More than 20,000 attendees gathered in Orlando, Florida in December 2013 for the American Society of Health-System Pharmacists Midyear Clinical Meeting. Topics included chemotherapy dosing, opioid safety and compounding
Laurence Goldberg FRPharmS
Editorial Consultant, HPE
Christine Clark PhD FRPharmS FCPP(Hon)
Editor, HPE
Keynote speaker Mark Ratain (Professor of Medicine – Haematology/Oncology, University of Chicago, US) urged pharmacists to use their critical thinking skills when evaluating the dosage and administration of cancer chemotherapy. “Don’t believe everything you read – sometimes you have to do your own due diligence”, he said.
Widely-accepted notions about cancer drugs are often wrong, said Professor Ratain. These include the view that chemotherapy doses should always be individualised on the basis of body surface area (BSA), the belief that labelling for the drugs is reliable, and the idea that patients are too sick to take oral cancer drugs with food.
Drugs are tested in early trials using BSA-based dosing because of concerns about potential toxicity. BSA-based dosing is then incorporated into drug labels and the calculated doses can leave compounding pharmacists with the problem of deciding whether to round up or down to the nearest whole vial or open another vial. However, BSA-based dosing correlates poorly with the area under the concentration–time curve (AUC) for most anti-cancer drugs, explained Professor Ratain. In fact, he argued, being over-focussed on a precise rather than an accurate dose could mean that a consistently wrong dose is always given. Dosage calculations based on renal function can also be problematic. When the standard method for estimating serum creatinine changed to isotope dilution mass spectrometry (IDMS), which gives lower levels than previous methods, reports of carboplatin toxicity started to rise. Some of the methods for calculating creatinine clearance, for example, the Modification of Diet in Renal Disease (MDRD) formula, were simply not designed for drug dosing, he noted. “Anybody who is worried about rounding a dose by 10% does not understand the intrinsic inaccuracy of the calculation”, he said.
Recommendations about the effects of food in the labelling of anti-cancer drugs do not always make sense, said Professor Ratain. For example, lapatinib is often taken with capecitabine but the lapatinib is labelled to be taken on an empty stomach and capectitabline should be taken with food. In fact, the bioavailability of lapatinib increases markedly with food. Indeed, taking lapatinib with food could lead to savings of $1700 per patient per month or more, as much lower doses would be needed, suggested Professor Ratain. Curiously, 23 drugs are associated with marked food effects and, of these, the oncology drugs are labelled to be taken fasting while the others are labelled to be taken with food. Abiraterone is another example – in practice, most of the dose is flushed down the toilet, he said. Nilotinib bioavailability is also markedly increased with food and its labelling is even more dramatic – it warns that sudden death (due to QT prolongation) is possible if the dose is taken with food. “It would have been better to label it for use in a lower dose with food”, he said.
Professor Ratain concluded that BSA-dosing is not accurate and clinicians should focus more on accuracy rather than precision in the interests of patient safety. “Medical colleagues need a lot of help thinking about patients holistically”, he added. He also said that the labelling of oncology drugs in relation to food intake may be counter intuitive or even dangerous and physicians, pharmacists, nurses and patients need more education in this area to reduce the risks of adverse events.
Pharmacist prescribing
Pharmacists in most provinces in Canada can now undertake prescribing, subject to local legislation. Describing the scope and development of pharmacist prescribing, Janet Cooper (Senior Director, Professional and Membership Affairs, Canadian Pharmacists Association, Ottawa, Ontario, Canada) said that pharmacists in Canada are not required to have rigorous specialty training in order to become prescribers.
Pharmacist prescribers can now order medicines to treat minor illnesses. For example, in Nova Scotia they can prescribe for a range of conditions, including minor sleep disorders, mild-to-moderate eczema, impetigo and dysmenorrhoea, and prescribe emergency contraception. In addition, they can monitor and authorise refills of existing prescriptions for long-term treatment, modify or adapt prescriptions, complete missing information on prescriptions, and provide emergency supplies of prescribed medicines, if required. Among other things, they can also undertake comprehensive drug therapy management, where the pharmacist, working with other health professionals, takes full responsibility for establishing and maintaining a patient’s chronic drug therapy. These developments enjoy strong support from the general public in Canada.
In Alberta, all pharmacists on the Alberta College of Pharmacists’ clinical register may amend prescriptions and prescribe in an emergency but only those who meet specific requirements, which may call for additional training, may initiate prescriptions or prescribe to manage ongoing therapy. Such individuals are granted ‘Additional Prescribing Authorization’ (APA). About 10% of pharmacists in Alberta have the APA, said Ms Cooper.
When the prospect of pharmacist prescribers was first raised there was considerable opposition from the Canadian Medical Association. However, in recent years this has changed and collaborative working is now welcomed. “What we need now is pharmacists at the frontline delivering these services – the money is there to pay them, said Ms Cooper. The main barrier to further adoption of the expanded scope of practice is pharmacists’ own confidence in themselves, she concluded.
In the US, the best-developed model of pharmacy practice is that of the Veterans’ Health Administration (VHA) – the system that provides healthcare for military veterans and their families. Rita Shane (Chief Pharmacy Officer, Cedars-Sinai Medical Center, Los Angeles, California) explained that, in the VHA, system pharmacists with direct patient care responsibilities may prescribe medications and this includes initiation, continuation, discontinuation, monitoring and altering therapy, based upon established formulary or protocols. They may also order, perform, review or analyse laboratory tests and diagnostic studies. Prescribing pharmacists have disease-specific scope of practice, she added.
In California, the Senate has enacted a law that allows pharmacists to study for the designation, Advanced Practice Pharmacist. Such pharmacists are authorised to perform assessments and prescribe in collaboration with other healthcare team members. At Cedars-Sinai Medical Centre, there was increasing demand for therapy-specific protocols. “Basically, physicians write the orders for pharmacists to manage”, explained Dr Shane. Currently, some 400 patient days per month are managed in this way, involving patients who require anticoagulation, antimicrobial therapy or anti-emetic treatment. The service is growing progressively as more areas of need are identified. It has been important to emphasise the interdependent and collaborative nature of the work and avoid terms such as ‘independent prescribing’ that could be alarming to physicians, said Dr Shane.
In the UK, a survey in 2010 showed that about 3% of the pharmacist workforce was qualified to prescribe, according to Claire Anderson (Professor of Social Pharmacy, University of Nottingham, UK). The study also showed that pharmacist prescribing was safe and clinically appropriate and well-accepted by the majority of patients.
The training for pharmacists who wish to become prescribers involves 26 days of classroom teaching and 12 days of practice under the supervision of a prescriber, who is usually a doctor. Those who have completed the training are know as independent pharmacist prescribers, although they almost always work as members of healthcare teams. A single competency framework has been developed for all prescribers – doctors, nurses and pharmacists. This sets out the aspects of practice that make up ‘good prescribing’ and that all prescribers are expected to follow.
Uptake of the prescribing qualification has been variable. One hospital trust requires all its pharmacists to undertake the training and 40% of all prescribing in the hospital is now carried out by pharmacists. In some hospitals, pharmacists only prescribe for patients with complex medication regimens. In primary care, many pharmacists have now demonstrated their ability to be good prescribers, and one pharmacist has even become a partner in a family doctor practice, said Professor Anderson.
Safe use of opioids
Voluntary error reporting does not tell the whole story when assessing the safe use of opioids, according to Matthew Fricker (Program Director, Institute for Safe Medication Practices, Philadelphia, US).
He noted that 47% of opioid-related sentinel events were the result of ‘wrong dose’ errors. The main causes or contributory factors were lack of knowledge about equi-analgesic potencies, improper prescribing, especially for acute care of post-operative patients, and failure to consider patients comorbidities and current opioid use. Healthcare staff were often unsure about the criteria for opioid tolerance and there was a clear knowledge gap about equi-analgesic doses of different opioids, he said.
A rising number of reports of patient harm due to accidental overdosage with hydromorphone prompted the Institute for Safe Medication Practices (ISMP) to undertake a project in nine local hospitals to examine the causes and implement solutions.
One key finding was that many staff were unable to identify opioid-tolerant patients. Another finding was that most of the staff surveyed were unaware that 1mg hydromorphone is equivalent to 7mg morphine. One emergency department physician believed the potency ratio was 1:1 and some healthcare professionals believed that hydromorphone was the generic name for morphine. ISMP recommends that 2mg and 4mg hydromorphone dosage forms should be removed from ward stocks and be replaced by a 0.5mg dosage form.
When adverse drug events were analysed, almost one-fifth involved the use of potentiating drugs, although the majority of staff claimed to be aware of drugs that could increase the effects of hydromorphone. Moreover, baseline data showed that many patients who received hydromorphone required rescue treatment or were the subject of rapid response calls. On several occasions, hydromorphone was prescribed on two-hourly or three-hourly dosing schedules. Staff may have been unaware that hydromorphone has a longer half-life than morphine, commented Mr Fricker.
A number of measures were implemented as a result of the project including modification of computerised and paper medication order sets, introduction of starting doses of 0.25 and 0.5mg hydromorphone and eliminating two- and three-hourly dosing schedules. In addition, a presentation was given to emergency department physicians on ‘understanding hydromorphone’. A subsequent survey showed that the frequency of rescue treatment for patients receiving hydromorphone had fallen by 50%.
Mr Fricker also noted that adverse events could arise because of failure to use smart pumps and drug libraries with hard stops for hydromorphone patient-controlled analgesia. Such events would not be identified through voluntary reporting.
Review of high-risk opioid prescriptions and assistance with opioid conversion calculations are tasks that pharmacists should be undertaking, Maria Foy (Pharmacy Clinical Specialist, Palliative Care, Abington Memorial Hospital, Philadelphia, US) told the audience. One area of concern is analgesic treatment for post-operative patients. Multimodal treatment is often used for these patients and is important to ensure that effective systems are implemented. Pre-existing sleep apnoea is a risk factor for postoperative respiratory depression and patients must be screened for this pre-operatively, said Dr Foy. Pulse oximetry cannot be used to identify respiratory depression because most post-operative patients are receiving oxygen. “Capnography is the way to go”, she said.
The presence of pinpoint pupils is still a useful clinical sign of overdose, but it should be remembered that sepsis can also cause patients to become drowsy. As much as 50% of naloxone use can be inappropriate if this is overlooked. In one case, a dying patient had been given a dose of naloxone for incorrectly diagnosed opioid overdose and died six hours later with diarrhoea. Small doses should be given to reverse respiratory depression without reversing the analgesic effects, she explained.
Pharmacists should recommend appropriate opioid medication based on patient-specific factors and should verify dose conversions, especially when a new drug is prescribed or the route of administration is changed. They should also verify that the medication prescribed is appropriate for the level of pain that the patient is experiencing, recommended Dr Foy.
Hazardous drugs
A new chapter in the United States Pharmacopeia (USP) – Chapter 800 – is now in development. Speaking at a satellite meeting sponsored by BD, Cynthia Reilly (Director Medication Safety and Quality Division, ASHP, Bethesda, Maryland, US) explained that this will focus on the handling, preparation and manipulation of sterile and non-sterile preparations. The goal of this initiative is to harmonise the current guidelines from ASHP and other bodies. USP chapters with numbers under 1000 are considered to be enforceable, she added.
Currently, the University Healthsystem Consortium (UHC) Consensus Statement provides detailed practical recommendations to minimise occupational exposure to hazardous drugs. The UHC is an alliance of 120 academic medical centres and 299 of their affiliated hospitals in the US. The consensus statement recognises the limitations of existing guidelines and attempts to reconcile the ‘grey areas’. It ranks the risks of hazardous drugs into low-, medium- and high-risk categories, with corresponding control and protection measures. It also contains advice on a range of topics that are often overlooked by other guidelines, including patient transport and room signage, said Ms Reilly.
Using a tool to identify hazardous drug safety gaps in an institution can be helpful, according to Fred Massoomi (Pharmacy Operations Coordinator, Nebraska Methodist Hospital, Omaha, Nebraska, US). In addition, Dr Massoomi recommended doing ‘hazardous drug rounds’. This involves following a dose from the pharmacy to the ward and observing the administration and disconnection procedures to see how this is done in practice.
The issue of ‘second-hand chemo’, a term used to described the exposure of relatives and healthcare personnel to cytotoxic drugs as a result of leaks and spillages, has been widely publicised. However, a survey in 2013 showed that only 13% of pharmacies conduct wipe sampling for hazardous drug residues in their compounding areas. Dr Massoomi also drew attention to the many situations where cytotoxic drugs are used outside oncology units, where staff are often less familiar with the types of safety measures required.
These include surgical procedures involving cytotoxic bladder instillations, topical use of cytotoxic products in ophthalmic and oesophageal surgery, and the use of a cytotoxic agent in the management of ectopic pregnancy.
Turning to the preparation of cytotoxic doses, Dr Massoomi said that, at present, the market is dominated by the first generation of ‘monster robots’ but, in future, smaller robots would become the norm.
Most occupational exposure to hazardous drugs could be eliminated if staff would wear gloves when handling the products and observe a ban on the consumption of food and drinks in the hazardous drug work area, Alex Truchot (Senior Environmental Health and Safety Manager, Seattle, Washington, US) told the audience. “Unions should be fighting to stop coffee and food in work areas”, he said. Staff should also pay careful attention to hand washing, before donning gloves, after removal and wherever hands are contaminated. Soap and water is adequate for this, he said.
In 2012, Washington State passed a law to ensure the safe handling of hazardous drugs including the prevention of occupational exposure. The law will apply to all employers in healthcare facilities, regardless of setting, where employees may be exposed to hazardous drugs in the course of their work. Full implementation of the law will occur over the next two years The Washington hazardous drugs initiative is regarded as a model for other States in the US.
CSTD extends shelf life
The ONGUARD™/Tevadaptor (Teva) closed system transfer device (CSTD) successfully maintains both microbiological sterility and physical and chemical drug product integrity over an extended period of 28 days and can therefore be used to extend the shelf life of compounded drugs, according to a study presented by Alan-Shaun Wilkinson (Director of Research and Development, Biopharma Stability Testing Laboratory Ltd, Nottingham, UK). The results showed that there is no microbiological growth and that compounded cisplatin remains unchanged after the 28-day study period. Studies with paclitaxel and methotrexate are ongoing and the work is likely to be extended to include other high-cost drugs, such as trastuzumab.
BOX 1:
Colin Powell: Keynote address
General Colin Powell, US (Ret.) was the keynote speaker at the ASHP Midyear Clinical Meeting.
In his address he paid tribute to the tireless work of pharmacists in the VHA. His wife had recently undergone surgical treatment in a VHA hospital and he commented that the teamwork had been impressive. Reflecting on the disparate nature of the US healthcare system he said, “The US should be able to care for all its citizens – other nations, for example, SouthKorea, are bewildered.”
Concerning pharmacy, he said that there was a need to change the image of the pharmacist as someone who sits behind a screen counting tablets. “We need to see freeing-up of senior pharmacists to get out and talk to patients”, he urged.
