December 2017
clinical initiatives, research and current updates in treatment
Medication Shortages John Evans, Slade Pharmacy and Erin Musgrave, Icon Group Pharmacy Practice Unit Medication shortages are a substantial problem for hospitals across Australia resulting in significant implications for patient care, staff resourcing and expenditure.1 The causes for shortages are complex and can be multifactorial (Refer Table 1). The Society of Hospital Pharmacists of Australia conducted a survey on the 4 April 2017 to ascertain the extent of drug shortages in Australian hospitals. The key findings were:1 ¬¬ 100% of respondents (n= 280 healthcare providers) had experienced a medicine shortage in the preceding 12 months ¬¬ 95% of respondents recorded at least one medicine shortage on the survey date ¬¬ Across all respondents 365 different commercial products across 154 different active ingredients were recorded as out of stock ¬¬ Entries covered a wide range of medicine classes; the most frequent recorded shortages were antimicrobials (20%), then anaesthetics/analgesia (12%), cardiology (10%), endocrinology (10%), chemotherapy (9.5%) and neurology (9%) ¬¬ There is a lack of accurate timely information provided by sponsors and wholesalers: –– in 70% of cases, medicines were found to be unavailable only after orders were unable to be filled –– Of the 365 different medicine product shortages reported in the survey, only 54 (14.8%) were reported on Therapeutic Goods Administration (TGA) Medicines Shortage Initiative website on the survey date
–– Information provided on the TGA Medicines Shortages Initiative website on 4 April did not align with reported hospital experience indicating the ‘date of supply’ information was largely inaccurate ¬¬ There is a need for proactive notification of medication shortages to reduce burdensome workarounds ¬¬ Recommendation for a legislative change to enforce the requirement for improved notification of medication shortages from manufacturers or wholesalers to the Federal Government
What is being done to manage medication shortages? 1. There are regulatory processes to enable access to substitute medications from overseas or supply of an otherwise unapproved medication therapy. Unfortunately these additional regulatory and logistical requirements often come at a significant cost increase which is passed on by the sponsors 2. The TGA has established the Medicines Shortages Information Initiative. This web site consolidates manufacturers information regarding current drug shortages and their estimated time of return availability. Unfortunately this is a voluntary initiative and the site has proven to be an unreliable and incomplete record, as was reflected in the recent SHPA survey 3. Wholesalers and manufacturers are now starting to control release of batches of affected drugs to ensure an equitable supply to all facilities
What are our pharmacies doing to manage medication shortages? 1. A dedicated procurement team analyse drug usage data to forecast requirements and manage ongoing supplies and advise where stock may require redistribution across the pharmacy network for equitable access 2. Automatic ‘second sourcing’ to find an available alternative brand to the out of stock drug 3. Identifying alternative sources - where there are no available brands with TGA registration, the procurement team works with agencies to identify overseas registered drugs and make them available under Special Access Scheme 4. Regular Communication: –– Drug-specific memos when supply issues are identified –– Stock status update emails 5. Researching and recommending clinical alternatives: –– The Pharmacy Practice Unit, clinical pharmacists (in consultation with specialist medical staff) provide advice regarding potential alternative treatments Given the multifactorial reasons for the medicine shortages there is no one-simple (or quick) fix. We can expect medicines shortages to remain a serious issue for the forseeable future. The key then is how to effectively handle the issue. A systematic approach to drug shortages when sourcing medications, in tandem with timely and effective communication from manufacturer through to clinical staff, is essential to support optimal patient care. Please contact your local pharmacist for further guidence. References are available on request.
Table 1: Causes of Medication Shortages
Medication Shortage Cause
Explanation
Supply of Raw Materials
¬¬ An increasing proportion of active ingredients is sourced from India and China. This supply has been inconsistent in availability and quality Example: piperacillin/tazobactam injections supply is severely restricted globally because one of the two sources of the active pharmaceutical ingredient had an extensive factory fire and cannot supply until mid-2018.
Quality
¬¬ Failing to meet TGA requirements/specifications ¬¬ Recalls, which then place pressure on the remaining brands in the market Example: recall of multiple batches of gentamicin injections due to excessive histamine content in October 2017 created a short term supply disruption.
Just-in-Time Supply Chains
¬¬ If one part of the manufacturing chain is affected there is little buffer to satisfy market demands ¬¬ Inadequate forecasting of supply requirements Example: Fentanyl earlier in 2017, the contracted supplier to at least three of Australia’s public health services was unable to obtain stock from their international source , forcing other suppliers to increase forecasts and ration / manage stocks for the entire Australian market at short notice.
Manufacturing Problems
¬¬ Issues with equipment, ingredients and packaging causes delay in supply Example: Major hack of Merck computer network as part of the global ransomware attack in June 2017 compromised the supply of the antiemetic aprepitant (Emend ®).
Rationalisation of Manufacturing Plants
¬¬ Company mergers result in closure of plants leading to a reduction in global manufacturing capacity ¬¬ Limited number of manufacturers – despite multiple brands being registered in Australia, a number of these may be produced by the same manufacturer and in the case of batch failure or premises closure, impacts multiple brand unavailability
Low Drug Prices
¬¬ Price discrepancy between regions – suppliers have been shown to prioritise supply to more profitable markets when supply is limited ¬¬ Prices are at such a low point in the Australian market they are ceasing to be viable for manufacturers, who then withdraw from the market for commercial reasons. This leaves the remaining manufacturers left to supply the needs of the market, the volume of which they have not forecast
Excessive Buying
¬¬ When notification of supply issues occurs, a number of larger hospitals/pharmacies reactively purchase one-off excessive quantities of up to 12 months of their normal usage which prevents other customers accessing those products and accelerates the impact of an imminent shortage
References are available on request.
What’s new Surgical Antibiotic Prophylaxis Anthony Fico, Epic Pharmacy Murdoch Surgical site infections (SSI) are one of the most common healthcare associated infections in patients. In Australia, infection of the surgical site occurs in approximately 3% of surgical procedures.1 Their impact leads to prolonged hospital stays, readmissions to the hospital, additional costs, and increased morbidity and mortality.1,2 Surgical antibiotic prophylaxis (SAP) refers to the prevention of infectious complications by administering an effective antimicrobial agent prior to exposure to contamination (due to colonising or contaminating organisms) during surgery. It is used as an adjunct to, rather than a replacement for, other evidence-based
interventions to prevent wound infection, such as the use of skin antiseptics. However, inappropriate use of SAP, in terms of prolonged duration and use of antibiotics with a broader spectrum than necessary, can select for resistant microorganisms, increase risk of adverse effects (such as Clostridium difficile-associated diarrhoea) and lead to higher costs.
that will be encountered. Individual risk factors must also be considered for every patient and may alter dose and drug selection, e.g. immune suppression, presence of prostheses, allergies, obesity, diabetes, infection elsewhere, available pathology or malignancy. Environmental factors such as institution specific resistance patterns may also have a bearing on selection.
General Principles of Surgical Prophylaxis
Appropriate SAP prescribing refers to4:
The type and site of surgery usually determines the need for SAP (Table 1) and drug choice is based on the likely pathogens
¬¬ Correct antimicrobial choice: includes correct medication, route of administration and dosing schedule. Antibiotic selection should be targeted at the most likely
organism to cause postoperative infection. The Australian Therapeutic Guidelines: Antibiotic recommends the avoidance of broad-spectrum antimicrobials, with first generation cephalosporins (e.g. cefazolin) remaining the preferred drug for the majority of procedures that require prophylaxis6 ¬¬ Correct timing of administration: ensures adequate tissue levels of the drug during the operation. Generally the antibiotic should be administered up to 60 minutes prior to skin incision and as a single dose. A second dose may be necessary if –– There is a delay in starting the operation –– A short acting antibiotic is used and the operation is prolonged (longer than 3 hours) –– Significant blood loss ¬¬ Correct duration: for most procedures, it is now only recommended to give one peri-operative dose of antibiotic prophylaxis. Postoperative use is specifically recommended for certain procedures (e.g. cardiac and vascular surgery or amputation of an ischaemic lower limb), however antibiotic prophylaxis should always be ceased within 24 hours of completion of surgery Non-antibiotic measures to reduce the risk of surgical site infection should not be ignored and include: optimal perioperative medical management, mechanical bowel preparation, adequate debridement, and good surgical technique.
SAP in practice Reviews of antimicrobial prescribing practices in Australian hospitals demonstrate that surgical prophylaxis is the most common indication for antimicrobial prescriptions, however approximately 40% of prescriptions are deemed as inappropriate.3,5 The 2015 National Antimicrobial Prescribing Survey (NAPS) survey found the most commonly identified
reasons for inappropriateness as per Figure 1 below5:
¬¬ Educational programs presented to all the surgical teams, including workshops, lectures and discussions
Surgical Prophylaxis: reasons for inappropriate prescribing – naps 2015 Incorrect duration Incorrect dose Antimicrobials not required Other
30% 28% 22% 20%
Antimicrobials prescribed for treatment of infection had a higher proportion of appropriateness when compared with antimicrobials prescribed for surgical prophylaxis (80.4% vs 40.6%).3 Studies recommend a concerted effort tackling inappropriate SAP prescribing would have the greatest effect on improving antimicrobial overuse.3,7
Factors affecting inappropriate SAP3,8: Prescriber adherence to SAP guidelines may be hindered by: ¬¬ Lack of awareness of appropriate guidelines due to ineffective distribution ¬¬ Lack of consensus with the recommendation in the guidelines ¬¬ Perceptions that prescribing antibiotics for their patients would not contribute to antimicrobial resistance ¬¬ Misconception that broad-spectrum or multiple antibiotics and prolonged therapy are more effective in preventing surgical site infection when compared to a short course of a narrow spectrum antibiotic ¬¬ Poor documentation of the indication for antimicrobial prescribing Findings from studies concluded that although positive attitudes towards guidelines are shown, the impact on prescribing practices are limited.8 Strategies to enhance improved adherence to appropriate SAP should be multi-factorial including8:
¬¬ Improved availability of guidelines such as access on all computers, posters in theatre, lanyard-sized guides ¬¬ Review of current facility SAP guidelines by a multidisciplinary team including a surgical, anaesthetic, infectious disease physician/microbiology specialties. Guideline development should follow the Therapeutic Guidelines, however local issues such as antimicrobial resistance patterns may cause deviation. All local guidelines should be evidence based and endorsed by relevant hospital committees with regular review ¬¬ Consider restriction of broad spectrum antibiotics on imprest in operating rooms. Restricting supply of cefazolin to 2g vials may reduce the chance of under dosing ¬¬ Computerised decision support systems aimed to assist in correct antibiotic selection ¬¬ Audit of SAP (e.g. Surgical National Antimicrobial Prescribing Survey) with data, analysed and communicated to the surgical teams Correct management of SAP significantly improves patient outcomes and ensuring the use of narrow spectrum antimicrobials (targeted at likely infective organisms) for the appropriate duration can mitigate the risk of resistance and adverse effects. Once an antimicrobial stewardship (AMS) program is established in a healthcare facility, a focus on activities to improve SAP prescribing may provide the greatest benefit to tackle inappropriate antibiotic use. On a broader scale the Commission will be working with key stakeholders, including the Royal Australasian College of Surgeons and National Centre for Antimicrobial Stewardship, to identify strategies and policies that can be implemented at the local, state and territory, and national levels to improve appropriate SAP.7 References are available on request.
Table 1: Classification of surgical procedures according to infection risk and requirement for surgical prophylaxis9,10
Type of surgery
Definition
Examples
Indication for SAP
Clean Surgery
Healthy skin incised Mucosa of respiratory, alimentary, genitourinary tract and oropharyngeal cavity not traversed
Herniorrhaphy, mastectomy, cosmetic surgery
Not recommended
Insertion of prosthesis or artificial device
Hip replacement, heart valve
Recommended
Respiratory, alimentary or genitourinary tract is penetrated under controlled conditions without unusual contamination
Laryngectomy, uncomplicated appendectomy, cholecystectomy, transurethral resection of prostate gland
Usually recommended
Macroscopic soiling of operative field
Large bowel resection, biliary or genitourinary tract surgery with infected bile or urine
Recommended
Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera
Excision and drainage of abscess, perforated bowel, peritonitis, ruptured appendix
Recommended
(Class I)
Cleancontaminated (Class II)
Contaminated (Class III)
Dirty or infected (Class IV)
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What’s New Entresto® (sacubitril with valsartan) Emily Pacecca, Epic Pharmacy Murdoch and Shan Heynes, Icon Group Pharmacy Practice Unit Entresto® is a combination of a firstin-class neprilysin inhibitor (sacubitril) and an angiotensin receptor blocker (valsartan), indicated in adults for the treatment of chronic heart failure (Class II – IV) with reduced ejection fraction.1,2 It is usually administered with other heart failure treatments, in place of an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).1 Evidence is currently insufficient to recommend Entresto® as a first-line treatment for heart failure.3 Sacubitril prevents neprilysin from deactivating natriuretic peptides, whilst valsartan blocks the renin-angiotensinaldosterone system thereby promoting vasodilation and diuresis, and reducing myocardial fibrosis and hypertrophy4 (refer Figure 1).
Precautions Entresto® should not be used in patients with a known history of angioedema related
to ACE inhibitor or ARB use. Treatment with an ACE inhibitor must be stopped 36 hours prior to commencing Entresto® to reduce the risk of angioedema.2,3 Entresto® is also contraindicated in patients with severe hepatic impairment and pregnancy.2,3 Some common adverse effects of Entresto® are hyperkalaemia, renal impairment, dizziness, and cough.3 Hypotension is also a common adverse effect and the risk of it occurring is higher in patients ≥ 75 years, patients with low baseline systolic blood pressure (SBP <112 mmHg), patients with renal disease and those being treated with high doses of diuretics. When initiating treatment or during dose titration with Entresto®, blood pressure should be monitored routinely.2 Entresto® interacts with potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), increasing serum potassium, therefore potassium level monitoring is recommended if these drugs are used together. Entresto® may also interact with nonsteroidal anti-inflammatory drugs
Figure 1: Entresto® mechanism of action5 Beneficial Physiological Response Natriuretic Peptide System
Natriuretic Peptides
Pathophysiological Response Damaged heart with CHF
NE PR SI ILY
Sacubitril
Renin-AngiotensinAldosterone System
Valsartan
Angiotensin-II
AT1 receptor
N
Inactive fragments
Vasodilation BP Sympathetic tone Aldosterone
Vasoconstriction Natriuresis/Diuresis Fibrosis Hypertrophy
BP Sympathetic tone Aldosterone
Fibrosis Hypertrophy
(NSAIDs) increasing the risk of renal impairment; monitoring of renal function is required on initiation of Entresto® and with dose changes. Careful monitoring of serum lithium levels is recommended for patients on Entresto® with lithium as increased lithium concentrations and toxicity have been reported with other ACE inhibitors and ARBs.
Dosing Entresto® is available as sacubitril/ valsartan 24mg/26mg, 49mg/51mg and 97mg/103mg tablets. Note: 26mg valsartan in Entresto® is equivalent to 40mg valsartan in other products3 due to the valsartan contained within Entresto® being better absorbed by the body than the valsartan in other marketed products.2 Dosing usually starts at 49mg/51mg twice daily, doubling after two to four weeks to a target maintenance of 97mg/103mg twice daily, as tolerated.2 A lower starting dose of 24mg/26mg twice daily should be considered for those with risk factors for hypotension (SBP 100-110 mmHg), patients not currently taking an ACE inhibitor or ARB, or on a low dose of these agents, elderly patients, and patients with severe renal impairment or moderate hepatic impairment.2,3 In a large clinical trial, Entresto® proved to be superior to treatment with an ACE inhibitor alone, however there are some limitations with the study that warrant further investigation: the comparator ACE inhibitor was not at maximal tolerated dosing, and a patient who completed the study may not be representative of the general heart failure population. There are numerous other clinical trials underway or in development at the moment. This novel treatment may become first-choice therapy in the future however, at this stage, available evidence only supports its use in patients stabilised on an ACE inhibitor or ARB, in combination with other heart failure medications.6 References are available on request.
If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: circuit.editor@epicpharmacy.com.au Every effort has been made to ensure this newsletter is free from error or omission.
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