National Medication Safety

Network

24th June 2015

Observatory of recent safe medication

bulletins, practice research, reports, and

publications

Presented by Samantha Owen,

samantha.owen@uhs.nhs.uk

Recent regulator and

statutory body activity

Recent regulator and

statutory body activity Hepatitis C medicines and amiodarone: risks of severe

bradycardia and heart block MHRA has reinforced EMA (24/4/15) and FDA (24/3/15) announcements to

avoid combination of certain hepatitis C medicines and amiodarone

• 8 reports of severe bradycardia or heart block in patients taking

amiodarone with sofosbuvir-ledipasvir (Harvoni) combination, or

sofosbuvir (Sovaldi) taken with daclatasvir (Daklinsa). 6 cases

occurred in the first 24 hrs and remaining 2 cases within 2-12 days of

starting the antiviral(s).

• Avoid concomitant use, unless no alternative. Otherwise, monitor

patients closely, partic in first few weeks, including those who have

stopped amiodarone in past few months.

• Monitor high risk patients continuously in appropriate clinical setting for

first 48 hrs.

• Advise patients to watch for signs and symptoms (e.g. SOB, light-

headed, palpitations, fainting).

https://www.gov.uk/drug-safety-update/sofosbuvir-with-daclatasvir-sofosbuvir-and-

ledipasvir-risks-of-severe-bradycardia-and-heart-block-when-taken-with-amiodarone

Recent regulator and

statutory body activity Pomalidomide (Imnovid▼): risks of cardiac failure,

interstitial lung disease and hepatotoxicity Review of data from clinical trials, reports from clinical practice and published

case reports

• Cardiac failure – common side effect (1/10 to 1/100), occurring mostly in

patients with cardiac disease or risk factors, within 6 months of starting

treatment. Pomalidomide can also cause AF and precipitate cardiac failure.

• Interstitial lung disease (ILD) and related events (e.g. pneumonitis) –

common side effect (1/10 to 1/100), usually within 6 months of starting

treatment, but cases of ILD approx 18 months after starting. ILD usually

resolves on stopping and treating with steroids.

• Hepatoxicity – as well as elevating ALT and bilirubin, can cause acute

hepatitis. Uncommon side effect (1/100 to 1/1,000). Also reports of acute liver

failure, but inconclusive cause. Highest risk in first 6 months. https://www.gov.uk/drug-safety-update/pomalidomide-imnovid-risks-of-cardiac-failure-

interstitial-lung-disease-and-hepatotoxicity

Recent regulator and

statutory body activity Pomalidomide (Imnovid▼): risks of cardiac failure,

interstitial lung disease and hepatotoxicity (continued) New monitoring instructions to detect these side effects as soon as

possible:

• CAUTION in patients with cardiac disease or cardiac risk factors. If used,

monitor for signs or symptoms of cardiac failure

• stop pomalidomide and carefully assess patients with any acute onset or

unexplained worsening of respiratory symptoms to confirm or exclude ILD

• if ILD is confirmed, treat appropriately and only resume pomalidomide

treatment after thoroughly evaluating benefits and risks

• regularly monitor liver function for the first 6 months of pomalidomide

treatment and as clinically indicated thereafter

https://www.gov.uk/drug-safety-update/pomalidomide-imnovid-risks-of-cardiac-

failure-interstitial-lung-disease-and-hepatotoxicity

Recent regulator and

statutory body activity Epoetin beta (NeoRecormon): increased risk of

retinopathy in preterm infants cannot be excluded Evidence

Two Cochrane systematic reviews: one focused on treatment started within 7

days after birth, the other on treatment started 8 to 28 days after birth.Taken

together, the reviews suggest that epoetin beta may increase the underlying

risk of retinopathy in premature infants.

European review of available data concluded more data needed to draw a firm

conclusion, but an increase in risk cannot be excluded.

The SmPC will be amended to include this possible risk.

Advice when using epoetin beta for preventing anaemia of prematurity:

• consider the benefits and risks, including the possible risk of retinopathy

• monitor the infant for features of retinopathy

• advise parents or carers that their baby’s eyes will be carefully monitored for

any ill effects

https://www.gov.uk/drug-safety-update/epoetin-beta-neorecormon-increased-risk-of-

retinopathy-in-preterm-infants-cannot-be-excluded

Device Alerts Ventilators with Adaptive ServoVentilation (ASV) -

increased risk of cardiovascular death in patients who

have a specific heart condition Includes ventilators manufactured by ResMed and Philips Respironics (see

MDA/2015/020 and MDA/2015/021R).

Patients with chronic, symptomatic heart failure (NYHA 2-4) with reduced

left ventricular ejection fraction (LVEF ≤ 45%).

Advice:

• assess all patients currently being treated with ASV ventilators for

symptomatic chronic heart failure and if necessary undertake an

assessment of LVEF- where appropriate discuss risks and possible

discontinuation of treatment with patients

• be aware that new at-risk patients should not use the ASV ventilators

‘Dear Healthcare Professional’

• Ketoprofen gel and risk of photosensitivity reactions:

reminder of risk minimisation measures (e.g. Avoid or

protect skin from sunlight; wash hands after use)– 20

April 2015

• Efavirenz (Sustiva): discontinuation of 30 mg/ml oral

solution formulation by end of Oct 2015. Use capsule

sprinkle method – 23 April 2015

• Fingolimod (Gilenya ▼): first reported case of

progressive multifocal leukoencephalopathy (PML) in MS

patient taking fingolimod without previous treatment with

natalizumab or other immunosuppressives – 29 April

2015

Issue raised previously

• 2007: Alert issued in England stipulating injections must be drawn up from the

source bottle or ampoule directly into syringes that are labelled and checked

prior to administration and that ‘open systems’ should never be used to contain

medication prior to injection.

• 2010: The particular risk of inadvertent injection of skin preparations was

reinforced.

However, errors still being reported.

Action by organisations required no later than 7 July 2015:

• Identify if invasive procedures involving injection alongside skin preparation are

taking place in circumstances where unintended injection of skin preparation

solution has or could occur.

• Consider if immediate action needs to be taken locally, and ensure an action

plan to reduce the risk of incidents occurring is underway if required http://www.england.nhs.uk/2015/05/27/psa-skin-prep-solution/

Heatwave Plan for England 2015

• Updated 22nd May 2015.

• Intended to protect the population from heat-related harm to health.

• Includes cautions on storage of medicines, increased vulnerability for

people taking multiple medications, or medications that increase

sensitivity to sun.

• Documents available on gov.uk website:

https://www.gov.uk/government/publications/heatwave-plan-for-england

Temazepam prescriptions now need to meet

requirements for Schedule 3 CDs

Home Office has removed current exemptions for temazepam.

From 1 June 2015 prescriptions must contain:

• dose

• form

• strength

• total quantity in both words and figures

Press Releases

May 2015 • EMA confirms recommendation to suspend medicines for which EU

authorisation was primarily based on flawed clinical studies at GVK Biosciences,

India.

Some medicines may remain on the market if they are of critical importance – final

decisions to be made by individual countries.

Recommendation will now be sent to the European Commission for a legally binding

decision, which will apply to all Member States.

List of products includes 81 relevant to the UK

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/05/WC50018

7078.pdf

• EMA endorses advice on use of high-dose ibuprofen. Confirms small

cardiovascular risk with daily doses ≥ 2,400 mg. Also applies to dexibuprofen at

doses ≥ 1,200mg.

Changes to the product information for ibuprofen- and dexibuprofen-containing

medicines will now be implemented by Member States, according to an agreed

timetable.

• Pharmacovigilance Risk Assessment Committee

(PRAC) May 2015

PRAC has started 2 new safety reviews:

1. Review of the MS medicine, natalizumab (Tysabri )

Aims to assess whether advice to healthcare professionals and patients on how to

manage the known risk of progressive multifocal leukoencephalopathy (PML)

needs revising. To use latest evidence to review methods used to calculate the risk

of PML and frequency of testing for PML.

2. Review of inhaled corticosteroids for COPD

Aims to further evaluate the known risk of pneumonia with these medicines, using

data from more recent studies.

FDA Medical Device Safety Alert 28 May 2015 -

Unintentional Injection of Soft Tissue Filler into Blood

Vessels in the Face - Risk of Serious Patient Injury

• Can cause embolisation and lead to vision impairment, blindness,

stroke, damage to skin (incl necrosis) and underlying facial

structures

http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm448255.htm?s

ource=govdelivery&utm_medium=email&utm_source=govdelivery

This months’ papers • Are ECG monitoring recommendations before prescription of QT-

prolonging drugs applied in daily practice? The example of

haloperidol. Pharmacoepidemiology and Drug Safety 2015;doi:

10.1002/pds.3792 (published early online)

http://onlinelibrary.wiley.com/doi/10.1002/pds.3792/pdf

• Number of drugs most frequently found to be independent risk factors

for serious adverse reactions: a systematic literature review. British

Journal of Clinical Pharmacology, DOI:10.1111/bcp.12600.

http://onlinelibrary.wiley.com/doi/10.1111/bcp.12600/abstract

• Drug Dosing and Pharmacokinetics in Children With Obesity: A

Systematic Review. JAMA Pediatr. Published online May 11, 2015.

doi:10.1001/jamapediatrics.2015.132

http://archpedi.jamanetwork.com/article.aspx?articleid=2291281

This months’ papers • Quality Indicators for safe medication preparation and

administration: A systematic review. PLoS ONE April 2015;10(4):

1932-6203 (17 Apr 2015)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401721/pdf/pone.012

2695.pdf

• The burden of adverse drug events. Br J Clin Pharmacol 2015, doi:

10.1111/bcp.12507 (published early online)

http://onlinelibrary.wiley.com/doi/10.1111/bcp.12507/pdf

• Non-vitamin K antagonist oral anticoagulants and major bleeding-

related fatality in patients with atrial fibrillation and venous

thromboembolism: a systematic review and meta-analysis. Heart

2015;0:1–8. doi:10.1136/heartjnl-2015-307489 (online publication)

http://heart.bmj.com/content/early/2015/06/02/heartjnl-2015-

307489.short?g=w_heart_ahead_tab

This months’ papers • Intercepting Wrong-Patient Orders in a Computerized Provider

Order Entry System. Annals of Emergency Medicine June 2015;

65(6): 679–686

http://www.annemergmed.com/article/S0196-0644(14)01558-

3/abstract

• Use of combined oral contraceptives and risk of venous

thromboembolism: nested case-control studies using the QResearch

and CPRD databases. BMJ 2015;350:h2135

http://www.bmj.com/content/350/bmj.h2135

• Drugs with anticholinergic effects and cognitive impairment, falls and

all-cause mortality in older adults: A systematic review and meta-

analysis Br J Clin Pharmacol 2015, doi: 10.1111/bcp.12617

(published early online)

http://onlinelibrary.wiley.com/doi/10.1111/bcp.12617/abstract

This months’ papers

• Pharmacovigilance in children: detecting adverse drug reactions in

routine electronic healthcare records. A systematic review. Br J Clin

Pharmacol 2015 (published early online), doi: 10.1111/bcp.12645.

http://onlinelibrary.wiley.com/doi/10.1111/bcp.12645/abstract

• A Pharmacist Based Intervention to Prevent Medication Errors at

Discharge [abstract]. Journal of Hospital Medicine 2015; 10 (suppl 2)

http://www.shmabstracts.com/abstract/a-pharmacist-based-intervention-

to-prevent-medication-errors-at-discharge/

• Liver injury with novel oral anticoagulants: assessing post-marketing

reports in the US Food and Drug Administration adverse event reporting

system. Br J Clin Pharmacol 2015 (published early online),

doi:10.1111/bcp.12611

http://onlinelibrary.wiley.com/doi/10.1111/bcp.12611/abstract

Number of Drugs most frequently found to be

independent risk factors for serious adverse reactions:

a systematic literature review

• Systematic review into relationship between patient-related risk

factors and occurrence of serious medication-related adverse

reactions (AR).

• Knowledge of risk factors could allow electronic risk stratification of

patients and targeted efforts to reduce the number of AR

• WHO/ EU definition of AR is “a response to a medicinal product

which is noxious and unintended” and includes medication errors,

non-compliance & overdose.

• Meta-analyses report overall rate of AR of 6.1-9.2% for inpatients,

and estimated prolonged period of hospitalisation of 1.2-8.5 days

per AR per patient.

• Retrospective review of 26 studies, mostly observational and

prospective, investigating risk factors in hospital settings; total

patients numbered 85,212, all ages, especially older patients (>65

years)

Number of Drugs most frequently found to be

independent risk factors for serious adverse reactions:

a systematic literature review (continued)

• Within the population, rate of serious ARs was 3,385 (4%)

• The number of drugs was the most consistent correlated risk factor to

AR. Applied to general population and elderly population.

• Discussion that although drugs now safer, and morbidity from drugs

has likely decreased, seem to reach a ‘tipping point’ where too many

drugs exceed the advantages of drug treatment.

• No evidence that age per se is a risk factor for ARs, though

polypharmacy and co-morbidities are confounding factors.

• Inconclusive as to whether female gender is risk factor, but studies

suggest females tend to take greater number of medications and have

higher co-morbidity.

• Results of this review limited by heterogeneity of populations in the

studies, varying study designs, and subjective reporting of ARs – much

higher rate of ARs (up to 12%) in smaller studies with exclusively

elderly patients. With fewer case notes, investigators may have been

more thorough in review of ARs.

Are ECG monitoring recommendations before

prescription of QT-prolonging drugs applied in daily

practice? The example of haloperidol.

• Drugs are a frequent cause of QT interval prolongation

• Studies have shown QT-prolonging drugs present a three-fold

increased relative risk for sudden cardiac death. Absolute risk

remains low (still a rare event) but is additive with other risk factors

(e.g. previous MI, heart failure, hypokalaemia, (family) history of

congenital long QT syndrome, concomitant QT-prolonging drugs)

• As risk minimisation strategy, manufacturers often recommend, prior

to initiating a QT-prolongating drug, a baseline ECG with ongoing

measurements decided on an individual basis.

• In general practice not clear to what extent this recommendation is

adhered to.

• Authors used haloperidol as an example and monitored the

proportion of adult patients (n=3,420) receiving baseline ECGs on

initiating treatment (Jan 2009 to May 2013) – 2 weeks before or 2

weeks after first prescription. Excluded patients with <365 days

follow-up to exclude prescriptions for terminally ill.

Are ECG monitoring recommendations before

prescription of QT-prolonging drugs applied in daily

practice? The example of haloperidol (continued)

• Adherence to ECG recommendations was extremely low

– In total, 1.8% new haloperidol patients received ECG vs. 0.8% in

control period.

– In patients with known additional QT risk factor(s), only 1.9%

received ECG vs. 1.0% in control period.

– Patients aged ≥45 years more likely to have ECG prior to starting

haloperidol than younger patients

• The first study of its kind to report on ECG monitoring on starting a

known QT-prolonging drug in the population at large.

• Paper suggests that recommendation for baseline ECG should be

revised ( low uptake by clinicians, recognised low risk of cardiac

abnormalities plus QT prolongation is a less than ideal marker of risk

of torsade des pointes/ sudden cardiac death)