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HEALTHLINE March 2006 FOCUS ON BONE DISEASE OF CHRONIC KIDNEY DISEASE NEW DRUGS AND INDICATIONS NEW DRUGS/INDICATIONS Aspirin Prevents Cardiovascular Disease in Healthy Adults A meta-analysis was conducted of prospective, randomized controlled trials of aspirin therapy in patients without cardiovascular disease published between 1966 and 2005. Among women, aspirin prophylaxis reduced the odds of a cardiovascular event by 12%. It did not significantly alter the risk of MI or hemorrhagic stroke, but it did reduce the risk of ischemic stroke by 24%. Among men, aspirin reduced the risk of major cardiovascular events by 14%, and of MI by 32%. While it had no effect on the risk of ischemic stroke among men, it did increase their risk of hemorrhagic stroke by 69%. Both genders taking aspirin had a 70% increased risk of major bleeding. The drug appeared to have no effect on cardiovascular or all-cause mortality among men or women. This is more evidence in favor of low dose aspirin (81 mg/day) for the prevention of cardiovascular disease. JAMA 2006;295:306-313. Ibandronate Sodium (Boniva) Injection for Osteoporosis The FDA has approved the first intravenous (IV) bisphosphonate for the treatment of postmenopausal osteoporosis. Boniva injection is administered as a 15-to-30 second injection once every three months for the treatment of postmenopausal osteoporosis. Boniva provides an alternative for patients who have difficulty with oral bisphosphonate dosing requirements, including an inability to sit upright for 30 to 60 minutes and/or swallow a pill. Letrozole (Femara) Tablets for Hormone-Sensitive Breast Cancer Femara is now approved as treatment for use after surgery in postmenopausal women with hormone-sensitive early breast cancer (adjuvant setting). Femara is a once-a-day oral aromatase inhibitor indicated for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. WARNINGS AND ADVERSE EFFECTS CDC Recommends against the Use of Amantadine and Rimantatine for the Treatment or Prophylaxis of Influenza during the 2005–2006 Season For the 2005–2006 season, 120 influenza A viruses isolated from patients in 23 states have been tested at Centers for Disease Control and Prevention through January 12, 2006; 109 of the isolates (91%) are resistant to amantadine and rimantadine. All influenza viruses from the United States that have been screened for antiviral resistance at CDC have demonstrated susceptibility to Tamiflu. On the basis of available antiviral testing results, CDC is providing an interim recommendation that neither amantadine nor rimantadine be used for the treatment or prophylaxis of influenza A in the United States for the remainder of the 2005–2006 influenza season. During this period, Tamiflu should be selected if an antiviral medication is used for the treatment and prophylaxis of influenza. Testing of influenza isolates for resistance to antivirals will continue throughout the 2005–2006 influenza season, and recommendations will be updated as Copyright 2006 All Rights Reserved Published by Omnicare, Inc. distributed by PBM Plus, Inc. Page - 1 HEALTHLINE March 2006 needed. Annual influenza vaccination remains the primary means of preventing morbidity and mortality associated with influenza. Specific information regarding the use of Tamiflu is available at http://www.cdc.gov/flu/protect/antiviral/index.htm NEW DRUG WARNING AND REVISION OF MONITORING FOR CLOZAPINE Clozapine is used in treatment of refractory schizophrenia when other antipsychotic agents have failed. Clozapine is available in tablet formulation and in a new oral disintegrating tablet FazaClo®. The Food and Drug Administration (FDA) has advised a new monitoring schedule for clozapine. The major changes include: o o o o Requirement that the absolute neutrophil count (ANC) be determined and reported along with each WBC count. The ANC is calculated by obtaining the percentage neutrophils (usually 50 to 60%) into an actual number of cells. Therefore, a complete blood cell (CBC) with differential will have to be obtained on patients in the future. New parameters for initiation of clozapine treatment: WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3. Initiation of monthly monitoring schedule after one year (six months weekly, six months every two weeks) of WBC counts and ANCs in the normal range (WBC ≥ 3500/mm 3 and ANC ≥ 2000/mm3). Increased risk of agranulocytosis (no WBCs) in patients who are re-challenged with clozapine following recovery from an initial episode of moderate leucopenia (3000/mm 3 > WBC ≥ 2000/mm3 and/or 1500/mm3 > ANC ≥ 1000/mm3). After recovering from such an episode, these patients are now required to undergo weekly monitoring for 12 months if they are rechallenged. Table 1: Frequency of Monitoring based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests Situation Hematological Values for Monitoring Initiation of therapy WBC ≥ 3500/mm3 ANC ≥ 2000/mm3 Note: Do not initiate in patients with 1) history of myeloperoliferative disorder or 2) clozapine induced agranulocytosis or granulocytopenia All results for WBC ≥ 3500/mm3 ANC ≥ 2000/mm3 All results for WBC ≥ 3500/mm3 ANC ≥ 2000/mm3 N/A N/A 6 months – 12 months of therapy ≥ 12 months of therapy Immature forms present Discontinuation of Therapy Substantial drop in WBC or ANC Copyright 2006 All Rights Reserved Single Drop or cumulative drop within 3 weeks of WBC ≥ 3000/mm3 or Published by Omnicare, Inc. distributed by PBM Plus, Inc. Frequency of WBC and ANC Monitoring Weekly for 6 months Every 2 weeks for 6 months Every 4 weeks Repeat WBC and ANC Weekly for at least 4 weeks from day of discontinuation or until WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3 1. Repeat WBC and ANC 2. If repeat values are 3000/mm 3 ≤ WBC ≤ 3500/mm 3 and ANC, Page - 2 HEALTHLINE March 2006 ANC ≥ 1500/mm3 Mild Leukopenia -----------------------------------------Mild Granulocytopenia 3500/mm3 > WBC ≥ 3000/mm3 and/or 2000/mm3 > ANC ≥ 1500mm3 Moderate Leukopenia -----------------------------------------Moderate Granulocytopenia 3000/mm3 > WBC ≥ 2000/mm3 and/or 1500/mm3 > ANC ≥ 1000mm3 Severe Leukopenia -----------------------------------------Severe Granulocytopenia WBC < 2000/mm3 and/or ANC < 1000mm3 Agranulocytosis ANC ≤ 500/mm3 Copyright 2006 All Rights Reserved Published by Omnicare, Inc. distributed by PBM Plus, Inc. 2000/mm3, then monitor twice weekly Twice-weekly until WBC >3500/mm 3 and ANC > 2000/mm 3 then return to previous monitoring frequency. 1. Interrupt therapy 2. Monitor daily until WBC > 3000/mm3 and ANC > 1500/mm3 3. Then, monitor twice-weekly until WBC> 3500/mm3 and ANC > 2000/mm3 4. May rechallenge when WBC > 3500/mm3 and ANC > 2000/mm3 5. If rechallenged, monitor weekly for 1 year before returning to the usual monitoring schedule of every 2 weeks for 6 months and then every 4 weeks infinitum. 1. Discontinue treatment and do not rechallenge patient 2. Monitor until normal and for at least four weeks from day of discontinuation as follows: o Monitor daily until WBC > 3000mm3 and ANC > 1500/mm3 o Then, monitor twice weekly until WBC > 3500/mm3 and ANC > 2000/mm3 o Then, monitor weekly After WBC > 3500/mm3 1. Discontinue treatment and do not rechallenge patient 2. Monitor until normal and for at least four weeks from day of discontinuation as follows: o Monitor daily until WBC > 3000/mm3 and ANC > 1500/mm3 o Then, monitor twice weekly until WBC > 3500/mm3 and ANC > 2000/mm3 o Then, monitor weekly after WBC >3500/mm3 Page - 3 HEALTHLINE March 2006 Modifications to the frequency of monitoring following interruptions in therapy were also revised. o o o Patients receiving clozapine who are being monitored on the previous schedule of weekly for the first 6 months are to continue this monitoring schedule and report ANCs from this point forward. If WBC ≥ 3500/mm 3 and ANC ≥ 2000/mm3, patients may transition to every 2 weeks monitoring for the next 6 months. Patients who are currently being monitored on the previous schedule of every other week, are to continue this monitoring schedule for a total of six months and should report ANCs from this point forward. If WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3, patients may transition to every monthly monitoring. WBC and ANC values following the discontinuation of clozapine therapy should be submitted to the Clozapine National Registry (CNR) for all non-rechallengeable patients (WBC <2000/mm3 and/or <1000/mm3), until WBC ≥ 3500/mm 3 and ANC ≥ 2000/mm 3. The National Registries by IVAX, Alamo and Novartis Pharmaceuticals have updated or will be updating their registry information to require insertion of the ANC value in the next several weeks. All pharmacies will be required to obtain a copy of the CBC with differential to calculate the ANC and record the WBC value on all Clozapine prescriptions. As a reminder, o o o Clozapine is contraindicated in patients with paralytic ileus as this is an adverse effect of clozapine. Clozapine has been associated with hypercholesterolemia and/or hypertriglyceridemia. Concomitant use of clozapine and citalopram results in clinically significant elevations of clozapine blood concentrations. Remember, clozapine is considered “Unacceptable” in older persons when safer, equally effective alternatives, such as atypical antipsychotics exist. References Novartis Pharmaceuticals Corporation (resource on the World Wide Web). URL: http://www.fda.gov/medwatch/safety/2006/Clozaril_chart_letter_final12-2005.pdf.com. Available from internet. Accessed 2006 January 25.] Alamo Pharmaceuticals Corporation (resource on the World Wide Web). URL: http://www.fazaclo.com/PDF_Files/FAZACLO_PI.pdf. Available from internet. Accessed 2006 January 25.] New Warning About Rosiglitazone (Avandia) GlaxoSmithKline and the Food and Drug Administration recently notified health care professionals about post-marketing reports of new onset and worsening diabetic macular edema for patients receiving rosiglitazone. In the majority of these cases, the patients also reported concurrent peripheral edema. In some cases, the macular edema resolved or improved following discontinuation of therapy and in one case, macular edema resolved after dose reduction. To read the complete MedWatch 2006 Safety summary, including a link to the GSK Dear Healthcare Professional letter, visit: http://www.fda.gov/medwatch/safety/2006/safety06.htm#Avandia FDA APPROVES BLACK BOX WARNING FOR ECZEMA CREAMS The Food and Drug Administration approved a black box warning that will be added to pimecrolimus (Elidel) and tacrolimus (Protopic) used to treat atopic dermatitis. The drugs' labels will now include the warning of a possible cancer risk associated with the drugs and clarify that the drugs should be used as second-line treatments. A Medication Guide will also Copyright 2006 All Rights Reserved Published by Omnicare, Inc. distributed by PBM Plus, Inc. Page - 4 HEALTHLINE March 2006 be distributed to inform patients of the potential risk. The FDA noted that these drugs are not recommended for use in patients 2 years of age or less. Medication Guides will be available shortly on the FDA web site and should be provided to patients who self-medicate. For more information visit: http://www.fda.gov/cder/drug/infopage/elidel/default.htm PATIENT CARE Bone Disease Associated With Chronic Kidney Disease Elevated concentrations of serum intact parathyroid hormone (iPTH) leads to a condition called secondary hyperparathyroidism (HPT) which is a common complication of chronic kidney disease (CKD). It is characterized by abnormalities in bone and mineral metabolism. The term renal osteodystrophy is used to collectively describe all of the skeletal changes of chronic renal disease. This serious disorder arises from disturbances in the regulation of the intracellular and extracellular concentrations of PTH, calcium, phosphorus, and vitamin D3 (calcitriol), which become more severe as kidney function declines. Abnormalities associated with secondary HPT begin in the early stages of CKD. Although most patients with renal osteodystrophy are asymptomatic, there are many pathologic features associated with this disease including bone and joint pain, fractures and deformities, extraskeletal calcification, osteoporosis, and osteopenia, skin ulceration, soft tissue necrosis, tendon rupture, periarthritis, and an increased risk of mortality. Lab Monitoring and Treatment Goals Serum concentrations of calcium, phosphorus, and intact plasma parathyroid hormone (iPTH) should be measured in all patients with CKD and glomerular filtration rate (GFR) < 60 mL/min/1.73 m2. Table 1: Patient Treatment Goals Concentration Corrected Calcium Phosphorus Ca x PO4 iPTH Stage 3 Stage of Kidney Disease Stage 4 Stage 5 GFR 30-59 mL/min/m2 GFR 15 – 29 mL/min/m2 GFR < 15 mL/min/m2 8.4-10.2 mg/dL 2.7-4.6 mg/dL 8.4-10.2 mg/dL 2.7-4.6 mg/dL 8.4-9.5 mg/dL 3.5-5.0 mg/dL < 55 < 55 < 55 35-70 mg/dL 70-110 mg/dL 150-300 mg/dL Phosphate Binders: Copyright 2006 All Rights Reserved Published by Omnicare, Inc. distributed by PBM Plus, Inc. Page - 5 HEALTHLINE March 2006 If phosphorus or iPTH concentrations cannot be controlled within the target range despite dietary phosphorus restriction, phosphate binders should be prescribed. There are two categories of phosphate binders, the calcium-based phosphate binders which include calcium carbonate (Tums, Oscal) and calcium acetate (Phos-Lo), and non calcium-based phosphate binders which include sevelamer (Renagel) and lanthanum (Fosrenol). All phosphate binders are similarly effective. Calcium-based products are often used as first line due to their ease of administration, and limited risk of toxicity. However, non-calcium based products are a safer alternative in patients who experience hypercalcemic symptoms or have an elevated calcium-phosphate product (>55 mg2/dL2). The total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1,500 mg/day, and the total intake of elemental calcium (including dietary calcium) should not exceed 2,000 mg/day. Patients should take their phosphate binder with meals and snacks for maximal effectiveness. Calcium acetate and sevelamer should be taken with meals, whereas calcium carbonate can be taken directly before meals. Clinicians should keep in mind that some multivitamins and laxatives may contain phosphorus and should be avoided. Gastrointestinal symptoms are common with all phosphate binders; however, patients may tolerate on product better than others. Table 2: Phosphate Binders Compound Estimate of (Brand name) % Calcium absorbed Calcium carbonate (Tums, Oscal, etc) Calcium Acetate (Phos-Lo) Approximately 20-30% is absorbed With meals: ~21% Between meals: ~40% Potential side effects Hypercalcemia, extraskeletal calcification, GI side effects, constipation Hypercalcemia, extraskeletal calcification, GI side effects Sevelamer (Renagel) None (non-calcium) GI side effects Lanthanum (Fosrenol) None (non-calcium) GI side effects Vitamin D Analogs Vitamin D analogs approved for treating secondary hyperparathyroidism include paricalcitol (Zemplar), doxercalciferol (Hectoral), and calcitriol. All three agents are effective in directly suppressing PTH synthesis and reducing PTH concentrations. Dosing must be individualized and based on iPTH concentrations (Table 1). When Vitamin D analogs are used to suppress PTH concentrations, they may increase intestinal absorption of calcium and phosphorus because vitamin D receptors also are present in the gastrointestinal tract. Hypercalcemia, hyperphosphatemia, and an elevated calcium-phosphorus product are limitations of vitamin D treatment, particularly when administered with calciumcontaining phosphate binders. Copyright 2006 All Rights Reserved Published by Omnicare, Inc. distributed by PBM Plus, Inc. Page - 6 HEALTHLINE March 2006 Calcium and phosphorus concentrations should be obtained weekly, and PTH concentrations should be obtained at least every 4 weeks when initiating or titrating vitamin D doses. Once patients are stabilized on a maintenance dose, monitoring frequency can decrease to monthly for calcium and phosphorus and quarterly for PTH concentrations. Bone disease is a complex disorder related to CKD, and there is a growing body of literature demonstrating its significant morbidity and mortality. Awareness of this disorder in long-term care facilities can help to prevent and treat this disease. Measurement of calcium, phosphorus and PTH serum concentrations should occur when the GFR is < 60ml/ min/1.73 m2, with appropriate treatment and follow up for abnormal results. Please contact your Consultant Pharmacist if you have questions or would like additional information. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. 2004. Editorial Board Karen Burton, R. Ph., GCP, FASCP Mark Coggins, Pharm. D., GCP, FASCP Kelly Hollenack, Pharm. D. CGP Philip King, Pharm. D., GCP, FASCP Susan Kleim, B.S., Pharm., GCP, FASCP Terry O’Shea, Pharm. D., GCP, FASCP Elmer Schmidt, Pharm. D., GCP, FASCP Barbara J. Zarowitz, Pharm. D., GCP, FASCP Copyright 2006 All Rights Reserved Published by Omnicare, Inc. distributed by PBM Plus, Inc. Page - 7