Epic Pharmacy Circuit Newsletter April 2015

April 2015

clinical initiatives, research and current updates in treatment

The green prescription A way forward for healthcare prevention in Australia?

Heidi Furlan, Epic Pharmacy Port Macquarie

Cardiovascular disease (CVD) is the leading cause of death in Australia, with 43,946 deaths attributed to CVD in Australia in 2012. 1 44% of Australians do less than two and a half hours of moderate activity per week. 1 The Heart Foundation currently recommends that at least 30 minutes or more of moderateintensity physical activity (such as brisk walking) should be included on most, if not all, days of the week for health benefits. 2 What other primary health prevention strategies could be employed to target these patients that are at a high risk of needing tertiary healthcare later on down the track?

One study conducted by the University of Auckland posed the question: Does written advice from a general practitioner, referred to as a green prescription, increase physical activity more than verbal advice alone?

456 sedentary patients received verbal advice on increasing physical activity and were then randomised to an exercise prescription group or verbal advice group. Results showed that the number of people engaging in physical activity at six weeks increased substantially — but significantly

more so in the green prescription group. More participants in the green prescription group increased their activity over the period. 3 The Green Prescription (GRx) is a counselling program funded by the New Zealand government which encourages general practitioners to offer physical activity advice to their patients. ¬ ¬ General practitioners consult with the patient and discuss increasing physical activity. ¬ ¬ Appropriate goals are identified and the patient is given a written prescription identifying the type of activity recommended and the “dose” (frequency and duration). ¬ ¬ The patient gives informed consent to be phoned by an exercise specialist at least three times over a 3-4 month period for motivational counselling and follow-up support.

Alternatively the patient can phone the service independently.

In New Zealand a GRx may be prescribed for medical conditions such as obesity, hypertension, diabetes, osteoporosis, anxiety or depression. 4 A systematic review of the evidence for cost effectiveness of physical activity

interventions was undertaken in 2011 5 and concluded that most interventions studied were cost-effective. The study goes on to note that “many physical activity interventions had similar cost-utility estimates to funded pharmaceutical interventions and should be considered for funding at a similar level”. 5 From a pharmacy perspective, it is an interesting concept that in some conditions, a prescription for exercise and good nutrition can be shown to be equally effective to prescribing a drug. The pharmacy department can be integral in promoting good health by encouraging an active lifestyle and a healthy diet.

References are available on request.

43,946 deaths attributed to CVD in Australia in 2012

44% of Australians do less than two and a half hours of moderate activity per week

Rivaroxaban Prevention of Venous Thromboembolism in Cancer Patients Chau-Anne Pham, Icon Cancer Care Adelaide

Extrinsic tenase Factor VIIa Tissue factor

Intrinsic tenase Factor IXa Factor VIIIa

Prothrombin

Indirect ¬ ¬ Unfractionated heparin ¬ ¬ Enoxaparin ¬ ¬ Fondaparinux Direct ¬ ¬ Rivaroxaban ¬ ¬ Apixaban ¬ ¬ Otamixaban

Factor X

Factors acted upon by warfarin

Factor Xa inhibitors

Free activated factor X (Xa)

Prothrombinase complex

Thrombin inhibitors

Phospholipids Factor Va-Factor Xa Ca 2+

Indirect Unfractionated heparin Direct Ximelagatran Dabigatran etexilate

Thrombin

Fibrinogen

Fibrin (clot)

Figure 1: Mechanism of action of anticoagulants.

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism is a significant cause of morbidity and mortality in patients with cancer. 1 Some studies have shown that 20% of patients with cancer are diagnosed with VTE whereas other studies have found through post-mortem examination that up to 50% of cancer patients are actually affected.

This difference highlights that the extent of the population affected by VTE may be underestimated. 2

Current available anticoagulants for the treatment of VTE include heparin, Low Molecular Weight Heparins (LMWH) such as enoxaparin, indirect factor Xa inhibitors including fondaparinux and vitamin K antagonists such as warfarin. 2 However, there are disadvantages with the use of each of these agents.

LMWH inconveniences patients with daily injections and frequent platelet monitoring, whilst warfarin requires frequent INR monitoring and dose adjustments. 3 Current guidelines for the treatment of VTE include initial use of parenteral LMWH followed by warfarin or continuing with LMWH

treatment. 4 Cancer patients are at an increased risk of VTE compared to the general population and chemotherapy can make anticoagulation management difficult affecting a patient’s quality of life. Clearly, there is still room for improvement in this area.

Rivaroxaban (Xarelto) is an oral anticoagulant and is a potent factor Xa inhibitor which selectively binds to factor Xa amplifying thrombin generation in the blood coagulation cascade. This prevents the activation of platelet and fibrin clot formation (see figure 1). 5 It is a simplified once daily dose without the need of regular blood coagulation monitoring, although routine clinical monitoring is still essential. Rivaroxaban is currently listed on the Pharmaceutical Benefit Scheme (PBS) for the treatment of symptomatic pulmonary embolism and symptomatic deep vein thrombosis.

Rivaroxaban provides practical advantages over LMWH and warfarin as patients do not require daily injections or frequent INR monitoring.

This provides patients with the convenience to travel and to continue their daily routines without the need of frequent doctor visits or having to self inject and dispose of needles. Unlike warfarin, rivaroxaban does not require the use of parenteral LMWH in the first week of treatment. This is because rivaroxaban has a rapid onset of action where the maximum inhibitory effect is reached within 1 to 4 hours. 3 There are no significant dietary interactions associated with rivaroxaban, whereas warfarin is well known to be associated with many food and drug interactions. 6 Continued on page 4

Whats new

Fruit juices and Atenolol interaction Medicines are often taken at breakfast time when fruit juices are commonly consumed. This can sometimes lead to unintended and unwanted outcomes due to potential juice-drug interactions.

Fruit juice-drug interactions may be clinically relevant for two reasons.

Firstly, because the increase or decrease in serum drug levels can be dramatic, and secondly because the interaction has greatest impact when fruit juice is given at the same time as the medications. 1 It has been known for some time that certain chemicals (flavonoids) in grapefruit (known as furanocoumarins) can interfere with the way our body metabolises many medicines. Systemic levels of drugs subject to such an interaction with grapefruit juice may increase resulting in enhanced effects or causing unwanted side effects. In the recent years, new research has shown that other juices, particularly apple and orange juice, can also significantly alter drug absorption but in the opposite way to grapefruit juice. 1

Orange and apple juice contain chemicals called hesperidin and phlorizin (and others) that can block some intestinal drug transporters called the OATP (organic anion transport protein), which reduce the oral uptake of drugs and decrease the serum levels of drugs reliant on this pathway. 2 A good example of a fruit juice-drug interaction is that which occurs between apple juice and atenolol. Atenolol is totally dependent on OATP for transport across the gut wall. A recently published study 2 found that 600ml apple juice consumed 1.5 hours after atenolol administration caused a 58% reduction in atenolol levels and 1200ml apple juice consumed 3 hours after lead to an average 82% reduction in levels. 1-3 The result would be that atenolol would be rendered ineffective by the effect of these fruit juices. 1

Fruit Juice

While the OATP family of proteins has been identified as transporters of many important drugs, it seems that the OATP blockade only lasts for a matter of hours, so the key issue is timing. The most significant interactions occur when the juice is given within two hours of drug administration, and it appears the interaction can be avoided completely if they are separated by four hours or more. 7 Hence, it would be wise to advise patients to generally take their medicines with water rather than fruit juice. 1 References are available on request.

Table 1. OATP-mediated fruit juice interactions 5,6

Drug

Researchers have described OATPmediated fruit juice interactions with grapefruit, orange, and apple juices in other publications as well. A summary of select medicines involved in these types of interactions is presented in Table 1. The absorption of some medications is decreased by less than 10%, which is not thought to be clinically significant in most patients. 4,5

Decrease in absorption

Some practice points: ¬ ¬ Check with the pharmacist if you are not sure if a certain medicines interacts with fruit juices

Atenolol

Apple Juice Orange Juice

40%

Ciprofloxacin

Apple Juice Orange Juice

Approx. 20%

Fexofenadine

Grapefruit Juice Orange Juice Apple Juice

Approx. 40%

¬ ¬ If a medicine interacts with apple, orange and/or grapefruit juices, space the juice 4 hours from giving the medication

Grapefruit Juice

0%–22%

¬ ¬ Advise patients to take their medicines with water rather than fruit juices

Montelukast

Continued from page 2

New Drug Brief Afatinib ( Giotrif ) Carissa Taylor, Icon Cancer Care Townsville

The ErbB family of receptors (EGFR/Erb1, HER2/ErbB2, ErbB3 and ErbB4) are involved in fundamental cellular processes including cell proliferation, migration, metabolism and survival. They are often overexpressed or mutated in many cancers, including nonsmall cell lung cancer (NSCLC). Afatinib, a tyrosine kinase inhibitor (TKI), targets the ErbB receptor family in patients with NSCLC to slow the growth and spread of tumour cells. 1 Unlike the first-generation TKIs, gefitinib and erlotinib, afatinib not only blocks signalling from EGFR/ErbB1, but also has activity against HER2/ ErbB2 and ErbB4. 2 Afatinib is TGA approved for use in EGFR mutation-positive locally advanced or metastatic NSCLC. 3 It may be used as first-line monotherapy or after failure of chemotherapy, although it is currently not PBS listed for either use. 3 In the phase 3 trial which compared afatinib to pemetrexed/cisplatin chemotherapy (LUX-Lung 3), afatinib demonstrated a higher response rate (56% versus 23%, P<0.001) and superior progression-free survival (11.1 months versus 6.9 months, P<0.001) in treatment-naive patients. 2, 3, 4 In a combined analysis of LUX-Lung 3 and 6, afatinib significantly improved overall survival in comparison to chemotherapy (27.3 months versus 24.3 months). 5 Afatinib is given as a once daily oral dose starting at 40mg, then

if tolerated well, may be increased to a maximum of 50mg after the first three weeks. 3 The absorption is significantly reduced by food intake and so it is best taken on an empty stomach at least one hour before or three hours after food. 3 As it is primarily excreted by the biliary/faecal route, no adjustments are required to the starting dose in patients with mild to moderate renal and/or hepatic impairment. 3 The most common adverse effects experienced with afatinib are diarrhoea, stomatitis, rash and paronychia. 1, 3 Skin-related toxicities can be managed in the same way as the first-generation TKIs with early intervention (e.g. sun protection, emollients and tetracycline’s) and dose adjustments if required. 3 Further studies are being conducted to define the role of afatinib in the firstline treatment setting (LUX-Lung 7), and in patients requiring second-line treatment after failure of platinumbased chemotherapy (LUX-Lung 8).

References are available on request.

It is eliminated by hepatic and renal pathways and has a short half-life of 5 to 9 hours in young adults and 11 to 13 hours in older patients with poorer renal function. 3 As two thirds of rivaroxaban is metabolised in the liver and a third is directly excreted by the kidneys, dose adjustments are not required for patients with mild renal or hepatic impairment.

However, patients with moderate to severe renal impairment (creatinine clearance less than 30mL/min) or moderate to severe hepatic impairment should not use rivaroxaban. 7 Two recent large phase 3 trials were conducted with the purpose of comparing the efficacy and safety of rivaroxaban compared to enoxaparin with warfarin therapy (EINSTEIN DVT and PE trial).

From the study a subgroup analysis of the pooled results was analysed looking specifically at patients with cancer.

The trial consisted of patients being treated for a period of 3, 6, or 12 months with rivaroxaban (15mg twice daily for 21 days followed by 20mg daily) or treatment with standard therapy (enoxaparin 1mg/ kg twice daily then warfarin (target INR of 2.0 to 3.0). 3 The analysis showed that recurrent VTE was seen in 5% of rivaroxaban patients compared with 7% of enoxaparin plus warfarin patients (hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.35–1.30). Furthermore, the analysis showed the incidence of major bleeding was reduced in patients taking rivaroxaban compared to those using LMWH plus warfarin (2% versus 5%). 7 Bleeding has always been a major risk with the use of anticoagulants, so this reduction is very encouraging.

The analysis demonstrates there is possibly a role for rivaroxaban in the prevention of VTE in cancer patients.

Whilst more research is required to confirm these results and determine the long term safety profile of the drug in the cancer population, rivaroxaban with its administration advantages could prove to be an excellent alternative for selected patients where existing treatments may not be suitable.

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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