Alert Title of Alert Source of Alert

Patient Safety Alert: Risk of severe harm 16.11.2016 and death due to NHS Improvement withdrawing insulin from pen devices Alert: Glass shards found in balloon 31.11.2016 CCG gastrostomy tube balloon ports.

Brimonidine gel 04.11.2016 (Mirvaso): risk of MHRA exacerbation of rosacea Report suspected side effects to help make 07.11.2016 medicines safer: MHRA MHRA launches social media campaign

BNF November 2016 31.11.2016 BNF update 31.11.2016 SPC Updates NICE 31.11.2016 SPC Updates NICE

Summary of Alert

Patient Safety Alert: Risk of severe harm and death due to withdrawing insulin from pen devices

This alert warns NHS providers of the risk of severe harm and death if an insulin needle and syringe is used to administer insulin withdrawn directly from a pen device/replacement cartridge. Providers should ensure staff have access to appropriate equipment and training. For further information click link: Patient Safety Alert - Withdrawing insulin from pen devices.pdf CASE STUDY: (Shared learning) Alert: Glass shards found in balloon gastrostomy tube balloon ports.

Prescribers: Take care to supply only plastic ampoules of water, for use to inflate the balloon port, in balloon gastrostomy tubes.

Incidents have been reported by Countess of Chester community dieticians where patients have been given glass ampoules of water, instead of plastic ampoules, to use to inflate the balloon in their balloon gastrostomy tubes.

Use of glass ampoules can result in small shards of glass entering the balloon port and breaking it. This has resulted in tubes falling out, and new ones needing to be inserted

When prescribing for patients with balloon gastrostomy tubes, please ensure that the prescription states: ‘Water for injections’ – 10mls amps plastic B Braun (4 per month) This may come up on EMIS as Mini-Plasco water for injection. (This is the typical amount required but see below.)

A balloon gastrostomy feeding tube (sometimes called a button or gastro tube) is a small feeding tube inserted directly into the stomach so that feed, fluid and medication can be administered without swallowing. Once inserted, the tube is held in place by a small retention balloon which is inflated with a specified amount of sterile water. The fluid level needs to be checked periodically by the patient or carer to prevent accidental removal of the balloon gastrostomy tube. The amount of water required and the checking and replacement intervals will depend on the exact balloon gastrostomy tube used and will be stated in the product instructions.

Acknowledgment to NHS WEST CHESHIRE CLINICAL COMMISSIONING GROUP.

Brimonidine gel (Mirvaso): risk of exacerbation of rosacea Brimonidine (Mirvaso) is a topical gel indicated for the symptomatic treatment of facial erythema of rosacea in adults.

Some patients may have exacerbation or rebound symptoms of rosacea. It is important to initiate treatment with a small amount of gel and increase the dose gradually, based on tolerability and treatment response.

For further information click link: https://www.gov.uk/drug-safety-update/brimonidine-gel-mirvaso-risk-of- exacerbation-of-rosacea Report suspected side effects to help make medicines safer: MHRA launches social media campaign The Medicines and Healthcare products Regulatory Agency (MHRA) has run a social media campaign to promote reporting of suspected side effects, as part of an EU-wide awareness week. At the centre of the campaign was an animation showing the story of a patient who has a suspected adverse reaction. It shows the medicine being taken, a suspected side effect being experienced, how reports are made by patients or healthcare professionals to the medicines regulator, and how this benefits future patients.

You Tube video: Reporting suspected side effects makes medicines safer

For further information click link: https://www.gov.uk/government/news/report-suspected-side-effects-to- help-make-medicines-safer-mhra-launches-social-media-campaign

BNF November 2016 update This update contains 9 significant changes, and 2 new preparations For further information click link: https://www.medicinescomplete.com/mc/bnf/current/whatsnew.htm#news644 SPC updates (Primary care):

Revised SPC: Klaricid (clarithromycin) Paediatric Suspension 125mg and 250mg/5ml (Green) The SPC has been updated with information on the contraindicated use of clarithromycin with ergot alkaloids, and with oral midazolam due to interactions. Mania and ventricular fibrillation have also been added as undesirable effects of unknown frequency.

Revised SPC: Securon (verapamil) SR (Green) SPC warns drug metabolism is delayed in patients with impaired liver function, potentiating/prolonging effects of verapamil, thus dose needs to be adjusted with carefully in such patients and low doses given initially. Also SPC advises tablets should be taken without sucking.

Revised SPC: Abilify (aripiprazole) – all presentations (Amber with ESCA) Section 4.8 has been updated to include the following adverse effects when used in the paediatric population: weight decreased, blood insulin increased, arrhythmia, and leukopenia.

Revised SPC: Migramax (acetylsalicylic acid/metoclopramide) 900mg/10mg Powder for Oral Solution (Non- Formulary) The SPC has been updated to include the addition of “transient increase in blood pressure” as an undesirable effect of unknown frequency.

Revised SPC: Paramax (paracetamol/metoclopramide) – all products (Non-Formulary) The SPC has been updated to include the addition of “transient increase in blood pressure” as an undesirable effect of unknown frequency. SPC updates (Primary care): continue…

Revised SPC: Triapin (felodipine/ramipril) prolonged release tablets – all products (Non-Formulary) The SPC has been updated to include an interaction with racecadotril which increases the risk of angioedema when used with ACE inhibitors such as ramipril.

Revised SPC: Nuvaring (etonogestrel/ethinylestradiol) (Non-Formulary) Information on interactions (INs) with bosentan as an inducer of cytochrome P450 enzymes has been added. New information has also been added on CYP3A4 enzyme inhibition and on INs with HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

Revised SPC: Lopid (gemfibrozil) capsules (Non-Formulary) Concomitant use with dasabuvir is now contraindicated. Gemfibrozil increases exposure to dasabuvir which may increase the risk of QT prolongation. Gemfibrozil inhibits CYP2C8; AUC and Cmax of dasabuvir increased 11 and 2 fold respectively on concomitant administration.

Revised SPC: Lopid (gemfibrozil) 600 mg film-coated tablet (Non-Formulary ) SPC states that concomitant use of gemfibrozil with dasabuvir is contraindicated; gemfibrozil inhibits CYP2C8 leading to increased exposure of dasabuvir, which can increase the risk of QT prolongation. Information on the interaction with repaglinide was also updated.

Formulary Reference: http://www.birminghamandsurroundsformulary.nhs.uk/

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The information displayed on the left hand side is in order of risk (top indicating highest risk)

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The information displayed on the left hand side is in order of risk (top indicating highest risk) Medicines Safety Assurance Tool (MASTER): Oct 2016

Date of Alert Title of Alert Source of Alert

Managing diabetes: patients should not change their insulin 10/26/2016 MHRA delivery device without checking with their healthcare specialist. EMA recommends measures to ensure The European 10/14/2016 safe use of Keppra oral Medicines Agency solution

Etoricoxib (Arcoxia): revised dose 10/3/2016 recommendation for MHRA rheumatoid arthritis and ankylosing spondylitis Use of metformin to treat diabetes now The European 10/14/2016 expanded to patients with moderately Medicines Agency reduced kidney function

The MHRA have produced a video for healthcare professionals and GPs 10/10/2016 MHRA on our latest advice about the risk of valproate medicine during pregnanc Parents of infants and young children should not use unlicensed homeopathic teething 10/19/2016 MHRA tablets or gels which are available to buy online due to the risk of side effects.

Implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy devices (CRT- D) – risk of loss of therapy due to rapid battery depletion

10/17/2016 LINK: MHRA https://www.gov.uk/drug -device- alerts/implantable- cardioverter- defibrillators-icd-and- cardiac- resynchronisation- therapy-devices-crt-d- risk-of-loss-of-therapy- due-to-rapid-battery- depletion

Automatic external defibrillator (AED) LIFEPAK CR Plus and 10/13/2016 MHRA LIFEPAK EXPRESS – risk of failure to deliver a shock. Class 2 medicines recall: Nacrez 75 10/19/2016 microgram Film-coated MHRA Tablets (Desogestrel) PL 00289/1706

The hard copy of the British National 10/31/2016 BNFc Formulary for Children 2016-2017

October BNF/BNF-C 10/31/2016 BNF eNewsletter

10/31/2016 SPC Updates NICE 10/31/2016 SPC Updates NICE

Summary of Alert Managing diabetes: patients should not change their insulin delivery device without checking with their healthcare specialist.

If patients are contacted directly by a manufacturer or other organisation to try using a different insulin therapy system they should first discuss this with their diabetes specialist to avoid risk of hyperglycaemia, hypoglycaemia or diabetic ketoacidosis.

Healthcare professionals are requested to have systems in place to remind their diabetic patients: • to use devices that have been recommended or prescribed for them by their diabetes specialist • not to stop or change their prescribed insulin management regimen without seeking the advice of their diabetes specialist • to contact their diabetes specialist if they are invited by a manufacturer to trial a new device e.g. via social media

For further information click: MDA-2016-020 Final.pdf EMA recommends measures to ensure safe use of Keppra oral solution

Medicine should only be used with dosing syringe included in the package Several measures have been put in place to ensure that the correct dosing syringe is used to measure Keppra oral solution, and thus avoid medication errors. Keppra (levetiracetam) is a medicine used to treat epilepsy in adults and children.

To avoid medication errors and the risk of overdose, parents and carers are advised that only the syringe provided with the package should be used to measure the dose of Keppra. The different medicine’s cartons and labels will be coloured differently and clearly indicate the volume of the bottle, the volume of the dosing syringe, and the age range of the child that the medicine should be used for:

The package leaflet will also include clearer instructions for parents and carers in order to minimise the risk of using an incorrect dose. Parents and carers are advised always to discard the syringe once the medicine’s bottle is empty.

In children, the dose of Keppra depends on the child’s bodyweight and age, and the oral solution is the preferred formulation for use in children less than 6 years of age. The medicine is available as a 100 mg/ml solution in either a 150 or 300 ml size bottle, and it comes with a 1, 3 or 10 ml syringe.

Healthcare professionals should follow these recommendations: • Doctors should ensure that the age-appropriate presentation of Keppra is prescribed. • Doctors should always prescribe the dose in mg with ml equivalence based on the correct age of the patient. • Pharmacists should ensure that the appropriate presentation of Keppra is dispensed. • With every prescription, healthcare professionals should advise the patient and/or caregiver on how to measure the prescribed dose. • With every prescription, healthcare professionals should remind patients or caregivers to use only the syringe Etoricoxibincluded in (Arcoxia): the medicine’s revised package. dose recommendation Once the bottle for is empty, rheumatoid the syringe arthritis should and ankylosing be discarded. spondylitis Prescribing information has been updated to introduce a lower recommended dose of 60 mg daily for patients with rheumatoid arthritis or ankylosing spondylitis. Advise for healthcare professionals: • The cardiovascular and other important risks of etoricoxib (Arcoxia) may increase with dose and duration of exposure. Therefore, the lowest effective daily dose should be used, and the need for treatment should be regularly reassessed • the recommended dose is 60 mg once daily • in patients with insufficient relief from symptoms, an increased dose of 90 mg once daily may improve efficacy • once the patient is clinically stabilised, down-titration to 60 mg once daily may be appropriate • in the absence of therapeutic benefit, other treatment options should be considered For further information click: https://www.gov.uk/drug-safety-update/etoricoxib-arcoxia-revised-dose- Use of metformin to treat diabetes now expanded to patients with moderately reduced kidney function

Recommendations for patients with kidney impairment updated in product information The European Medicines Agency (EMA) has concluded that metformin-containing medicines can now be used in patients with moderately reduced kidney function (GFR [glomerular filtration rate]=30–59 ml/min) for the treatment of type 2 diabetes. The product information for these medicines will be updated to revise the current contraindication and give information about doses, monitoring and precautions in patients with reduced kidney function.

The recommendations are the result of a review by EMA of metformin-containing medicines following concerns that current scientific evidence does not justify a contraindication in patients with moderate reduction of kidney function. The current product information also varies between countries and products in the EU and is no longer consistent with clinical guidelines. Metformin may increase the risk of a rare but serious complication called lactic acidosis, which occurs when naturally produced lactic acid builds up in the blood faster than it can be removed. Currently, the product information states that metformin must not be used in patients with reduced kidney function because these patients are considered to be at a higher risk of developing lactic acidosis as their kidneys do not remove metformin efficiently enough.

However, after considering the scientific literature, clinical data, epidemiological studies and clinical guidelines from medical bodies, EMA concluded that the large patient population with moderately reduced kidney function can benefit from use of metformin. Clear dosing recommendations and monitoring before and during treatment aim to minimise any possible increased risk in these patients. The contraindication for patients with severely reduced kidney function will remain (GFR less than 30 ml/min).

For further information click: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/10/news_detail_002620.j sp&mid=WC0b01ac058004d5c1 Discussing Valproate

The MHRA have produced a video for healthcare professionals and GPs on our latest advice about the risk of valproate medicine during pregnancy. The MHRA toolkit also includes booklets, a checklist, and a patient information card. The video can be found here (open link in chrome) https://www.youtube.com/watch?v=KxczXWCjOTk and here: https://www.facebook.com/mhragovuk/videos/1149193091785165/ Clinicians in your networks reviewing people taking valproate may find it helpful. Parents of infants and young children should not use unlicensed homeopathic teething tablets or gels which are available to buy online due to the risk of side effects. MHRA are warning all Parents of infants and young children that they should not use unlicensed homeopathic teething tablets or gels which are available to buy online due to the risk of side effects. This advice follows a US Food and Drug Administration (FDA) investigation into homeopathic teething tablets and gels which could cause serious side effects such as seizures, difficulty breathing, lethargy, excessive sleepiness, muscle weakness, skin flushing, constipation, difficulty urinating, or agitation. These particular products are made and supplied by manufacturers in the USA and are not licensed for use in the UK and are not known to be available in UK outlets. However the unlicensed products may be advertised on online shopping or pharmacy websites. For further information click: https://www.gov.uk/government/news/parents-advised-not-to-use-unlicensed- homeopathic-teething-products-in-infants-and-children

Medical Device Alert Implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy devices (CRT-D) – risk of loss of therapy due to rapid battery depletion Manufactured by St Jude Medical – risk of unpredictable, rapid battery depletion leading to potential device failure and loss of therapy. This Medical Device Alert is being sent to GPs for information only, in circumstances where patients may seek advice about the contents of this notice.

GPs need take no further action on receipt of this alert – For your information only

Medical Device Alert

Automatic external defibrillator (AED) LIFEPAK CR Plus and LIFEPAK EXPRESS – risk of failure to deliver a shock. Manufactured by Physio-Control – risk of delay to defibrillation due to an intermittent component failure. Specific serial numbers are affected. See link for further details https://www.cas.dh.gov.uk/ViewAndAcknowledgment/viewAttachment.aspx?Attachment_id=102622 DRUG RECALLS Class 2 medicines recall: Nacrez 75 microgram Film-coated Tablets (Desogestrel) PL 00289/1706 Teva UK Limited is recalling the above batches because out of specification results for impurities were obtained during routine stability testing. No complaints relating to this issue have been received by the company to date. Women currently using this product are advised to finish the pack and if they have any concerns they should speak to their doctor or pharmacist. Remaining stock of these batches should be quarantined and returned to the original supplier for credit.For stock enquiries, please contact Teva UK Limited Customer Service on 0800 590 502.For medical information enquiries please contact Teva UK Limited by phone on 0207 5407117 or by email to [email protected]. GPs need take no further action on receipt of this alert – For your information only

The hard copy of the British National Formulary for Children 2016-2017 The hard copy of the British National Formulary for Children 2016-2017 has been updated and published. Electronic versions are updated monthly.

Significant changes in this revision are highlighted in this link: https://www.medicinescomplete.com/mc/bnfc/current/PHP107699-changes.htm October BNF/BNF-C eNewsletter This month's issue includes notifications of new drug monographs for tedizolid, brinzolamide with brimonidine, and rilpivirine, as well as updated NICE guidance on treatment of Alzheimer's disease, and on azacitidine for acute myeloid leukaemia.

Revised SPCs: Adalat, Adalat 5, Adalat retard 10mg and 20mg modified-release tablets (nifedipine) The SPCs have been updated with information on the use of nifedipine in patients with hepatic impairment. Nifedipine should be used with caution in severe hepatic impairment. Careful monitoring and dose reduction may be required with any severity of liver impairment.

Revised SPCs: Aldomet (methyldopa) 250mg and 500mg tablets Angioedema and urticaria have been added as undesirable effects of methyldopa with unknown frequency.

Revised SPC: E45 Cream Patients using large quantities (>100g) of paraffin (PF) product are advised to regularly change clothing/bedding/dressings impregnated with it and keep away from naked flames as there is a fire hazard. Also absorption of topical minoxidil can be increased with topical soft PF.

Revised SPC: Iressa (gefitinib) 250mg film-coated tablets Allergic reactions including angioedema and urticarial are now listed as common undesirable effects. The SPC has also been updated with information regarding a causal association between QT prolongation and gefitinib. Revised SPC: Lenvima (lenvatinib) 4mg and 10mg hard capsules Arterial thromboembolism has been added to SPC as a serious adverse reaction and section 4.4 has been updated to include special warnings/precautions on non-gastrointestinal fistula and diarrhoea.

Revised SPC: Sovaldi (sofosbuvir) tablets Bradyarrhythmia when used with another direct-acting antiviral and amiodarone has been added as a caution. Life threatening cases have been reported and amiodarone should only be used when other alternative anti-arrhythmic treatments are not tolerated or contraindicated.

Revised SPC: Tracleer (bosentan) 62.5 mg and 125mg film-coated tablets SPC states patients should be advised not to swallow desiccant found in white high-density polyethylene bottles, and mentions risk of blurred vision which could affect ability to drive/use machines. Tablets in above-mentioned bottles should be used within 30 days after opening.

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The information displayed on the left hand side is in order of risk (top indicating highest risk)

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The information displayed on the left hand side is in order of risk (top indicating highest risk)