March 2017
clinical initiatives, research and current updates in treatment
Deprescribing Elke Fisher, Epic Pharmacy Greenslopes Two thirds of all Australians aged 75 and over and half of those aged between 65 and 74 take 5 or more medications every day.1 Whilst these medications may be considered necessary, taking multiple medications does not come without risk. 1 in 3 people, taking 5 or more medications, experience an adverse drug reaction (ADR) annually. More than one quarter of these ADR’s are considered preventable.2 The number of prescribed medications is emerging as the single most important predictor in the risk of ADR’s in older patients.3 The risk of an older person having an ADR is estimated to increase from 10% to 75% as the number of medications taken concurrently increases from 1 to 5 or more.4 More specifically, the risk of an older person having an ADR-related hospitalisation increases by 24% with each additional drug.4 One study focused on community dwelling older Australian men found taking 4.5 medicines concurrently was associated with an increase in falls and mortality, 5.5 medicines with disability and 6.5 medicines with increased frailty.5 Deprescribing has been defined as “the systematic process of identifying and discontinuing potentially inappropriate drugs with the aim of minimising
polypharmacy and improving patient outcomes”.6 Numerous events, such as increased frequency of falls, delirium, cognitive impairment, terminal illness and extreme frailty can all be triggers to deprescribing. Any older patients presenting with a new symptom or suspected of having an ADR, should be considered a candidate for deprescribing. Deprescribing is an essential component of the appropriate prescribing continuum, involving medicine initiation, review, dose titration, cessation or a complete medication change. It is not denying patients’ access to appropriate medications.3 Evidence based deprescribing involves systematically reviewing all medications, determining if a medication is considered of high or low utility, identifying and documenting any medications without a current indication and assessing the likelihood of misuse, toxicity or nonadherence, all within the context of each individual patient. Only one agent is to be ceased or reduced at a time. The “CEASE” deprescribing framework is explained in table 1.3 Providing an explanation to the patient of the rationale for deprescribing (i.e. reducing unnecessary medications that have
Table 1. CEASE deprescribing framework3
C E A S E
Current medications Elevated risk
Identify all of the patient’s current medications and their indication.
Assess
Determine the risk benefit ratio for each medication.
Sort
Identify possible medications for discontinuation, prioritizing those which are easy to discontinue and considered to be of minimal benefit. Patient preferences also need to be considered.
Eliminate
Implement a discontinuation plan and monitor patients closely.
Ascertain the risk of the patient experiencing an ADR, taking into consideration factors such as age, total number of medications, the presence of any high risk medications and specific patient characteristics.
minimal benefit or the potential to cause harm) increases the chance of success and empowers the patient to take better control of both their health and medications.6 Qi et al found if the doctor recommended stopping one or more of their medications, 89% of patients would be willing to trial it.7 Despite finding most patients are in favour of deprescribing, the following barriers may be encountered:6 ¬¬ Prior negative experience with drug withdrawal (e.g. rebound insomnia after ceasing a benzodiazepine) ¬¬ Anxiety and fear associated with the consequences of stopping a long term medication ¬¬ Reluctance to stop or reduce a medication the patient believes may prolong life or be of benefit ¬¬ A perception the patient is no longer worth treating i.e. the prescriber has given up A pilot study investigating deprescribing in 50 older patients (mean age 82.5 years) found it was possible to cease 186 of 542 regular medications (34.3%). 94% of participants had their medication load reduced by at least 1 and 50% by 4 or more.8 The most common discontinued medications were:8 ¬¬ Nitrates [8/11 (73%)] ¬¬ Inhaled bronchodilators [14/20 (70%)] ¬¬ Oral hypoglycaemics [9/15 (60%)] ¬¬ Antihypertensives other than ACE Inhibitors/Angiotensin Receptor Blockers [10/17 (59%)] ¬¬ Statins [21/37 (57%)] ¬¬ Benzodiazepines [8/15 (53%)] Continued on page 4
Anti-HER2 Receptor Therapies in Breast Cancer Nick McGraw, Icon River City Pharmacy Human epidermal growth factor receptor, HER2, over-expression is present in approximately 20–30% of breast cancer tumours. HER2 over-expression is associated with a more aggressive disease, higher recurrence rate, and shortened survival.1 HER2 is part of the epidermal growth factor (EGF) family, along with 3 other receptors: epidermal growth factor receptor (HER1, erbB1), HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4).2 The introduction of targeted therapy against HER2 has significantly changed the prognosis of patients with HER2 positive breast cancer. Trastuzumab, which has become the standard of care, significantly improves overall survival in patients with HER2-positive early breast cancer3 and HER2-positive metastatic breast cancer (MBC).4 Yet, despite the proven efficacy of trastuzumab plus chemotherapy, some patients with HER2-positive breast cancer do not respond, and the disease in the majority of patients with MBC progresses within 1 year. The medical need for targeted therapy in advanced disease has been recognised and recent PBS changes have seen the inclusion of pertuzumab and trastuzumab-emtansine to the treatment landscape. The mechanism of action of Trastuzumab is perceived to be through both innate and adaptive immunities. Innate mechanisms lead to cell cycle arrest, with a noted increase in p27 (cell cycle suppressor) levels, and decrease in cyclin D1 and cyclin-dependent kinase 2 (causes of proliferation).5 Trastuzumab alone does not seem to promote a significant level of cell death, but is synergistic with most chemotherapeutics. This synergism is felt in part to be explained by inhibition of the PI3K/Akt signalling pathway, which normally promotes cell survival.6 However, the innate response alone does not fully explain the effect of trastuzumab on tumour regression. Adaptive mechanisms are also present. Trastuzumab recruits immune cells to tumour sites that overexpress HER2, by a mechanism called antibody dependent cell-mediated cytotoxicity. This is likely to be T-cell mediated and leads to increased cell death.7 The HER2 receptor extracellular domain has no identifiable ligand, unlike the other EGF family receptors. It is present in an active conformation and can undergo ligand-independent dimerization (binding)
with other EGF receptors.8 The most active and tumour promoting combination is thought to be the HER2/HER3 dimer.9 Pertuzumab is a monoclonal antibody that binds to a different site on the extracellular domain of HER2 than trastuzumab. Pertuzumab blocks ligand-induced dimerization of HER2 and HER3.10 Preclinical experiments show that pertuzumab is effective in disrupting HER2–HER3 heterodimers, leading to inhibition of downstream cell signalling, and anti-tumour activity.11 The use of combined HER2 blockade with trastuzumab and pertuzumab in breast cancer enhanced tumour regression for the combination over monotherapy. In addition, the combination also demonstrated antitumour activity in models of trastuzumab resistance, suggesting that trastuzumab and pertuzumab have complementary mechanisms of action.12 Inhibition of HER2 signalling with combined HER2-targeting antibodies has shown clinical activity in patients with metastatic breast cancer with progression on trastuzumab-based therapies.12 Pertuzumab is listed on the PBS for first line treatment of metastatic breast cancer, in combination with trastuzumab and a taxane. The PBS listing came on the back of the successful Cleopatra trial. The results of this trial showed a median progression-free survival of 12.4 months in the control group, as compared with 18.7 months in the pertuzumab group. The analysis of overall survival also showed a strong trend in favour of the pertuzumab group (56.5 compared to 40.8 months). The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhoea of grade 3 or above were higher in the pertuzumab group than in the control group.13 Therefore, similar monitoring to that of trastuzumab is required, but patients should also be advised to report signs of diarrhoea to their doctor. In an attempt to improve the potency of trastuzumab therapy, an antibody–drug conjugate has been designed to utilise the antibody to deliver cytotoxic therapy to antigen-expressing tumours. Trastuzumab has been conjugated to DM1, a derivative of emtansine 1, a potent microtubule inhibitor, to create the trastuzumab– emtansine conjugate (TDM-1). Potent anti-tumour activity of TDM-1 was seen in
trastuzumab-refractory HER2-amplified cell lines.14 The Phase I trial of TDM-1 monotherapy in patients with HER2-amplified metastatic breast cancer with prior trastuzumabbased therapy described the maximum tolerated dose to be 3.6 mg/kg every 3 weeks. Dose limiting toxicity was grade 3–4 thrombocytopenia; common drugrelated adverse events included fatigue, nausea and elevated transaminases, while no significant cardiotoxicity was noted. Phase II evaluation of TDM-1 demonstrated a response rate of 32.7% in patients with metastatic HER2-amplified breast cancer with prior anthracycline, taxane, capecitabine, trastuzumab and lapatinib therapy.14 TDM-1 was added to the PBS for metastatic breast cancer on the back of the successful EMELIA trial. To be eligible, metastatic patients must have progressed on pertuzumab and trastuzumab or have progressed within 6 months of completing adjuvant trastuzumab treatment. In the EMELIA trial, of the 991 randomly assigned patients, median progression-free survival was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine and median overall survival at the second interim analysis demonstrated superiority in the TDM-1 group. The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001). Rates of adverse events of grade 3 or above were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhoea, nausea, vomiting, and hand-foot syndrome were higher with lapatinib plus capecitabine.15 Overall, TDM-1 is a better tolerated alternative than capecitabine plus lapatinib, but blood counts and LFTs should be closely monitored. The landscape of treatment for HER2positive breast cancer is rapidly evolving. The incorporation of anti-HER2 targeted agents as part of the standard of care for HER2-positive MBC has led to dramatic improvements in outcome for patients with this aggressive disease. The introduction and availability of novel agents now offer clinicians the ability to provide a more robust and durable inhibition of the HER2 pathway across multiple lines of treatment. References are available on request.
What’s new IV to Oral Switch Briony Davidson, Epic Pharmacy Hollywood
Why switch? On any given day, 38.4% of patients in Australian hospitals are prescribed at least one antibiotic.1 Switching from intravenous to oral administration of antibiotics reduces the risk of potentially serious complications, including thrombophlebitis and catheter related infections, which can progress to sepsis. The oral method of administration is also likely to be preferred by the patient, and reduces the amount of nursing time required to prepare the medication for administration.2,3 Oral administration also reduces the cost to the hospital, due to the costs of the IV medication, needles, diluents and nursing time. The patients may also be able to leave the hospital earlier and complete their course of oral antibiotics at home, which is associated with reduction in both direct and indirect costs of disease.2,4
When to Switch It is important to identify patients who are appropriate candidates for switching to oral formulations. In some cases, switching to oral therapy may not be appropriate. For example, some types of infections require very high tissue concentrations for effective treatment and therefore require extended therapy with IV antibiotics like endocarditis, meningitis, deep abscesses, or infections in the bones or joints.3 Furthermore, life-threatening infections such as febrile neutropenia, or hospital acquired infections, require prolonged courses of IV antibiotics. In addition, IV antimicrobial therapy recommended by a specialist infectious diseases team should continue until advised to change to oral form by the team. Furthermore, some patients have compromised oral absorption of medications, which may reduce the effectiveness of oral antibiotics. Patients with severe nausea, vomiting or diarrhea, with a short gastrointestinal (GI) transit time, active GI bleeding, or paralytic ileus are likely to have compromised ability to absorb medications, and therefore may not be able to achieve therapeutic concentrations with oral therapy. Other patients may not have oral access — for example, oral therapy may not be possible
for patients who are strictly nil by mouth, who have nasogastric tubes with continuous suction, or who refuse oral therapy. In these cases, it is not practical to switch to oral therapy.3 In addition, if patients have continuous enteral feeding that cannot be interrupted, medications that should be given on an empty stomach to optimise absorption (e.g. ciprofloxacin, rifampicin) are not good candidates for oral switch.3 Switching to oral therapy is appropriate when a patient does not have any of the contraindications described above, has had at least 48 hours of IV therapy, has negative blood cultures and is displaying clinical signs of improvement. Patients should be afebrile for at least 24-48 hours before switch is considered, and should be vitally stable, with no tachycardia, hypotension or tachypnoea. Blood tests should also be taken to confirm C-Reactive Protein (CRP) is reducing, and that white cell count (WCC) is between 4 and 12 x109/L .2,3,5 Patients who do not display clinical stability should continue on IV therapy and be reassessed in 24 hours for eligibility to switch.2,4 Examples of common infections that are good candidates for IV to oral switch include pneumonia, skin and soft tissue infections, urinary tract infections and uncomplicated gram negative bacteraemia.2
Choosing an Appropriate Oral Option It is important to ensure an appropriate oral antibacterial is available before switching. This may or may not be the same drug the patient was receiving intravenously, and may or may not require dosage adjustment. If an oral formulation of the IV antibiotic is available, it will usually be an appropriate choice for oral switch. However, in some cases, low bioavailability may mean it is not suitable. For example, vancomycin is often used intravenously to treat serious systemic gram-positive infections. An oral form of vancomycin is not absorbed orally and it is available for the treatment of C. difficile, and therefore should never be prescribed to treat systemic
A mnemonic that can be used to aid in choosing an appropriate antimicrobial is ‘MINDME3’.
M I N D M E
Microbiology guides therapy where possible Indications should be evidence based Narrowest spectrum therapy required Dosage individualised to the patient and appropriate to the site and type of infection Minimise duration of therapy Ensure monotherapy in most cases/Ensure oral therapy used where clinically appropriate
infections.6 When there is no suitable oral formulation of the same antibiotic available, it is usually still possible to switch to oral therapy using another agent. The selected oral antibiotic should cover the same proven or suspected pathogens, whilst retaining the narrowest spectrum possible.3 When changing from IV to oral forms of the same drug, dosage adjustment may be required. For some agents with high oral bioavailability or high tissue distribution (fluconazole, linezolid, moxifloxacin, azithromycin)3,4 little to no dosage adjustment may be required. For other antimicrobials with lower bioavailability, oral dosage may need to be higher in order to reach therapeutic concentrations at the site of infection e.g. ciprofloxacin. Doses prescribed should be based on guidelines where available, and individualised for the indication and to the patient’s renal and liver function.3 Some recommended dosage adjustments can be found in the table on the next page. References are available on request.
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Mirabegron (Betmiga) Rachel Taylor, Epic Pharmacy Port Macquarie micturition frequency and/or urgency incontinence in patients with overactive bladder (OAB) syndrome.3
Symptoms of overactive bladder can include urgency, increased frequency, nocturia and incontinence. The condition appears to occur equally in men and women and prevalence increases with age. Muscarinic receptors predominate in the bladder. Excitation of the parasympathetic nerves releases acetylcholine and results in bladder emptying. Antimuscarinic medications (such as oxybutynin) act by blocking the action of acetylcholine on bladder smooth muscle.1 Unfortunately antimuscarinic medications can also cause a number of side effects such as dry mouth, gastrointestinal upset, and blurred vision.
Whilst the clinical efficacy of mirabegron has been assessed by clinical trials as being as or slightly more effective than some antimuscarinics agents, there is a lack of head to head clinical studies showing which is the best available treatment for overactive bladder. Mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolised by CYP2D6 enzyme such as metoprolol, desipramine, thioridazine, flecainide and propafenone is increased when coadministered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.3 In addition, patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered, serum digoxin
Mirabegron is not an antimuscarinic medication. Instead it has its action by relaxing bladder smooth muscle through stimulation of beta 3 adrenoceptor.2 Mirabegron is indicated for symptomatic treatment of urgency, increased
concentrations should be monitored and dose adjusted accordingly.3 The most commonly reported side effects of mirabegron are hypertension, nasopharyngitis, urinary tract infection and headache.2 These are different from the commonly reported side effects of the antimuscarinic drugs which include dry mouth, gastrointestinal upset, drowsiness, and blurred vision. The recommended starting dose is 25mg once daily, which may be increased to 50mg daily. It can be taken with or without food. Mirabegron is a possible alternative agent to Oxytrol patches in patients with overactive bladder. It is currently not PBS listed but is available as a private prescription. References are available on request.
IV to Oral Switch Continued from page 3 Figure 1: South Australian Expert Advisory Group on Antibiotic Resistance (SAAGAR). Clinical Guideline: intravenous to oral switch guideline for adult patients — can antibiotic S.T.O.P. 2015.2 Common oral antibiotic options. Use the following guide to select appropriate oral therapy.
Deprescribing
Current IV therapy
Oral option (adult doses)
Continued from page 1
Amoxycillin 500mg-1g tds
Amoxycillin 500mg-1g tds
Benzylpenicillin 600mg-1.2g qid
Amoxycillin 500mg-1g tds
Ceftriaxone 1g-2g daily
Amoxycillin 875mg with clavulanic acid 125mg bd*
Cephazolin 1g-2g tds
Cephalexin 500mg-1g qid
Ciprofloxacin 200mg-400mg bd#
Ciprofloxacin 500mg-750mg bd#
Clindamycin 600mg tds
Clindamycin 150mg-450mg tds
Flucloxacillin 1g-2g qid
Di/Flucloxacillin 500mg-1g qid#
Metronidazole 500mg bd
Metronidazole 400mg bd or tds
Piperacillin with tazobactam 4.5g tds or Ticarcillin with clavulanic acid 3.1g tds
Amoxycillin 875mg with clavulanic acid 125mg bd Pseudomonas: Seek advice from Clinical Microbiology or Infectious Diseases
Amoxycillin + gentamicin ± metronidazole
Amoxycillin 875mg with clavulanic acid 125mg bd or 500/125mg bd or tds
Cefepime, gentamicin, meropenem, vancomycin
Seek advice from Clinical Microbiology or Infectious Diseases
Follow up was possible with 39 of the 50 patients (mean follow up time 78 days). Out of the 149 ceased medications in these 39 patients, only 5 had been recommenced.8 Medication management for many individuals is a complex, challenging, costly, yet essential part of life. Deprescribing may assist in ensuring individuals are prescribed only the most appropriate, safe and effective medications, resulting in a decrease in ADR related events and hospital admissions. References are available on request.
The following IV drugs have equivalent oral doses: Azithromycin, Linezolid, Fluconazole, Trimethoprim/Sulphamethoxazole * Consider patient allergy status when converting to a penicillin. # Some drug doses may need to be reduced with decreased renal function.
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