MHRA drug safety update: SGLT2 inhibitors - reports of Fournier’s gangrene

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National Institute for Health and Care Excellence

  • Brigatinib now recommended for advanced lung cancer in final draft guidance.
  • Cerliponase alfa not recommended for Batten disease in final draft guidance.
  • Barnett Continent Intestinal Reservoir to be used only with special arrangements.
  • Cardiac contractility modulation device implantation for heart failure recommended for research purposes in draft guidance.

Medicines and Healthcare products Regulatory Agency

  • The MHRA has issued the following drug safety updates:
    • SGLT2 inhibitors: reports of Fournier’s gangrene
    • Carbimazole: risk of acute pancreatitis
    • Carbimazole: increased risk of congenital malformations; strengthened advice on contraception issued
  • The MHRA has also issued the following alerts:
    • Class 4 defect information: Atropine Sulfate 3mg/10ml Solution for injection in pre-filled syringe.
    • Professional use monitor/defibrillator: LIFEPAK 15 – risk of device failure during patient treatment and possible failure to deliver therapy.
    • Accu-Chek® Insight insulin pumps – some need to be fitted with key frames to reduce the risk of accidentally unlocking keys or pressing the bolus buttons.

European Medicines Agency

  • Suspension of fenspiride medicines recommended due to potential risk of heart rhythm problems

NHS England

  • Gabapentin and pregabalin to be reclassified as schedule 3 controlled drugs

Department of Health and Social Care

  • NHSX: new joint organisation for digital, data and technology announced.


NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

BRIGATINIB RECOMMENDED FOR ADVANCED LUNG CANCER IN FINAL DRAFT GUIDANCE

Brigatinib (Alunbrig) is now recommended, within its marketing authorisation, for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) in adults who have already had crizotinib in final draft guidance. In an earlier appraisal consultation document, NICE had said the drug was not cost-effective. An improved commercial agreement from the company and further clarifications about its economic model mean it is now recommended for routine use in the NHS.People with ALK-positive advanced NSCLC that has been treated with crizotinib are currently offered ceritinib as their next treatment. Clinical evidence based on indirect comparisons of trials suggests that people having brigatinib live longer than those having ceritinib, and that they live longer before their condition worsens. Brigatinib may be more effective for brain metastases and better tolerated than existing treatments. The cost-effectiveness estimates are uncertain, particularly because of whether brigatinib’s treatment benefit continues after stopping treatment. The most plausible estimates for brigatinib compared with ceritinib are around the higher end of what NICE normally considers acceptable for an end-of-life treatment. But the population eligible for brigatinib is small and will decrease because crizotinib is no longer considered first-line treatment for ALK-positive NSCLC. Future treatments will be limited for those who have crizotinib. Taking these exceptional circumstances into account, brigatinib is recommended for ALK-positive advanced NSCLC in adults who have had crizotinib.

CERLIPONASE ALFA NOT RECOMMENDED FOR BATTEN DISEASE IN FINAL DRAFT GUIDANCE

NICE has published final draft Highly Specialised Technology guidance which confirms its earlier decision not to recommend cerliponase alfa (Brineura) for children with neuronal ceroid lipofuscinosis type 2 (CLN2). The decision comes at the end of year-long negotiations between the company and NHS England during which the company was unable to price the treatment at a level that would have addressed the problems highlighted during NICE’s assessment of it. Costing over £500,000 per person for each year’s treatment, cerliponase alfa is an enzyme replacement therapy administered directly into the brain via a surgically implanted permanent access device. In its earlier draft guidance, published last year, the independent committee had agreed that, although cerliponase alfa is not a cure for CLN2 disease, it is an important development for treating the condition and that it had shown substantial short-term benefits in slowing the rate at which it progresses. However, in the absence of long-term evidence about its effectiveness in stabilising the disease and preventing death, and having taken all the health and non-health-related benefits of cerliponase alfa into account, the independent committee considered that the drug was not value for money within the context of a highly specialised service.

BARNETT CONTINENT INTESTINAL RESERVOIR TO BE USED ONLY WITH SPECIAL ARRANGEMENTS

NICE has published evidenced-based recommendations which suggests that the evidence on the safety of Barnett Continent Intestinal Reservoir (modified continent ileostomy), to restore continence after colon and rectum removal, shows there are serious but well-recognised safety concerns. NICE says current evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Clinicians wishing to do Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal should:

  • Inform the clinical governance leads in their NHS trusts.
  • Ensure that patients understand the procedure's safety and efficacy, as well as any uncertainties about these. They should provide them with clear written information to support shared decision making. In addition, the use of NICE's information for the public is recommended.
  • Audit, review and publish clinical outcomes of all patients having Barnett Continent Intestinal Reservoir (modified continent ileostomy) to restore continence after colon and rectum removal. This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).

NICE recommends the procedure should only be done by experienced colorectal surgeons with training and mentoring in the specific technique. Further research should include details of patient selection, durability and the incidence of complications. Outcomes should be published.

CARDIAC CONTRACTILITY MODULATION DEVICE IMPLANTATION FOR HEART FAILURE RECOMMENDED FOR RESEARCH PURPOSES IN DRAFT GUIDANCE

NICE has published draft guidance which finds the evidence on cardiac contractility modulation device implantation for heart failure raises no major safety concerns. However, it says the evidence on efficacy is inadequate in quantity and quality. Therefore, it recommends this procedure should only be used in the context of research. Further research should ideally be in the form of blinded randomised controlled trials. These should report details of patient selection, duration and timing of stimulation, and duration of effect of stimulation. Outcomes should include ejection fraction, oxygen consumption, New York Heart Association classification and patient-reported outcomes, including quality of life. Closing date for comments is 21 March.

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MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY

DRUG SAFETY UPDATE: SGLT2 INHIBITORS - REPORTS OF FOURNIER’S GANGRENE

The MHRA has received reports of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum) with the use of Sodium-Glucose-Co-Transporter 2 (SGLT2) inhibitors, indicated for the treatment of type 2 diabetes. Medicines in the UK are those containing dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin▼. If Fournier’s gangrene is suspected, the MHRA advises healthcare professionals to stop the SGLT2 inhibitor and to start treatment urgently (including antibiotics and surgical debridement). Fournier’s gangrene is a rare but potentially life-threatening infection that requires urgent medical attention. Urogenital infection or perineal abscess may precede necrotising fasciitis and patients should be advised to seek urgent medical attention if they experience severe pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise. An EU review has assessed reported cases of Fournier’s gangrene across the class of SGLT2 inhibitors. Although diabetes mellitus is a risk factor for the development of Fournier’s gangrene, some of the EU post-marketing reports were considered possibly to be related to the use of SGLT2 inhibitors. Fournier’s gangrene usually occurs almost exclusively in men. However, around a third of the EU cases reviewed were reported in women. The MHRA are also aware of rare occurrences of Fournier’s gangrene in patients on SGLT2 inhibitors in the USA. Warnings about Fournier’s gangrene will be added to the product information for all SGLT2 inhibitors. A letter has also been sent to advise healthcare professionals of the risk. Adverse drug reactions to a SGLT2 inhibitor should be reported to the Yellow Card Scheme without delay.

DRUG SAFETY UPDATE: CARBIMAZOLE - RISK OF ACUTE PANCREATITIS

The MHRA has issued a drug safety update on the risk of acute pancreatitis with the use of carbimazole. An EU review has found post-marketing reports of acute pancreatitis associated with the use of products containing carbimazole and thiamazole (not authorised for use in the UK). In the UK, no Yellow Card reports of acute pancreatitis associated with carbimazole treatment have been received over a period of 55 years; however, a small number of reports have been received in other countries. Although the mechanism for development of acute pancreatitis is poorly understood, the presence of cases reporting recurrent acute pancreatitis with a decreased time to onset after re-exposure to carbimazole suggests a possible immunological mechanism. The MHRA advises that carbimazole must be immediately discontinued in patients who develop acute pancreatitis during treatment. Patients should be switched to an alternative therapy on the basis of an assessment of the individual benefits and risks. Re-exposure to carbimazole must be avoided in patients who have previously experienced acute pancreatitis with carbimazole or thiamazole as re-exposure may result in recurrence of potentially life-threatening acute pancreatitis, with a decreased time to onset. The product information for products containing carbimazole is being updated to include risk of acute pancreatitis.

DRUG SAFETY UPDATE: CARBIMAZOLE - INCREASED RISK OF CONGENITAL MALFORMATIONS; STRENGTHENED ADVICE ON CONTRACEPTION ISSUED

The MHRA has issued another drug safety update concerning carbimazole due to an associated increased risk of congenital malformations, especially when administered in the first trimester of pregnancy and at high doses (15mg or more daily). Women of childbearing potential should use effective contraception during treatment with carbimazole – see FSRH statement on contraception for women using known teratogenic drugs or drugs with potential teratogenic effects. The Patient Information Leaflet advises patients to tell their doctor straight away if they think they may be pregnant or are planning to have a baby. Carbimazole must only be used during pregnancy when clinically indicated and after a strict individual benefit/risk assessment and only at the lowest effective dose without additional administration of thyroid hormones. The use of carbimazole during pregnancy should be preserved for the situations in which a definitive therapy of the underlying disease (thyroidectomy or radioiodine treatment) was not suitable prior to pregnancy and in case of new occurrence or reoccurrence during pregnancy. If carbimazole is used during pregnancy, close maternal, foetal and neonatal monitoring is recommended. 

CLASS 4 DEFECT INFORMATION: ATROPINE SULFATE 3MG/10ML SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE

The Medicines and Healthcare products Regulatory Agency (MHRA) has issued a drug alert for some batches of Atropine Sulfate 3mg/10ml Solution for injection in pre-filled syringe as Aguettant Limited has informed the MHRA that there is an error in the Patient Information Leaflet (PIL). In Section 6 of the Leaflet included in the batches affected, the equivalent content of Atropine base is expressed incorrectly as 0.17mg per ml and 0.83mg in10ml. The corrected PIL will state the following: Each ml of solution for injection contains 0.3mg atropine sulfate monohydrate equivalent to 0.25mg atropine. Each 10ml syringe contains atropine sulfate monohydrate equivalent to 2.5mg atropine. In addition to this, minor errors on the Summary of Product Characteristics (SPC) and the carton are also being corrected. In the current versions of both, the equivalent content of Atropine base is expressed as 0.26mg per ml and 2.49mg in10ml. This is being corrected to give equivalent contents of 0.25mg per ml and 2.5mg in 10ml. Steps have already been taken to correct the PIL, the SPC and the carton. Distribution of the affected batches will cease once corrected stock is available. It is anticipated that new batches will be available in June 2019.

PROFESSIONAL USE MONITOR/DEFIBRILLATOR: LIFEPAK 15 – RISK OF DEVICE FAILURE DURING PATIENT TREATMENT AND POSSIBLE FAILURE TO DELIVER THERAPY

A medical device alert has been issued for professional use monitor/defibrillator LIFEPAK 15 due to the risk of device failure during patient treatment and possible failure to deliver therapy. Manufactured by Stryker, the potential for a lock-up condition where the device becomes non-responsive after a defibrillation shock has been delivered affects specific serial numbers. Healthcare professionals are advised to:

  • Identify affected devices – see the manufacturer’s Field Safety Notice.
  • Ensure alternative devices are available or request a loan device from Stryker. If no alternatives are available, perform a local risk assessment.
  • Follow actions recommended in the manufacturer’s Field Safety Notice.
  • Report adverse events involving these devices through the local incident reporting system and/or the national incident reporting authority as appropriate: England, Scotland, Northern Ireland, Wales. Also, report directly to manufacturers if local or national systems do not.

ACCU-CHEK® INSIGHT INSULIN PUMPS – SOME NEED TO BE FITTED WITH KEY FRAMES TO REDUCE THE RISK OF ACCIDENTALLY UNLOCKING KEYS OR PRESSING THE BOLUS BUTTONS

The MHRA has issued a medical device alert for Accu-Chek® Insight insulin pumps (Roche Diabetes Care) as some need to be fitted with key frames to reduce the risk of accidentally unlocking keys or pressing the bolus buttons. Healthcare professionals are advised to:

  • Identify affected patients and pumps (serial numbers below 32100000)
  • Ensure that all patients and carers:
    • receive a copy of manufacturer’s Field Safety Notice (FSN) and instructions for use dated December 2018
    • understand the information detailed in the FSN
    • apply the new key frames as instructed by the manufacturer
    • Return the FSN acknowledgment form to Roche as currently they have not received enough responses.

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EUROPEAN MEDICINES AGENCY

SUSPENSION OF FENSPIRIDE MEDICINES RECOMMENDED DUE TO POTENTIAL RISK OF HEART RHYTHM PROBLEMS

The European Medicines Agency’s safety committee (PRAC) has recommended an EU-wide suspension of fenspiride medicines, used in children and adults to relieve cough caused by lung diseases. The suspension is a precautionary measure to protect patients while the PRAC reviews the risk of QT prolongation and torsades de pointes. Cases of heart rhythm problems had been reported in patients who had taken these medicines in the past. To explore the potential link between fenspiride and these heart rhythm problems, animal studies were carried out which now show that fenspiride has the potential to prolong QT in humans. The PRAC will examine all the available evidence and make recommendations on the action to be taken on marketing authorisations for fenspiride medicines across the EU. Once the review is concluded, the EMA will communicate further and provide updated guidance to patients and healthcare professionals.

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NHS ENGLAND

GABAPENTIN AND PREGABALIN TO BE RECLASSIFIED AS SCHEDULE 3 CONTROLLED DRUGS

NHS England has issued reminder guidance that gabapentin and pregabalin will be reclassified to Schedule 3 Controlled Drugs (CDs), following rising numbers of fatalities linked to the drugs. The move means it will be illegal to possess pregabalin and gabapentin without a prescription and it will be illegal to supply or sell them to others. From 1 April 2019:

  • Prescriptions for gabapentin and pregabalin need to meet full prescription requirements for Schedule 3 CDs.
  • As with other Schedule 2, 3 and 4 CDs, there is strong recommendation from the Department of Health and the Scottish government that the maximum quantity prescribed should not exceed 30 days.
  • Gabapentin and pregabalin are exempt from safe custody requirements.

NHS England has also produced a briefing note on the rescheduling of gabapentin and pregabalin as Schedule 3 CDs for community pharmacies and GP Practices in England.

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DEPARTMENT OF HEALTH AND SOCIAL CARE

NHSX: NEW JOINT ORGANISATION FOR DIGITAL, DATA AND TECHNOLOGY ANNOUNCED

The Department of Health and Social Care has announced the launch of a new joint unit, NHSX, which aims to work with the NHS and the wider digital economy to improve digital services, improve patient care and enable medical research. NHSX’s responsibilities will include:

  • setting national policy and developing best practice for NHS technology, digital and data - including data-sharing and transparency
  • setting standards – developing, agreeing and mandating clear standards for the use of technology in the NHS
  • ensuring that NHS systems can talk to each other across the health and care system
  • helping to improve clinical care by delivering user-focused projects
  • supporting the use of new technologies by the NHS, both by working with industry and via its own prototyping and development capability
  • ensuring that common technologies and services, including the NHS App, are designed so that trusts and surgeries can use them
  • making sure that all source code is open by default so that anyone who wants to write code for the NHS can see what is needed
  • reforming procurement – helping the NHS buy the right technology through the application of technology standards, streamlined spend controls and new procurement frameworks that support our standards
  • setting national strategy and mandating cyber security standards
  • championing and developing digital training, skills and culture so staff are appropriately trained and skilled
  • delivering an efficient process for technology spend, domain name management and website security.

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