MHRA drug safety update: rivaroxaban - reminder that 15 mg and 20 mg tablets should be taken with food

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National Institute for Health and Care Excellence

  • Final draft guidance recommends:
    • Ribociclib in combination with fulvestrant for advanced breast cancer
    • Risankizumab for moderate to severe plaque psoriasis
    • Dapagliflozin with insulin for treating type 1 diabetes
  • Medtech innovation briefing published for HemaClear for bloodless surgical field during limb surgery.
  • Lung cancer in adults - quality standard: draft update published.

Medicines and Healthcare products Regulatory Agency

  • Drug safety update published for:
    • Febuxostat (Adenuric): increased risk of cardiovascular death and all-cause mortality in clinical trial in patients with a history of major cardiovascular disease
    • Tocilizumab (RoActemra): rare risk of serious liver injury including cases requiring transplantation
    • Rivaroxaban (Xarelto▼): reminder that 15 mg and 20 mg tablets should be taken with food.
  • EAMS positive scientific opinion: avelumab in combination with axitinib for advanced renal cancer.

European Medicines Agency

  • PRAC recommends new measures to avoid dosing errors with methotrexate.

British Journal of General Practice

  • Type 2 diabetes medication de-prescription protocol published

Scottish Intercollegiate Guidelines Network

  • Management of osteoporosis and the prevention of fragility fractures guideline: draft update published

European Centre for Disease Prevention and Control

  • Syphilis notifications in the EU/EEA up by 70% since 2010.

World Health Organisation

  • New essential medicines and diagnostics lists published.

Public Health England

  • Advice issued to people travelling to Egypt.

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

RIBOCICLIB RECOMMENDED IN COMBINATION WITH FULVESTRANT FOR ADVANCED BREAST CANCER

NICE has published final draft guidance which recommends ribociclib (Kisqali,) with fulvestrant for use within the Cancer Drugs Fund as an option for treating hormone receptor-positive, human epidermal growth factor receptor2 (HER2)-negative, locally advanced or metastatic breast cancer in people who have had previous endocrine therapy only if:

  • exemestane plus everolimus is the most appropriate alternative to a cyclin-dependent kinase4 and 6 (CDK4/6) inhibitor and
  • the conditions in the managed access agreement for ribociclib with fulvestrant are followed

Clinical trial evidence suggests that, compared with fulvestrant alone, ribociclib with fulvestrant increases the length of time before the disease progresses in people who have had previous endocrine treatment. It is not known whether ribociclib increases the length of time people live because the final trial results are not available yet. According to NICE, the results of an indirect comparison of ribociclib and fulvestrant with exemestane and everolimus are very uncertain. The cost-effectiveness estimates are also very uncertain, and above the range NICE normally considers an acceptable use of NHS resources. While NICE does not recommend ribociclib with fulvestrant for routine use in the NHS, it recognises ribociclib with fulvestrant has the potential to be cost effective for the population considered in the appraisal, but that more data are needed to resolve the uncertainties in the clinical evidence. This is why ribociclib with fulvestrant is recommended for this population in the Cancer Drugs Fund while these data are collected.

RISANKIZUMAB RECOMMENDED FOR MODERATE TO SEVERE PLAQUE PSORIASIS

NICE has published final draft guidance which recommends risankizumab (Skyrizi) as an option for treating plaque psoriasis in adults, only if:

  • the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and
  • the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
  • the company provides the drug according to the commercial arrangement.

Risankizumab has been studied in four randomised controlled trials including a total of about 2,200 adults with plaque psoriasis. Direct comparisons show risankizumab is more effective than adalimumab and ustekinumab. Indirect comparisons suggest risankizumab is likely to provide similar health benefits compared with guselkumab, and better PASI response rates compared with many other biologicals.

DAPAGLIFLOZIN RECOMMENDED WITH INSULIN FOR TREATING TYPE 1 DIABETES

NICE has published final draft guidance which recommends dapagliflozin (Forxiga) with insulin as an option for treating type 1 diabetes in adults with a body mass index (BMI), of at least 27kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy, only if:

  • they are on insulin doses of more than 0.5 units/kg of body weight/day and
  • they have completed a structured education programme that includes information about:
    • the risk of diabetic ketoacidosis
    • how to recognise risk factors for diabetic ketoacidosis, and its signs and symptoms
    • how and when to monitor blood ketone levels
    • what actions to take for elevated blood ketones, and
  • treatment is started and supervised in a hospital diabetes clinic.

NICE says evidence from the clinical trials shows small improvements in blood glucose (HbA1c levels) and weight loss and very small improvements in quality of life, when dapagliflozin plus insulin is compared with placebo plus insulin in adults with type 1 diabetes and inadequate blood glucose control despite optimised insulin therapy. The company extrapolates the effects of the small improvement in HbA1c level with dapagliflozin seen at one year in the trials to a lower risk of long-term complications over a patient’s lifetime.

MEDTECH INNOVATION BRIEFING PUBLISHED FOR HEMACLEAR FOR BLOODLESS SURGICAL FIELD DURING LIMB SURGERY

NICE has published a medtech innovation briefing for HemaClear, a sterile elastic tourniquet designed to stop severe loss of blood during limb surgery. The technology provides several innovative aspects and several specialist commentators identified potential patient benefits as well as potential system benefits, including better theatre and resource use. In its summary, NICE highlights however uncertainty surrounding some outcomes such as pain and complications and a lack of medium- to long-term follow up.

LUNG CANCER IN ADULTS - QUALITY STANDARD: DRAFT UPDATE PUBLISHED

NICE has published a draft update of its 2012 quality standard on the diagnosis and management of lung cancer in adults. The statements prioritised in 2012 have been updated (2012, updated 2019) or replaced (new 2019):

  • Local authorities and their partners use coordinated campaigns to raise awareness of the symptoms and signs of lung cancer and encourage people to seek medical advice if they need to. [2012, updated 2019]
  • Adults with suspected or confirmed lung cancer who smoke are referred to an evidence-based stop smoking service. [new 2019]
  • Adults with suspected or confirmed lung cancer have access to a named lung cancer clinical nurse specialist. [2012, updated 2019]
  • Adults with lung cancer have investigations to complete diagnostic staging and assess lung function before starting treatment with curative intent. [new 2019]
  • Adults with non-small-cell lung cancer stage IIIb, IIIc or IV who are having tissue samples taken, have them taken in a suitable form for pathological diagnosis and assessment of predictive biomarkers. [2012, updated 2019]
  • Adults with non-small-cell lung cancer stage I or II and good performance status have treatment with curative intent. [new 2019]

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MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY

FEBUXOSTAT: INCREASED RISK OF CARDIOVASCULAR DEATH AND ALL-CAUSE MORTALITY

The Medicines and Healthcare products Regulatory Agency (MHRA) has published a drug safety update for febuxostat (Adenuric) due to reports of increased risk of cardiovascular death and all-cause mortality in clinical trial in patients with a history of major cardiovascular disease. The MHRA advises to avoid treatment with febuxostat in patients with pre-existing major cardiovascular disease (for example, myocardial infarction, stroke, or unstable angina), unless no other therapy options are appropriate. Findings from a phase 4 clinical study (the CARES study) in patients with gout and a history of major cardiovascular disease show a higher risk for cardiovascular-related death and for all-cause mortality in patients assigned to febuxostat than in those assigned to allopurinol.

TOCILIZUMAB: RARE RISK OF SERIOUS LIVER INJURY INCLUDING CASES REQUIRING TRANSPLANTATION

The MHRA has published a drug safety update for Tocilizumab (RoActemra) due to the rare risk of serious liver injury including cases requiring transplantation. Serious liver injury has been reported on treatment with tocilizumab from two weeks to more than five years after initiation. Healthcare professionals are advised to:

  • advise patients to seek medical help immediately if they experience signs and symptoms of liver injury, such as tiredness, abdominal pain, and jaundice
  • monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at initiation, every 4–8 weeks during the first six months of treatment, and every 12 weeks thereafter in patients with rheumatological indications
  • exercise caution when considering treatment initiation in patients with ALT or AST higher than 1.5-times the upper limit of normal (ULN); initiation of treatment is not recommended in patients with ALT or AST higher than five-times the ULN (see table in MHRA notice)
  • if liver enzyme abnormalities are identified, consult the dose modifications recommended, which have not changed
  • report any suspected adverse reactions associated with tocilizumab to the Yellow Card Scheme

RIVAROXABAN (XARELTO▼): REMINDER THAT 15 MG AND 20 MG TABLETS SHOULD BE TAKEN WITH FOOD

The MHRA has published a drug safety update for rivaroxaban (Xarelto▼) that 15 mg and 20 mg tablets should be taken with food. The MHRA has received a small number of reports suggesting lack of efficacy (thromboembolic events) in patients taking 15 mg or 20 mg rivaroxaban on an empty stomach. For patients who have difficulty swallowing, tablets can be crushed and mixed with water or apple puree immediately before taking; this mixture should be immediately followed by food; rivaroxaban 2.5 mg and 10 mg tablets can be taken with or without food. Healthcare professionals are advised to report suspected adverse drug reactions, including any suspected events associated with lack of efficacy to rivaroxaban, on a Yellow Card.

EAMS POSITIVE SCIENTIFIC OPINION: AVELUMAB IN COMBINATION WITH AXITINIB FOR ADVANCED RENAL CANCER

The (MHRA) has published an early access to medicines scheme (EAMS) positive scientific opinion on avelumab in combination with axitinib for first-line treatment of advanced renal cell cancer (RCC). Benefits of the treatment include slower disease progression and better response rate compared to standard current treatment. After 12 months, the proportion of patients without progression of disease was 53% in the group of patients treated with avelumab and axitinib compared to 41% in those treated with sunitinib. In addition, the overall response rate was 51% with avelumab and axitinib compared to 25% with sunitinib. On the other hand, almost all patients experienced a side effect with avelumab and axitinib. The most common side effects, affecting at least 30% of patients, were diarrhoea, hypertension, fatigue, nausea and a hoarse voice. Severe side effects were frequent, particularly high blood pressure (26%), diarrhoea and increased liver function tests. Avelumab in combination with axitinib is also associated with side effects resulting from excessive activity of the immune system; although most resolved following initiation of appropriate medical therapy or withdrawal of avelumab.

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EUROPEAN MEDICINES AGENCY

PRAC RECOMMENDS NEW MEASURES TO AVOID DOSING ERRORS WITH METHOTREXATE

The European Medicines Agency’s safety committee (PRAC) has recommended new measures to avoid dosing errors that have led to some patients incorrectly taking methotrexate-containing medicines daily instead of weekly. The risk of dosing errors with methotrexate-containing medicines is well known. However, despite several measures already in place, these errors continue to be reported. Mistakes in prescribing or dispensing methotrexate as well as misunderstandings of the dosing schedule have led to patients taking the medicine daily instead of weekly for inflammatory diseases, with serious consequences, including fatalities. The new measures include restricting who can prescribe these medicines to doctors with expertise in using methotrexate-containing medicines, making warnings on the packaging more prominent and providing educational materials for patients and healthcare professionals. In addition, to help patients follow the once-weekly dosing, methotrexate tablets for weekly use will be provided in blister packs and not in bottles (or tubes).

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BRITISH JOURNAL OF GENERAL PRACTICE

TYPE 2 DIABETES MEDICATION DE-PRESCRIPTION PROTOCOL PUBLISHED

A new guide has been published to provide guidance on adapting diabetes medication for patients following a low carbohydrate diet to manage their type 2 diabetes. The authors of the paper note that low carbohydrate diets are becoming increasingly popular for managing type 2 diabetes and can lead to significant metabolic improvements as well as reduced medication burden. However, clinicians should be confident in adjusting diabetes medications to achieve safe and effective care. The paper recommends three key clinical considerations when determining the safety and appropriateness of type 2 diabetes medications. These include:

  • Is there a risk of the drug causing hypoglycaemia or another adverse event?
  • What is the degree of carbohydrate restriction?
  • Once carbohydrate is reduced, does the drug continue to provide health benefit. If so, are the potential drug benefits greater than or less than possible risks and side effects?

The paper separates common diabetic medications into several categories. These include:

  • Those which create a risk of hypoglycaemia (low blood sugar levels): sulphonylureas and meglitinides, insulins
  • Medications that risk ketoacidosis: SGLT2 Inhibitors (‘flozins’)
  • Medications that pose no excess risk with a low carbohydrate diet: metformin, GLP-1 agonists, thiazolidinediones (‘glitazones’), DPP-4 inhibitors (‘gliptins’), acarbose.

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SCOTTISH INTERCOLLEGIATE GUIDELINES NETWORK

MANAGEMENT OF OSTEOPOROSIS AND THE PREVENTION OF FRAGILITY FRACTURES GUIDELINE – DRAFT UPDATE PUBLISHED

The SIGN 142 guideline on the management of osteoporosis and the prevention of fragility fractures was published in March 2015. Since then new evidence has been published on HIV as a risk factor, population screening and pharmacological therapies. A selective update of the guideline has been undertaken to provide more current advice in these areas. The sections in the consultation draft will replace the corresponding sections in SIGN 142. The other sections of SIGN 142 will remain the same.

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EUROPEAN CENTRE FOR DISEASE PREVENTION AND CONTROL

SYPHILIS NOTIFICATIONS IN THE EU/EEA UP BY 70% SINCE 2010

The number of syphilis cases has been consistently going up across Europe since 2010, mostly affecting men who have sex with men living in urban areas. In 2017, notification rates reached an all-time high in the EU/EEA countries with more than 33,000 reported cases. An in-depth ECDC study describes the factors behind this increase and outlines the evidence-based options for public health control of syphilis, including case finding and management as well as educational activities. Between 2010 and 2017, 15 countries reported an increase in the notification rate of more than 15%. However, this varied greatly among countries with rates more than doubling in five countries: Iceland (876%), Ireland (224%), the United Kingdom (153%), Germany (144%) and Malta (123%). On the other hand, Estonia and Romania reported a drop of 50% or more over the same period. During this period, syphilis diagnoses were consistently higher among men, with rates doubling from 6.1 per 100 000 in 2010 to 12.1 in 2017. Between 2007 and 2017, close to two-thirds (62%, 94,015 of the 152,233 cases where sexual orientation was known) were reported among men who have sex with men. Heterosexual men contributed 23% of cases and women 15%. The proportion of cases diagnosed among men who have sex with men ranged from below 20% in Latvia, Lithuania and Romania to more than 80% in France, Germany, Ireland, the Netherlands, Sweden and the United Kingdom.

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WORLD HEALTH ORGANISATION

NEW ESSENTIAL MEDICINES AND DIAGNOSTICS LISTS PUBLISHED

The World Health Organisation (WHO) has published updates of global guidance on medicines and diagnostic tests to address health challenges, prioritise highly effective therapeutics, and improve affordable access. The updated Essential Medicines List adds 28 medicines for adults and 23 for children and specifies new uses for 26 already-listed products, bringing the total to 460 products deemed essential for addressing key public health needs. WHO adds that while this figure may seem high, it corresponds to a fraction of the number of medicines available on the market. By focusing the choices, WHO is emphasising patient benefits and wise spending with a view to helping countries prioritise and achieve universal health coverage. The updated List of Essential Diagnostics also contains 46 general tests that can be used for routine patient care as well as for the detection and diagnosis of a wide array of disease conditions, and 69 tests intended for the detection, diagnosis and monitoring of specific diseases.

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PUBLIC HEALTH ENGLAND

ADVICE ISSUED TO PEOPLE TRAVELLING TO EGYPT

Public Health England has issued advice to people travelling to Egypt after a number of people, including children, have returned with a serious illness caused by E. coli infection. All travellers had been to the Hurghada region of Egypt. PHE’s scientists are gathering further information to understand the cause of these infections. PHE recommends travellers to the region to:

  • where possible, avoid eating salads and uncooked vegetables
  • only eat fruit they can peel
  • avoid unpasteurised milk, cheese and ice cream
  • avoid food that has been left uncovered in warm environments and exposed to flies
  • ensure all meat is cooked thoroughly before you eat it, avoiding any meat that is pink or cold
  • avoid ice, unless made with filtered or bottled water, and tap water, even when brushing teeth
  • only drink bottled water or use ice made from bottled/filtered water
  • wash your hands thoroughly after visiting the toilet, and always before preparing or eating food. Alcohol gel can be helpful (but not entirely effective) when hand washing facilities are not available
  • when swimming, try and avoid swallowing water where possible and supervise children when swimming
  • don’t swim whilst ill.

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OnMedica

Editorial team, Wilmington Healthcare

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