RGH E-Bulletin Digest Number 51

Transcription

1 RGH E-Bulletin Digest Number 51 The next in our 2012 series of continuing education activities is the RGH E-Bulletin Digest No. 50 edited by Associate Professor Chis Alderman. This CE activity assesses your understanding of four recent s (Volumes July/August 2012). Learning Objectives: After completing this activity, pharmacists should be able to: Discuss the clinical pharmacology of vemurafenib Discuss principle of dose adjustment of antibiotics in renal impairment Describe therapeutic drug monitoring approaches used during antibiotic treatment in renally impaired people Outline clinical issues relating to the use of low molecular weight heparin products in people with liver disease. Competencies addressed by this activity include: 4.1, 4.2, 4.3, 6.1, 6.2, 7.1, 7.2 This activity has been accredited by the Australian College of Pharmacy as a Group 2 activity for 1 CPD credit suitable for inclusion in an individual pharmacist's CPD plan. Accreditation number: A1209AP0. Under the auspices of the Australian Pharmacy Council, the Australian College of Pharmacy may accredit continuing professional development for pharmacists that is eligible to be used as supporting evidence of continuing competence. Chris Alderman B Pharm, FSHP, BCPP (USA), CGP Chris Alderman is the Director of Pharmacy at the Repatriation General Hospital in Daw Park, South Australia, and also holds a dual appointment as Associate Professor, Pharmacy Practice at the Quality Use of Medicines and Pharmacy Research Centre, University of South Australia. He has nearly 20 years experience as a specialist clinical pharmacist in psychiatry, and holds specialist qualifications in psychiatry and geriatric pharmacy with the US Board of Pharmaceutical Specialties. He is a past president of the Society of Hospital Pharmacists of Australia and achieved admission as a Fellow of SHPA in He is the author of over 80 peer-reviewed publications and several book chapters, and his research interests focus upon strategies to achieve safe and effective use of psychotropic drugs. He has a special interest in veteran psychiatry, in particular in the management of post-traumatic stress disorder. AusPharm gratefully acknowledges the financial support provided by the sponsors of our CE program, MIMS

2 Volume 47 (2): July 23, 2012 Vemurafenib for metastatic melanoma Melanoma is the fourth most common cancer affecting Australians, accounting for 9.5% of all cancers in this country, with more than 10,300 new cases diagnosed annually. While melanoma is the least common dermatological cancer, it is associated with the highest rates of mortality and accounts for around 75% of all skin cancer related deaths. Vemurafenib (Zelboraf ) is a targeted new oral therapy for metastatic and unresectable melanomas which carry the BRAF-V600E gene mutation. This BRAF-kinase inhibitor was approved by the US FDA as well as the European committee for medical products for human use in 2011 after publication of a phase 3 efficacy study: the BRIM-3 trial (n = 675). The trial showed a greater overall survival rate at six months (84% vs. 64%) and greater mean progression-free survival (5.3 months vs. 1.6 months) with vemurafenib when compared to the standard first line chemotherapy agent dacarbazine. Approximately 50% of melanoma patients have tumours which express the targeted BRAF-V600E gene. As such a companion diagnostic test (the Cobas 4800 BRAF V600 mutation test) has been developed in composite with vemurafenib to ensure that only those patients whose tumours are most likely to respond to the mechanism of the drug are treated. Thus vemurafenib, when used together with the diagnostic test, allows for a highly individualised and targeted approach to chemotherapy. Adverse effects associated with vemurafenib caused 38% of patients participating in the BRIM-3 trial to require a dose reduction. Cutaneous squamous cell carcinomas were a reported adverse effect in 18% of Vemurafenib treated patients and were dealt with by simple excision of the lesion. As such patients treated with vemurafenib are encouraged to regularly check their skin for new lesions or changes to moles. Other adverse effects of vemurafenib include severe skin reactions (such as Stevens Johnson Syndrome and Toxic Epidermal Necrolysis), increased photosensitivity, QT prolongation, abnormal liver function tests, blurred vision and other eye problems. Common adverse effects noted in the BRIM-3 trial were arthralgia, rash, fatigue, nausea, alcopenia, diarrhoea, vomiting and headache. Haematological adverse effects such as neutropenia seemed to be minimal (effecting only one study patient) and aside for the increased incidence of squamous cell carcinomas, no other secondary neoplasias were detected. Vemurafenib is a substrate of the cytochrome P450 isoenzyme CYP3A4 and thus interacts with both potent inhibitors (protease inhibitors, azole antifungals etc) and inducers (phenytoin, rifamycin antibiotics, carbamazepine etc). Vemurafenib is also a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6 and thus caution should be used in patients treated with low therapeutic index drugs metabolised by these enzymes (including warfarin). The recommended dose of vemurafenib is 960 mg twice daily, and this is reduced in increments of 240 mg according to adverse effects. In May of this year, the Australian Therapeutic Goods Administration approved the use of vemurafenib in Australia for patients with metastatic melanoma. A submission to have vemurafenib and its companion diagnostic test subsidised under the Pharmaceutical Benefits Scheme and Medicare respectively is currently under review. Vemurafenib is also currently being investigated as a potential treatment option for thyroid cancers. Acknowledgment This E-Bulletin is based on work by Nerida Grosser, Utility Pharmacist, RGH.

3 Volume 47 (3): July 30, 2012 Antibiotics in renal impairment Confusion surrounds the prescribing of antimicrobials in renal impairment; whether to reduce the dose or extend the dosing interval. Suggested dose adjustments in renal impairment for many commonly used antibiotics are provided here, based on tables which can be found in the Therapeutic Guidelines (TG) Antibiotic, 14 th edition. No dose adjustment is required for some agents these include azithromycin, roxithromycin, ceftriaxone, cefaclor, clindamycin, doxycycline, linezolid, moxifloxacin, phenoxymethylpenicillin, metronidazole among others. The dosing of antibiotics such as penicillins (beta-lactams) and vancomycin is time-dependent, meaning that these exert optimal bactericidal effect when drug concentrations are maintained above the minimum inhibitory concentration (MIC). Therefore reducing the frequency of administration by extending the dosing interval (rather than changing the magnitude of individual doses) is the strategy for dosing these antibiotics in renal impairment. Concentration-dependent antibiotics achieve increasing bactericidal action with increasing levels of drug. In addition, these agents have an associated concentration-dependent post-antibiotic effect in which bactericidal action continues for a period of time after the antibiotic level falls below the MIC. Therefore the magnitude of the individual dose given is important. Area under the curve (AUC) methods are commonly used to calculate total exposure to aminoglycosides, while for other concentration-dependent antibiotics (fluoroquinolones, azithromycin and metronidazole) AUC calculations are not performed. Penicillins - Penicillins have quite a large therapeutic window; doses generally only need to be significantly adjusted for GFR < 10ml/min. GFR 10-50mL/min GFR <10mL/min Amoxycillin 100% 8-12 hourly 100%24-hourly Ampicillin 100% 8-12 hourly for GFR<30 100% hourly benzylpenicillin (penicillin G) 75% dose at normal interval 20-50% dose at normal interval Flucloxacillin or dicloxacillin Normal g 6-8 hourly Beta-lactamase inhibitors are also renally cleared. The Therapeutic Guidelines advocate extended dosing interval for combination products as follows: amoxycillin/clavulanate: 500/125mg 12-hrly for GFR <30ml/min (and once per 24 hours if the GFR <10ml/min as per the product information); piperacillin/tazobactam: 100% dose 12-hourly for GFR < 20ml/min; ticarcillin/clavulanate: 100% dose 8-12 hourly for GFR 10-30mL/min, 12-hourly for GFR <10mL/min (while the product information recommends reducing dose to 2g for GFR less than 30mL/min). Cephalosporins - Many of have a wide therapeutic window. Suggested guidance: cefepime: % hourly for GFR 10-50mL/min, 25-50% 24-hourly for GFR <10mL/min; cefotaxime: 1g 24-hourly for GFR <10mL/min; ceftazidime: 1g hourly for GFR 16-30mL/min, 0.5-1g 24-hourly for GFR<15mL/min; cefuroxime: 500mg 24-hourly for GFR <10mL/min;cephazolin: 0.5-1g 6-8 hourly for GFR 20-40mL/min, hourly for GFR <20mL/min; cephalexin: 100% 8-12 hourly for GFR <10mL/min Fluoroquinolones - Ciprofloxacin: 50-75% 12-hourly for GFR 10-50mL/min, 50%12-hourly for GFR<10ml/min (or 100% 24-hourly); norfloxacin: 100% hourly for GFR 10-50mL/min, 24-hourly for GFR<10mLmin Macrolides - Erythromycin: 50-75% at normal dosing interval for GFR<10mL/min; Clarithromycin: 50% 12-hourly for GFR <30mL/min Miscellaneous- Nitrofurantoin: avoid if GFR <60mL/min; teicoplanin: 100% every 48hr for GFR 10-50mL/min, every 72hr for GFR <10mL/min; trimethoprim: if unavoidable in GFR <15mL/min, use 150mg/day; trimethoprim with sulfamethoxazole: usually normal dosing interval for three days then once-daily, for GFR < 25mL/min Meropenem: 100% 12-hourly for GFR 26-50mL/min, 50%12- hourly for GFR 10-25mL/min, 50% 24-hourly for GFR<10mL/min. Acknowledgment This E-Bulletin is based on work by Jenny Casanova, Senior Clinical Pharmacist, RGH.

4 Volume 47 (4): August 6, 2012 Dosing of antibiotics and therapeutic drug monitoring Aminoglycosides Aminoglycosides exert a post-antibiotic effect: high peak levels are required to penetrate the bacterial cell wall, where the drug continues to have a bactericidal effect after systemic levels have declined. Monitoring is used to ensure adequacy of dosing, to delay or prevent the onset of nephrotoxicity and reduce the risk of vestibular and auditory ototoxicity. Initial gentamicin dosing is based on bodyweight to ensure an adequate peak concentration. Modified dose is needed with increasing age (as per the Therapeutic Guidelines Antibiotic, below). Clearance of aminoglycosides is increased in children, patients with sepsis, and patients with cystic fibrosis; these patient groups require increased initial doses. Age Initial dose (gentamicin, tobramycin) Initial dose (amikacin) 10 to 29 years 6 mg/kg up to 560 mg 24 mg/kg up to 2.25 g 30 to 60 years 5 mg/kg up to 480 mg 20 mg/kg up to 2 g > 60 years 4 mg/kg up to 400 mg 16 mg/kg up to 1.5 g Subsequent dosing may be based either on trough levels or area under the curve (AUC) methods. There are a number of computer software programmes for AUC monitoring, which help to achieve/maintain adequate levels in younger patients with good renal function; yet the simplest method for elderly patients with impaired renal function is to not greatly reduce the starting dose, but to check trough levels before repeat/extended dosing. Since aminoglycosides are nephrotoxic, prolonged low levels of drug exposure are best avoided if possible; it is important for the kidneys to have a period of no exposure to the aminoglycoside. Trough levels taken immediately before the next dose ought to be below the limit of quantification, to guarantee complete clearance of aminoglycosides. Once-daily dosing is now well accepted for all indications (apart from endocarditis). For GFR <60 ml/min, single dosing every 24 hours is appropriate, while for GFR 30-40mL/min alternate day dosing may be necessary, and for GFR<30mL/min it is best to give subsequent doses when a zero trough level is confirmed. Renal failure does not preclude giving the original stat dose of aminoglycoside. Vancomycin Some antibiotics have been classified as time-dependent, however, because of their post-antibiotic effect, they also have concentration-dependent features. Vancomycin is an example, and while efficacy is best determined by the 24-hour AUC to MIC ratio, currently vancomycin monitoring is by trough levels for practical reasons. Monitoring is used to ensure adequate levels & reduce under-dosing, but is also useful to prevent accumulation in renal impairment. Steady-state levels are usually achieved after approximately five doses (normal renal function), i.e. on the third day if dosing 12-hourly. With impaired renal function therapeutic levels may be reached sooner & lower doses/less frequent dosing is required. The target therapeutic range for pre-dose trough levels is often reported as 15-20mg/L, although this varies slightly between references. For patients on continuous infusion, aim for steady-state concentration 20-25mg/L. Creatinine clearance (ml/min) Starting dose Timing of trough concentration measurement greater than g 12-hourly before the fourth or fifth dose 60 to 90 1 g 12-hourly before the fourth or fifth dose 20 to less than 60 1 g 24-hourly before the third dose less than 20 1 g 48-hourly before the second dose Vancomycin should not be infused faster than 1g/hour (ideally 10 mg/minute) to minimise the risk of red man syndrome. Acknowledgment This E-Bulletin is based on work by Jenny Casanova, Senior Clinical Pharmacist, RGH.

5 Volume 47 (5): August 13, 2012 Use of LMWH in patients with advanced liver cirrhosis Low molecular weight heparins (LMWH) are commonly used in the prophylaxis and treatment of venous thromboembolic (VTE) diseases. However, there is limited evidence to guide the use of LMWH in patients with advanced liver cirrhosis. It is well known that patients with advanced liver disease are affected by haemostatic alterations that can create a hypocoagulable state. The mechanisms that create this issue are firstly, decreased synthesis of vitamin K clotting factors II, V, VII, IX, X and XI, and secondly, decreased platelet production. These abnormalities are reflected through routine laboratory tests showing a deficiency in procoagulants - i.e. decreased platelet count and elevated prothrombin time, international normalised ratio and partial thromboplastin time. It was once thought that this deficiency in procoagulants resulted in protection against VTE and an increased bleeding risk. However, patients with advanced liver disease also have increased levels of procoagulants (factor VIII and von Willebrand factor) which all lead to a hypercoagulable state. Routine laboratory tests do not reflect this. The complex haemostatic alterations in the patient with advanced liver disease implies they have an increased propensity to bleed during procedures and from varices but are also at increased risk of thrombosis, namely portal vein thrombosis. A recent literature review published in the Annals of Pharmacotherapy assessed the risk of VTE in patients with chronic liver disease (CLD). The review included six retrospective studies that assessed the incidence of VTE in this patient group: the overall findings of these studies suggested that the incidence varied in the range of %. Populationbased studies have reported VTE relative risks of in patients with CLD compared to controls. To date, there is no data comparing the efficacy or risks of using pharmacological prophylaxis in patients with CLD with other hospitalized patients. Further studies are needed to determine if patients with CLD would benefit from receiving pharmacological VTE prophylaxis. There is one study assessing the efficacy and usefulness of anti-xa monitoring of LMWH under prophylactic doses of enoxaparin (20mg or 40mg once daily) and therapeutic doses of enoxaparin (1mg/kg twice daily) in 84 patients with advanced liver cirrhosis. The study found that anti-xa activity was negatively correlated with the severity of liver disease using standard doses of enoxaparin, cirrhotic patients failed to reach recommended anti-xa levels, implying that lower anti-xa levels might be an optimal target in patients with CLD, or that the acquired deficiency of antithrombin (AT) in cirrhotic patients leads to reduced efficacy of LMWH. Adjusting doses to achieve recommended anti-xa levels may be inappropriate in patients with CLD, and may actually result in an increased incidence of bleeding. In summary, it would appear that the risks and benefits of VTE prophylaxis in patients with CLD are yet to be clearly determined. The use of anti-xa monitoring for patients with CLD also warrants further investigation and at this stage should be used with caution. Alternative novel monitoring methods may prove to provide better monitoring options in the future. Acknowledgment This E-Bulletin is based on work by Winnie Tran, Senior Clinical Pharmacist, RGH.

6 References used in the preparation of the relevant E-Bulletins: 1. Therapeutic Guidelines: Antibiotic (14th Ed). Therapeutic Guidelines Limited Chapman et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. New Engl J Med 2011; 364: Cancer council website : 4. Pincus KJ, Tata AL, Watson K. Risk of venous thromboembolism in patients with chronic liver disease and the utility of venous thromboembolism prophylaxis. Ann Pharmacother 2012;46: Bechmann LP, Sichau M, Wichert M et al. Low-molecular weight heparin in patients with advanced cirrhosis. Liver Int 2011;31: Northrup PG, Intagliata NM. Anticoagulation in cirrhosis patients: what don t we know? Liver Int 2011;31:4-6 MCQs Questions based on the above articles: Select ONE alternative that best represents the correct answer to each of the following multiple choice questions (only one answer per question is correct) 1. In Australia, the Therapeutic Goods Administration has approved the use of vemurafenib for the treatment of: a) thyroid cancer b) colon cancer c) basal cell carcinoma d) malignant melanoma 2. Vemurafenib is a substrate of which of the cytochrome P450 isoenzymes a) CYP1A2 b) CYP2D6 c) CYP3A4 d) CYP2C19 3. For patients with significantly impaired renal function, dose adjustment is required for which of the following agents? a) azithromycin b) cefaclor c) roxithromycin d) none of these

7 MCQs continued 4. With respect to dosing of amoxycillin for patients with an estimated GFR of < 10ml/min, the recommended approach is: a) no dosage adjustment is suggested b) Give 50% of the usual dose once every 24 hours c) Give 100% of the usual dose once every 24 hours d) Give 100% of the usual dose once every 48 hours 5. Relative to young adults with unimpaired renal function, the clearance of aminoglycosides is increased for: a) children b) people with liver disease c) people with nephritic syndrome d) older people with renal disease 6. To reduce the likelihood of red man syndrome IV vancomycin should not be infused at a rate greater than: a) 500 mg per hour b) 1000 mg per hour c) 2000 mg per hour d) 3000 mg per hour 7. Research suggests that relative to people without chronic liver disease (CLD), the risk for venous thromboemobolism for those with CLD is: a) markedly reduced b) slightly reduced c) somewhat increased d) not different 8. Which of the following may influence haemostasis for people with CLD? a) decreased synthesis of some clotting factors b) thromocytopaenia c) increased levels of procoagulants such as factor VIII and von Willebrand factor d) all of the above