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National Medication Safety
Network
24th June 2015
Observatory of recent safe medication
bulletins, practice research, reports, and
publications
Presented by Samantha Owen,
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)