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Medication Guidelines for Pediatric Cystic Fibrosis Patients Cameron Jordan, PharmD, BCPS Pediatric Pharmacy Satellite Hours: 07:00-23:30 Pediatric Pharmacy #: 984-974-6679 Blue Team Pharmacist Pager #: 123-7108 After 23:30, call Central Pharmacy for questions: 984-974-8761 Oral Antibiotics Drug Dosing Maximum single dose 2000 mg Amoxicillin/ clavulanic acid 15 mg/kg TID (standard dose) or 45 mg/kg BID (high dose) Cefpodoxime 5 mg/kg BID 200 mg Cefuroxime axetil 10-15 mg/kg BID (suspension) or 250-500mg BID (tablet) 500 mg Cephalexin 25 mg/kg QID 1000 mg Ciprofloxacin 20 mg/kg BID 1000 mg Clarithromycin 15 mg/kg/day divided BID 500 mg Clindamycin 600 mg Dicloxacillin2 30-40 mg/kg/day divided TID 6.25-12.5mg/kg QID Doxycycline 1-2 mg/kg BID 100 mg Levofloxacin < 5 yo: 10 mg/kg BID > 5 yo: 10 mg/kg daily 750 mg 250mg*, 500mg*, 750mg tablets* 25mg/mL solution* Linezolid < 12 yo: 10 mg/kg Q8 > 12yo: 10 mg/kg Q12 600 mg 600mg tablet* 100mg/5mL suspension* Minocycline 4 mg/kg once, then 2 mg/kg Q12 100 mg 50mg*, 75mg*, 100mg capsules* Sulfamethoxazole/ Trimethoprim (SMX/TMP) 4-6 mg TMP/kg Q12 160mg TMP 80 mg TMP+400 mg SMX tab* 160 mg TMP+800 mg SMX DS tab* 40mg TMP+200mg SMX/5mL suspension* 500 mg Available preparations Other considerations 500mg*, 875mg tablets* 200mg*, 400mg chewables* XR tablets 1000mg 200mg/5mL*, 400 mg/5mL suspension* ES suspension: 600 mg/5mL (less clavulanic acid) 100mg, 200mg tablets 50mg/5mL, 100mg/5mL suspension 125mg*, 250mg*, 500mg tablets* 125mg/5mL, 250mg/5mL suspension 600mg/5mL for high dose only 250*, 500mg capsules* 125mg/5mL*, 250mg/5mL suspension* 100mg, 250mg*, 500mg*, 750mg tablets* 100 mg/mL*, 250mg/5mL suspension 500mg, 1000mg XR tablets 250mg*, 500mg tablets* 500mg XR tablets 125mg/5mL*, 250mg/5mL suspension* 75mg, 150mg*, 300mg capsules 75mg/5mL suspension* 125mg*, 250mg*, 500mg capsules* 50mg*, 100mg capsules* 25mg/5mL suspension* Suspension and tablet are not interchangable Suspension must be administered with food Do not give oral suspension via G-tube or NG tube Hold tube feeds 1 hr before and 2 hrs after administration Avoid within 2hrs of antacids, Ca, Fe, Mg, and cholestyramine Suspension should be administered 1 hr before or 2hrs after eating Consider continuing q8 hour dosing if > 12 yr but less than 45 kg Avoid within 2hrs of antacids, Ca, Fe, Mg, and cholestyramine *Indicates UNC formulary item 1 Intravenous Antibiotics Double-cover Pseudomonas, do not combine anti-pseudomonal beta lactams, as they can be antagonistic Initial doses for Tobramycin and Amikacin should be based on patients’ previous doses; see pharmacist consult note for past dosing information If patient has not received aminoglycosides in the past, use the following guide for dosing Drug Amikacin Dosing 15 mg/kg Q12 Maximum single dose Aztreonam1,2 Cefepime1,3 50-75 mg/kg Q6 50 mg/kg Q8 8-12 g/day 2000 mg Ceftaroline4 < 6 months: 8 mg/kg Q8 > 6 months and <33 kg: 12 mg/kg Q8 > 33 kg: 400 mg Q8 200-400 mg/kg/day divided Q6-8 50-100 mg/kg Q12 75 mg/kg Q8 10 mg/kg Q8 10-13.3 mg/kg Q8 3-5 mg/kg/day divided Q8 25 mg/kg Q6 400 mg < 5 yo: 10 mg/kg Q12 > 5 yo: 10 mg/kg daily < 12 yo: 10 mg/kg Q8 ≥ 12 yo: 10 mg/kg Q12 750 mg 40 mg/kg Q8 50 mg/kg Q6 100 mg/kg Q6 (based on piperacillin component) 10 mg/kg Q24 or previous total daily dose 6mg Q12 2000 mg 2000 mg 4000mg piperacillin (4.5g Zosyn®) 15-20 mg/kg Q6-8 2000 mg Ceftazidime1,3 Ceftriaxone Cefuroxime Ciprofloxacin1,5 Clindamycin Colistin1,6 Imipenem/ Cilastatin1,2 Levofloxacin1,5 Linezolid Meropenem1,2 Oxacillin1 Piperacillin/ Tazobactam1,3 Tobramycin (extended interval) Tobramycin (traditional dosing) Vancomycin10 Other considerations Draw peak and trough with 3rd dose May require 50 mg/kg Q6 for Pseudomonas MIC > 161 8-12 g/day 2000 mg 1500 mg 400 mg 2700 mg/day 100mg Monitor renal function closely Can use up to 8 mg/kg/day 1000 mg 600 mg Consider continuing q 8 hour dosing if > 12 yr but less than 45 kg Draw levels at 2 and 8 hours after 1st or 2nd dose started Draw peak and trough with 3rd dose Draw trough prior to 4th dose 2 Nontuberculous Mycobacterium – Antibiotics *Typically start only one drug each day to assess for nausea/vomiting from each drug Recommended Regimens (vary by physician preference): 1. Clarithromycin or azithromycin 2. Amikacin 3. Cefoxitin, imipenem/cilastatin, tigecycline, or linezolid Drug Amikacin12 Dosing 15 mg/kg IV daily Maximum single dose Azithromycin12 5 mg/kg PO daily Cefoxitin12 200 mg/kg/day divided TID-QID 15 mg/kg PO BID 20-25 mg/kg IV Q6 250mg (<40kg), 500mg (> 40 kg) 2g Clarithromycin12 Imipenem/ cilastatin12 Linezolid12 Tigecycline12,13 < 12 yo: 10 mg/kg Q8 ≥ 12 yo: 10 mg/kg Q12 < 10 yo: 1.2 mg/kg IV Q12 > 10 yo: 50mg IV daily 500mg 500mg 600mg Other considerations Draw peak and trough with 3rd dose; goal peak = 20-30 mg/L Can utilize TID dosing for home convenience Can consolidate to Q8 dosing for home 1:1 PO to IV conversion 50mg Synergy for Staphylococcus aureus: Rifampin: 10 mg/kg/dose PO q 12 hours (max dose 600 mg daily for adults) 3 Antifungals *These have lots of drug interactions! Drug Dosing Fluconazole 12 mg/kg x 1, then 6-12 mg/kg IV/PO Q24 Itraconazole 5 mg/kg PO Q12 Voriconazole (IV) Loading doses: < 12 yo: 9 mg/kg IV Q12 x 2 doses > 12 yo: 6 mg/kg IV Q12 x 2 doses Maintenance doses: < 12 yo: 5-7 mg/kg IV Q12 > 12 yo: 4 mg/kg IV Q12 9 mg/kg PO Q12 Voriconazole (PO) Posaconazole19 Maximum single dose 800mg 200 mg Suspension: 3-4 mg/kg QID Tablets: 300mg PO BID x 1 day, then 300mg daily IV: 300mg IV BID x 1 day, then 300mg daily Suspension: 400mg Available oral preparations 50mg*, 100mg*, 150mg*, 200 mg tablets* 50mg/5mL*, 200mg/5mL suspension 100mg capsules* 50mg/5mL solution* 50mg*, 200mg tablets* 40mg/mL suspension* 40mg/mL suspension* 100mg DR tablet* Considerations for antifungal therapies: Fluconazole Itraconazole Posaconazole Voriconazole Renally Dose Adjust Yes No No No, but do not use IV formulation if CrCl<50 Drug Interactions PPIs: May decrease fluconazole levels May increase tacrolimus levels Capsules: food increases absorption PPIs: May decrease itraconazole levels May increase tacrolimus levels Capsules: food increases absorption PPIs: May decrease posaconazole levels May increase tacrolimus levels Best absorption with a highfat meal PPIs: May increase voriconazole levels May increase tacrolimus levels Solution: food decreases absorption. Take on empty stomach Day 5 of therapy Solution: food decreases absorption. Take on empty stomach Day 14 of therapy Meals Steady State Food may decrease voriconazole absorption Give 1 hour before or 1 hour after a meal Day 5 of therapy Day 5 – 7 of therapy in the absence of a loading dose Goal Trough Concentrations (30 min prior to dose) N/A Itraconazole + hydroxyitraconazole > 1 and < 10 mcg/mL > 700 ng/mL Day 2 of therapy following a loading dose 1 – 5.5 mcg/mL Recommend Adjustments N/A < 1 mcg/mL – increase dose by 50% < 700 mg/mL – increase dose by 50% < 1 mcg/mL – increase dose by 50% > 10 mcg/mL – decrease dose by 25-50% > 5.5 mcg/mL – decrease dose by 25-50% (may consider alternative agents if clinically significant toxicities) 4 Pharmacokinetic Monitoring for Aminoglycosides and Vancomycin Peaks and troughs of aminoglycosides are monitored for efficacy and safety, beginning with the 3rd or 4th dose. For traditional dosing, the trough is drawn immediately before a dose, the dose is given and followed by a flush, and the peak is drawn 2 hours after hanging the dose. All peaks and troughs must be obtained via peripheral sticks unless otherwise discussed with pulmonary service. For extended interval dosing, timed tobramycin levels are drawn at 2 hours and 8 hours after the 1st or 2nd dose is started. The service pharmacist will use these to extrapolate peak and trough concentrations. Desired parameters are as follows: Tobramycin (traditional): trough < 1 mg/dL; extrapolated peak 12-15 mg/dL Tobramycin (extended interval): trough < 1 mg/dL; extrapolated peak 20-30 mg/dL Amikacin (for Mycobacterium abscessus): trough < 5 mg/dL; extrapolated peak 20-30 mg/dL Amikacin (other indications): trough < 5 mg/dL; extrapolated peak 35-45 mg/dL Usually monitor troughs only for Vancomycin. Trough is drawn immediately before the fourth dose is due. Desired parameters are: Vancomycin: trough 15-20 mg/dL BUN/SCr should be obtained twice weekly. Ensure adequate hydration and discontinue all other nephrotoxic drugs (including ibuprofen at any dose). Patients should also receive an annual hearing evaluation to evaluate for ototoxicity from aminoglycosides. If on vancomycin + aminoglycoside, consider obtaining BUN/SCr more frequently. Nebulized Medications Albuterol: 2.5-5 mg nebulized QID Hypertonic Saline: to transition patient to 7% 3% Hypertonic Saline: 5mL nebulized BID-QID 5.45% Hypertonic Saline: 4mL nebulized BID-QID 1mL 0.9% Sodium Chloride + 3mL 7% Sodium Chloride 7% Hypertonic Saline: 4mL nebulized BID-QID Dornase Alfa (Pulmozyme®): 2.5mg/2.5mL ampule nebulized daily-BID Use with PARI® LC + nebulizer Nebulized antibiotics are administered via nebulizer after the patient’s usual inhaled treatments (including bronchodilators and dornase) and chest physiotherapy. Amikacin: Doses vary based on patient tolerance (outpatient therapy only) 250 mg nebulized BID, if tolerated can increase to 500 mg nebulized BID Aztreonam: 75 mg nebulized TID Patients must supply own medication, Altera device, and cleaning supplies for inpatient use Colistin: Doses vary based on patient tolerance < 6 years: 75 mg nebulized BID > 6 years: 150 mg nebulized BID Tobramycin: 300 mg nebulized BID Vancomycin: 250 mg nebulized BID (outpatient therapy only) 5 Other CF Therapies Pancreatic Enzyme Supplements: Use patient’s home brand, OK to use home meds if not available at UNC. Infants: Initiate therapy with 1 capsule of Pancreaze 4,200 or equivalent mixed with one teaspoon of applesauce at beginning of feed. Do not place enzymes in baby bottles. Usual doses: 1500-2500 units lipase/kg/feed. Children: Initiate therapy with 500-2000 units lipase/kg/meal. Usual doses are 10,000-15,000 units lipase/kg/day. Goals: Adjust doses based on degree of steatorrhea and stool frequency: 3-4 stools/day for infants; 1-2 stools/day for children and adolescents. If enzyme requirement is large (>3000 units lipase/kg/meal) consider use of a H2 blocker (acidity inactivates enzymes). Do not exceed 3000 units/lipase/kg/meal. Doses > 20,000 units/kg/day increase risk of fibrosing colonopathy. Product Pancreaze® 4,200 10,500 16,800 21,000 Creon® 3,000 6,000 12,000 24,000 Zenpep® 3,000 5,000 10,000 15,000 20,000 Viokace® 10,440 20,880 Pertzye® 8,000 16,000 Ultresa® 13,800 20,700 23,000 Common Pancrelipase Products Dosage Form Lipase Units Amylase Units 4,200 17,500 Capsule, enteric 10,500 43,750 coated microspheres 16,800 70,000 21,000 61,000 3,000 15,000 6,000 30,000 Capsule, enteric coated microspheres 12,000 60,000 24,000 120,000 3,000 16,000 5,000 27,000 Capsule, enteric 10,000 55,000 coated microspheres 15,000 82,000 20,000 109,000 Tablet, non-enteric 10,440 39,150 coated 20,880 78,300 Capsules, enteric8,000 30,250 coated microtablets 16,000 60,500 Capsules, delayed13,800 27,600 release 20,700 41,400 23,000 46,000 Protease Units 10,000 25,000 40,000 37,000 9,500 19,000 38,000 76,000 10,000 17,000 34,000 51,000 68,000 39,150 78,300 28,750 57,500 27,600 41,400 46,000 Vitamin D Supplementation – Cholecalciferol Age Routine dosing with CF specific vitamins (IU) Step 1: Step 2: Dose increases (IU) Dose titration maximum (IU) 25OH = 20-30 * 25OH = 10-20 * Birth – 12 months 400 – 500 800 – 1,000 Not > 2,000 > 12 months – 10 yr 800 – 1,000 1,600 – 3,000 Not > 4,000 > 10 yr – 18 yr 800 – 2,000 1,600 – 6,000 Not > 10,000 > 18 yr 800 – 2,000 1,600 – 6,000 Not > 10,000 * Indicates total vitamin D (IU) intake per day, including Source CF vitamins ** Adapted from 2011 CF Update on Treatment of Vitamin D Deficiency 1 Source CF Softgel/Tablet = 1,000 units cholecalciferol 6 ADEK/SourceCF Vitamins: 1 SourceCF chew tab = 2 mL liquid SourceCF < 1 yr: Liquid SourceCF vitamins 1 mL QDay 1-3 yr: Liquid SourceCF vitamins 2 mL QDay May initiate chewable vitamins (1 QDay) at 2 yr 3-9 yr: SourceCF chewable vitamins 1 QDay > 10 yr: SourceCF chewable vitamins 2 QDay Vitamin K: For patients receiving oral or intravenous antibiotics < 1 yr: 2.5 mg PO additional twice a week > 1 yr: 5 mg PO additional twice a week May require daily vitamin K if PT elevated at admit Salt Supplement: Add supplemental salt to newborn and infant formula and food < 6 months: 1/8 teaspoon per day > 6 months – 1 yr: 1/4 teaspoon per day Ursodiol: 10-15 mg/kg/dose PO BID Azithromycin (Anti-inflammatory): < 25 kg: 10 mg/kg/dose PO Q MWF 25 – 39kg: 250 mg PO Q MWF > 40 kg: 500 mg PO Q MWF References: 1. Zobell JT, Young DC, Waters CD, et al. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: VI. Executive summary. Pediatr Pulmonol. 2013;48:525-537. 2. Zobell JT, Young DC, Waters CD, et al. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: I. Aztreonam and carbapenems. Pediatr Pulmonol. 2012;47:1147-1158. 3. Zobell JT, Waters CD, Young DC, et al. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and penicillins. Pediatr Pulmonol. 2013;48:107-122. 4. Ceftaroline clinical trial 5. Stockmann C, Sherwin CMT, Zobell JT, et al. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: III. Fluoroquinolones. Pediatr Pulmonol. 2013;48:211-220. 6. Young DC, Zobell JT, Waters CD, et al. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: IV. Colistimethate sodium. Pediatr Pulmonol. 2013;48:1-7. 7. Flume PA, Mogayzel PJ, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180:802-808. 8. Trust UCF. Antibiotic treatment for cystic fibrosis in UK Cystic Fibrosis Trust Antibiotic Working Group. 2009. 9. Doring G, Conway SP, Heijerman HGM, et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J. 2000;16:749-767. 10. Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook, 21st edition, 2014-2015. 11. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Resp Crit Care Med 2003;168:918-51. 12. Chimel JF, Aksamit TR, Chotirmall SH, et al. Antibiotic management of lung infections in cystic fibrosis: II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi. Ann Am Thorac Soc. 2014;11(8):12981306. 13. Wallace RJ, et al. Clinical experience in 52 patients with tigecycline-containing regimens for salvage treatment of Mycobacterium abscessus and Mycobacterium chelonae infections. J Antimicrob Chemother. 2014;69:1945-1953. 14. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial disease. Am J Respir Crit Care Med. 2007;175:367-416. 15. Andes D, Pascual A, Marchetti O: Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009;53(1):24-34. 16. Hope WW, Billaud EM, Lestner J, Denning DW: Therapeutic drug monitoring for triazoles. Curr Opin Infect Dis 2008;21:580-586. 7 17. Pascual A et al. Voriconazole TDM in patients with invasive mycoses improves efficacy and safety outcomes. CID 2008;45:201-211. 18. Scott LJ, Simpson D. Voriconazole: a review of its use in the management of invasive fungal infections. Drugs 2007;67:269--98. 19. Bernardo VA, Cross SJ, Crews KR, et al. Posaconazole therapeutic drug monitoring in pediatric patients and young adults with cancer. Ann Pharmacother. 2013;47(7-8):976-983. Revised 5/15 Cameron Jordan, PharmD, BCPS 8