The Dosing of Medications in Patients Receiving Continuous Enteral Feedings

Home , Carvedilol, Enteral administration, Hydralazine, Levofloxacin, Posaconazole

Dosing of Medications in Patients Receiving Continuous Enteral Feedings – Adult – Inpatient Clinical Practice Guideline

Table of Contents EXECUTIVE SUMMARY ...... 2 SCOPE ...... 3 METHODOLOGY ...... 3 DEFINITIONS ...... 3 INTRODUCTION ...... 3 RECOMMENDATIONS ...... 4 Table 1: Medications Interacting with Continuous Enteral FeedingsMedication ...... 5 UW HEALTH IMPLEMENTATION ...... 24 APPENDIX A. EVIDENCE GRADING SCHEMES ...... 25 REFERENCES ...... 26

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CPG Contact for Changes: CPG Contact for Content: Name: Philip Trapskin, PharmD Name: Sara Shull, PharmD, MBA Phone Number: 263-1328 Phone Number: 262-1817 Email Address: [email protected] Email Address: [email protected]

Guideline Author(s): Coordinating Team Members: Jeff Fish, PharmD Sara Shull, PharmD, MBA, BCPS David Hager, PharmD, BCPS Melissa Heim, PharmD Suppachai Insuk, PharmD Sara Shull, PharmD, MBA, BCPS

Committee Approvals/Dates: Nutrition Support Committee: November 2014 Pharmacy and Therapeutics: January 2011, November 2014, September, 2015

Release Date: September 2015 Next Review Date: September 2018

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 Executive Summary Guideline Overview: The purpose of this guideline is to provide recommendations for administering oral medications in a patient concurrently receiving enteral feedings. The goal of the guideline is to prevent or minimize interactions between medications and nutritional feeds in order to maximize absorption and clinical benefit of medications.

Key Practice Recommendations1-3 This clinical practice guideline is intended to establish a consistent, efficient, and safe standard for the administration of oral medications concurrently with enteral feedings to patients at UWHC. See Table 2 and Figure 1 for evidence classifications.

1. All patients receiving enteral feeds and medications should be assessed for potential interactions and their severity. (Class B) 2. When possible, separate the administration of feeds and medications. (Class A) 3. Use immediate release, non-enteric coated formulations when administering medications with continuous enteral feeds (Class B) 4. Enteral tubes should be flushed with water (at least 15 mLs) before and after medications administration. (Class A) 5. Patients should be monitored periodically for appropriate clinical response to medications (Class B)

Summary of key recommendations for management of medications interacting with continuous enteral feedings2 (See Table 1 for complete recommendations)

1. Increase medication dose: 1.1. ciprofloxacin (mild-to-moderate infections) (Class IIa Level of Evidence B) 2. Increase frequency of medication: 2.1. If changing from extended release formulation: 2.1.1. carbamazepine and phenytoin (Class IIa, Level of evidence B) 2.1.2. diltiazem and divalproex/valproic acid (Class IIB, Level of Evidence C) 2.2. Phosphate binders: calcium acetate, lanthanum, sevelamer (all Class IIb, Level of Evidence C) 3. Hold tube feedings for a period both before and after medication administration: 3.1. penicillin V, phenytoin (one alternative) , theophylline (all Class IIa, Level of Evidence B) 3.2. levothyroxine (if giving concomitantly for >7 days (Class IIa, Level of Evidence C) 3.3. warfarin (one alternative)(Class IIb, Level of Evidence B) 3.4. itraconazole, levofloxacin (mild-to-moderate infections), tamsulosin,, voriconazole (all Class IIb, Level of Evidence C) 4. Administer medication with enteral feeding: 4.1. atovaquone (Class IIa,Level of Evidence B), 4.2. posaconazole (or give with canola oil) (Class IIb,Level of Evidence B) 5. Do not give medication via enteral route / down enteral tube. Use an alternative agent: 5.1. ciprofloxacin (severe infection give IV; do not give via tube ending in jejunum) (Class I, Level of Evidence B) 5.2. phenytoin (one alternative is give fosphenytoin/phenytoin IV) (Class IIa, Level of Evidence B) 5.3. levofloxacin (severe infection give IV; do not give via tube ending in jejunum) (Class IIb, Level of Evidence C) 5.4. dabigatran (do not open capsule) (Class III, Level of Evidence A) 5.5. rivaroxaban (use alternative anticoagulant if enteral tube ends distal to the stomach) (Class III,Level of Evidence B) 5.6. sucralfate (give proton pump inhibitor or histamine-2 receptor antagonist) (Class III, Level of Evidence C) 2

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 Companion Documents 1. Table 1. Medications Interacting with Continuous Enteral Feeds 2. Appendix A. Medication Administration via Enteral Tubes

Pertinent UW Health Policies & Procedures 1. Adult Enteral Nutrition Support Handbook

Patient Resources 1. Health Facts for You: Enteral Feeding: Gastrostomy Tube Feeding #295 2. Health Facts for You: Enteral Feeding: Jejunostomy Tube Feeding #296 3. Health Facts for You: Enteral Feeding: Dobhoff Tube Feeding #5969 Scope To establish recommended dosage adjustments for a pre-defined list of oral medications that may interact with enteral nutrition for adult patients only. Methodology

A PubMed search of the English-language literature was performed to identify primary literature on enteral nutrition. Specific medications researched were cross referenced by using MeSH Database headings. Those medications having no primary or secondary published literature identifying the presence or absence of interactions with continuous enteral nutrition were identified. The manufacturers of these medications were then contacted. If no specific recommendations were made by the pharmaceutical manufacturer concerning administration of their product with continuous enteral nutrition, experts were asked to provide recommendations on administration of drug therapy and continuous enteral nutrition.

The strength of general practice recommendations is based on a modified version of the method used by the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services and adopted by the American Society for Parenteral and Enteral Nutrition (ASPEN) to classify evidence supporting recommendations in enteral nutrition practice recommendations published in 2009.1

A modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) developed by the American Heart Association and American College of Cardiology (Appendix 1.) has been used to assess the Quality and Strength of the Evidence for specific medications in this clinical practice guideline (Figure 1).4 Definitions

Enteral Nutrition: Nutrition provided through the gastrointestinal tract via a tube, catheter, or stoma that delivers nutrients distal to the oral cavity.

Continuous Enteral Feedings: Mode of enteral feedings that provides the daily nutritional goal continuously over 24 hours.

Introduction Interactions between oral medications and enteral nutrition have been appreciated for many years, yet specific recommendations on how to administer these medications to patients is lacking in the literature. Ensuring that medications delivered to a patient will be adequately absorbed is often difficult. With the increased emphasis on changing medication from parenteral to oral dosage formulations to manage infection risk, afford patients greater mobility, and reduce cost, this is becoming more of a consideration.2,5,6

Since enteral tubes are placed into different sites of the gastrointestinal tract (ie. stomach, duodenum, jejunum), drug absorption from different sites was included, if available. Evidence derived from patients who have received Roux-en-Y gastric bypasses was included to help determine absorption of medications from the jejunum.

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 By recognizing the severity of potential drug-nutrient interactions, practitioners may prevent possible interactions and ultimately improve patient outcomes.2 The following guidelines were generated to aid practitioners in their decision on how to best administer medications to patients receiving continuous enteral nutrition. All included medications have been designated with one of the following recommendations: 1. adjust the dose of the oral medication; 2. no dose adjustment necessary; 3. hold enteral nutrition around the administration of the medication; or 4. hold the oral medication while the patient is on enteral nutrition or use an alternate administration route for the medication. Holding enteral nutrition was recommended conservatively, due to the risk of not meeting nutritional goals.

Recommendations1 1. Do not add medication directly to an enteral feeding formula. (Class B) 2. Avoid mixing together medications intended for administration through an enteral feeding tube given the risks for physical and chemical incompatibilities, tube obstruction, and altered therapeutic drug responses (ie, do not mix medications together, but do dilute them appropriately prior to administration). (Class B) 3. Each medication should be administered separately through an appropriate access. Liquid dosage forms should be used when available and if appropriate. Only immediate-release solid dosage forms may be substituted. Grind simple compressed tablets to a fine powder and mix with sterile water. Open hard gelatin capsules and mix powder with sterile water. (Class B) 4. Prior to administering medication, stop the feeding and flush the tube with at least 15 mL water. Dilute the solid or liquid medication as appropriate and administer using a clean oral syringe (≥ 30 mL in size). Flush the tube again with at least 15 mL water taking into account patient’s volume status. Repeat with the next medication (if appropriate). Flush the tube one final time with at least 15 mL water. (Class A) 5. Restart the feeding in a timely manner to avoid compromising nutrition status. Only hold the feeding by 30 minutes or more when separation is indicated to avoid altered drug bioavailability. (Class A) 6. Consult with a pharmacist for patients who receive medications co-administered with EN. (Class C)

Suggest no dose adjustment No interaction with food. Solubility required 8 Amantadine No data available increases with water. (Class IIb, Level of Evidence C)

Suggest no dose adjustment required 9 Amlodipine No data available No interactions with food (Class IIb, Level of Evidence C)

Food may enhance rate and extent of absorption. After consuming a high- Suggest no dose adjustment fat meal, the AUC of amiodarone required. 10 Amiodarone No data available. increased 2.3 times the fasting and the Cmax increased 3.8 times the (Class IIb Level of Evidence C) fasting value.

Optimally administered at the start of a standardized meal. Absorption of Suggest no dose adjustment Amoxicillin/ amoxicillin is decreased in the fasting required. 11 No data available. Clavulanate state. High fat meals decrease the absorption of the clavulanate (Class IIb, Level of Evidence C) component.

Suggest no dose adjustment required. 12 Apixaban No data available No interactions with food. (Class IIb, Level of Evidence C)

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 Table 1: Documented interaction Medications Recommendation: with continuous enteral Interacting with Documented Food Interaction Adjustments with regards to Reference feedings / site of enteral Continuous Enteral continuous enteral feedings access FeedingsMedication The mean AUC of atovaquone suspension in Food significantly increases Suggest no dose adjustment serum after enteral bioavailability. Therapeutic plasma required, but it needs to be administration with concentrations may not be achieved if administered with tube feedings 13 Atovaquone concomitant Sustacal Plus administered during fasting. for maximal absorption. enteral feeds was significantly greater when compared with (Class IIa, Level of Evidence B) fasting.

Food produces no clinically significant change in bioavailability. Suggest no dose adjustment Tablets: Food was shown to increase required. 14 Azithromycin No data available. Cmax by 23% but had no effect on AUC. (Class IIb, Level of Evidence C) Suspension: Food increased Cmax by 56% and AUC was unchanged.

Suggest no dose adjustment required 15 Baclofen No data available No interactions (Class IIb, Level of Evidence C)

Suggest scheduling 4-6 times per day for maximum effect. If a combination of phosphate binders Therapeutic effect of drug requires 16 Calcium Acetate No data available. is needed, they should be that it be taken with food. scheduled at different times

(Class IIb, Level of Evidence C)

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 Table 1: Documented interaction Medications Recommendation: with continuous enteral Interacting with Documented Food Interaction Adjustments with regards to Reference feedings / site of enteral Continuous Enteral continuous enteral feedings access FeedingsMedication Administration of the commercially available suspension through the NGT results in drug adherence to the polyvinyl chloride walls of the feeding tubes resulting in inadequate drug delivery. The bioavailability of Suggest total daily dose should carbamazepine suspension be divided into four equal doses with enteral feeding Food decreases bioavailability (90.1% of carbamazepine suspension administration was 90.1% of of fasted state). and diluted with equal amount of 17-21 Carbamazepine that during fasting. Although diluent. Monitor carbamazepine absorption of carbamazepine levels. suspension was generally slower and slightly diminished (Class IIa, Level of Evidence B) during NGT feeding, this interaction may lessen unwanted side effects. Carbamazepine should be given diluted to prevent the significant loss seen when given undiluted.

Carbidopa/ See Sinemet Levodopa

No data. Suggest no dose adjustment Rate of absorption is decreased required. 22-24 Carvedilol Decreased rate of absorption however, bioavailability remains beyond jejunum site of unchanged (Class IIb, Level of Evidence C) administration.

Suggest no dose adjustment Concentration of cephalexin Food has no effect on bioavailability required. 25,26 Cephalexin with enteral nutrition is or AUC. Food delays absorption. reduced to 90%. (Class IIba, Level of Evidence C)

(Class I, Level of Evidence B) Increased T , while max Mild-to-moderate infections: decreasing C and max Suggest administering higher bioavailability. Enteral feeds doses, 750mg twice a day. No have sufficient concentrations dose adjustment needed for of Calcium, Aluminum, urinary tract infections due to Magnesium, and Zinc, to Food decreases bioavailability (31- drug concentrating at site of chelate drug and decrease 82% of fasting state). 27-31 Ciprofloxacin infection.. If administering absorption. through a tube ending in the jejunum, therapeutic levels may Absorption decreased if given not be achieved; in this case, thru a jejunostomy tube as suggest administering IV or using opposed to a gastrostomy another enteral route, if available. tube due to the site of drug When using feeding tubes, use absorption. crushed tablets as the suspension form cannot be used with any feeding tube.

(Class IIa, Level of Evidence B)

Suggest no dose adjustment required 33 Clonidine No data No interactions (Class IIb, Level of Evidence C)

No data Suggest no dose adjustment required 34,35 Clopidogrel No interaction Two fold increase in AUC with NG tube administration (Class IIb. Level of Evidence C)

Suggest no dose adjustment High-fat meals (45 g fat) within 0.5 required. Monitor cyclosporine hour of a dose decreased AUC 13% 36 Cyclosporine No data available. levels. and decreased Cmax 33%; effects of low-fat meals (15 g fat) were similar. (Class IIb, Level of Evidence C)

The capsules should not be A high-fat meal delays the time to broken or opened, so suggest C by approximately 2 hours but max using another form of has no effect on the bioavailability. anticoagulation be administered The oral bioavailability of dabigatran 37 Dabigatran No data available until patient is able to take increases by 75% if the pellets are capsule whole. taken without the capsule shell compared to the intact capsule formulation. (Class III, Level of Evidence A)

No data. Suggest no dosing adjustment Administration via NG tube required 38 Dantrolene No data without food resulted in clinically effect 30 minutes (Class IIb, Level of Evidence C) after administration.

Food increases absorption by 28% (increased maximal plasma Suggest administering same total concentrations 73 +/- 19 ng/mL vs daily dose, but use immediate 130 +/- 82 ng/mL in the fasting and release tablets dosed every 6-8 41,42 Diltiazem No data available. nonfasting states, respectively). Co- hours. administration of the tablets with high- fat meals does not affect systemic (Class IIb, Level of Evidence C) exposure.

Divalproex / See Valproic Acid / Valproic Acid Divalproex

The mean AUC of fluconazole in serum after enteral administration with concomitant enteral feeds did Suggest no dose adjustment not significantly differ from IV. required. 43-45 Fluconazole The concentrations of Minimal food effect on bioavailability. fluconazole reached via (Class IIa, Level of Evidence B) enteral administration were lower than those in serum for IV, but adequate to treat most cases of deep mycoses.

Suggest no dose or tube feed AUC and C increases by 14% with adjustments required 46,47 Gabapentin No data available max food administration (Class IIb, Level of Evidence C)

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 Table 1: Documented interaction Medications Recommendation: with continuous enteral Interacting with Documented Food Interaction Adjustments with regards to Reference feedings / site of enteral Continuous Enteral continuous enteral feedings access FeedingsMedication Oral hydralazine given with a 6 hour infusion of Ensure via NGT resulted in a 16% increased AUC and 30% Studies have demonstrated Suggest no dose adjustment.. increased C compared to max inconsistent (increased, unchanged, 21,48 Hydralazine fasting. The same 470 ml and decreased) bioavailability of oral Ensure given as an enteral hydralazine when given with food. (Class IIa, Level of Evidence B) bolus, reduced the AUC by 62% and decreased Cmax by 87% as compared to fasting states.

Capsule formulation is maximally absorbed when administered with Suggest administration of the oral food and in the presence of normal solution in patients who are gastric acidity Commercially available receiving enteral feedings. . oral liquid is maximally absorbed Suggest holding tube feeds 1 when administered in a fasting state. hour before and 1 hour after 49 Itraconazole No data available. administration. Monitor Itraconazole oral solution was itraconazole levels. compared to capsules given to healthy volunteers under fed conditions. The AUC for the solution (Class IIb, Level of Evidence C) was 149+68% of that obtained for the capsule.

Suggest no dose adjustment Rate and extent of absorption not required 50 Lacosamide No data affected by food (Class IIb, Level of Evidence C)

Suggest no dose adjustment required 51 Lamotrigine No data No interactions (Class IIb, Level of Evidence C)

(Class IIb, Level of Evidence C)

The overall rate and extent of absorption of levetiracetam was not significantly impaired Suggest no dose adjustment The overall rate and extent of after mixing the tablet with required. absorption of oral levetiracetam was 53 Levetiracetam enteral nutrition. C may be max not significantly impaired when mixing slightly reduced after mixing, with food. although the difference was (Class IIb, Level of Evidence B) not significant when compared to control.

(Class IIb, Level of Evidence C)

Mild-to-moderate infection: Oral administration of levofloxacin Suggest no change in dosing if tablets with food prolongs the Tmax using TABLET. Suggest holding by 1 hour and decreases the Cmax by tube feedings 1 hour before and 1 54 No data available. 14% (not deemed clinically hour after SOLUTION Levofloxacin significant). When levofloxacin administration. If administering solution was given with food, Cmax is through a tube ending in the decreased approximately 25%. jejunum, based on ciprofloxacin data, therapeutic levels may not be achieved; in this case, suggest administering IV or using another enteral route, if available.

(Class IIb, Level of Evidence C)

For use < 7 days: Suggest no dose adjustment required. Decreased levels as levothyroxine may bind to (Class IIb, Level of Evidence C) enteral feeding tubes and/or Levothyroxine Food may decrease absorption and 55,56 may be lost during crushing Sodium may increase fecal elimination. For use > 7 days: Suggest and transfer. holding tube feedings 1 hour pre and post dose. Monitor thyroid function weekly.

(Class IIa, Level of Evidence C)

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 Table 1: Documented interaction Medications Recommendation: with continuous enteral Interacting with Documented Food Interaction Adjustments with regards to Reference feedings / site of enteral Continuous Enteral continuous enteral feedings access FeedingsMedication Linezolid oral suspension is rapidly and completely absorbed via the enteral route. Bioavailability of linezolid remains unaltered in the presence of continuous Suggest no dose adjustment enteral feedings. High fat meal may delay T (from max required. 1.5 to 2.2 hours) and decrease Cmax 57,58 Linezolid by 17%. AUC remains relatively Linezolid after Roux-en-y unaffected. (Class IIa, Level of Evidence B) gastric bypass surgery results in an ~86% increase in AUC than patients prior to bypass. This increase in AUC was associated with a decrease in total body weight.

Suggest no dosing adjustment High amounts of caffeine increase required 59,60 Lithium No data clearance. Food may increase therapeutic levels (Class IIb, Level of Evidence C)

Suggest no dose adjustment required. 61 Lorazepam No data available. No interactions.

(Class IIb, Level of Evidence C)

Suggest no dose adjustment required. Medication should be taken with food 62 Metoprolol No data available. or directly following meals. (Class IIb, Level of Evidence C)

(Class IIb, Level of Evidence C)

A single dose of moxifloxacin 400mg was given to healthy volunteers in a crossover fashion. Moxifloxacin AUC was slightly decreased when given with enteral nutrition Moxifloxacin 400 mg has through an NGT compared to Suggest no dose adjustment demonstrated bioequivalance with oral dosing. The difference required. May be given without respect to C and AUC when given was not deemed clinically max respect to site of enteral tube. in fasting and fed states. T is also 64-66 Moxifloxacin significant. max similar between fed and fasted (Class IIa, Level of Evidence B) conditions. High fat food may delay Moxifloxacin after Roux-en-y rate of absorption; however, the gastric bypass surgery results extent of absorption is unaffected. in ~25% reduction in Cmax and an absolute bioavailability of ~88%. These values are higher than those found in patients without gastric bypass.

Suggest no dose adjustment Food has no effect on mycophenolic required. Do not manipulate acid AUC, but has been shown to tablets/capsules due to No data available. decrease mycophenolic acid C by max teratogenic effect, use 67,68 Mycophenolate 40%. Administration with iron has no SUSPENSION. Mofetil change in the AUC.

(Class IIb, Level of Evidence C)

No data available. Food decreases bioavailability by Suggest no dose adjustment Holding tube feeds before 38% and lowers peak plasma required. and after the frequent 70 Nimodipine concentration by 68%, compared to administration required for fasting. Bioavailability with food is nimodipine would 9% compared to 13% while fasting. (Class IIb, Level of Evidence C) dramatically decrease daily enteral intake.

The median and trough plasma concentrations of the active metabolite of Coadministration with food had no oseltamivir given via a NGT significant effect on the peak plasma or NJT tube with or without concentration (551 ng/ml under Suggest no dose adjustment enteral feedings, were similar fasted conditions and 441 ng/ml required. 71,72 Oseltamivir or higher than ambulatory under fed conditions) and the AUC patients. There was a delay (6218 ng h/ml under fasted conditions (Class iia, Level of Evidence B) in absorption in the NGT / and 6069 ng h/ml under fed NJT group, but the AUC for conditions) of the active metabolite. the metabolite was similar to ambulatory patients.

Suggest no dose adjustment required 73 Oxcarbazepine No data Food does not affect bioavailability (Class IIb, Level of Evidence C)

(Class IIb, Level of Evidence C)

Suggest no dose adjustment required when using compounded pantoprazole Crushing the delayed-release suspension. tablet can result in tube clogging. Dissolving the Food has no effect on pantoprazole enteric-coated granules in pharmacokinetics. Neither food nor (Class IIb, Level of Evidence B) water prior to administration antacids altered the bioavailability of 75-77 Pantoprazole can destroy the medication pantoprazole. Tmax is highly variable Pantoprazole delayed-release before it reaches its and may increase when pantoprazole and enteric-coated tablets should absorption site in the small is given with meals. not be crushed for administration intestine. This is avoided by down gastric or jejunal feeding the compounded suspension. tubes.

(Class III, Level of Evidence C)

Unpredictable absorption Suggest holding enteral nutrition Reduces and prolongs peak serum Penicillin V with tube feeds. 1 hour before and 2 hours after 78 level; extent of absorption Potassium Bioavailability may vary from dose unchanged. 30 to 80%. (Class IIa, Level of Evidence B)

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 Table 1: Documented interaction Medications Recommendation: with continuous enteral Interacting with Documented Food Interaction Adjustments with regards to Reference feedings / site of enteral Continuous Enteral continuous enteral feedings access FeedingsMedication Suggest using IV fosphenytoin or 79,80 phenytoin; alternatively suggest Feeding tubes may hold tube feeds 1 hour before and Food has no effect on the absorption decrease absorption of 1 hour after dose. Total daily UWHC of brand-name Dilantin® or generic phenytoin suspension up to dose should be divided into twice Fosphenyt Phenytoin phenytoin made by Teva. Food 80% via protein binding, poor daily dosing. Monitor phenytoin oin and decreases the absorption of the solubility, or binding to levels. Phenytoin generic phenytoin made by Mylan. feeding tubes. guideline

(Class IIa, Level of Evidence B)

Giving posaconazole with 240ml of a nutritional supplement (Boost Plus) increased Cmax 3.4-3.5-fold and AUC 2.6-2.9-fold over the fasting state in healthy volunteers.

Administering a single dose A 4-fold and 2.6-fold increase in C Suggest giving each of posaconazole via an NGT max and AUC was observed in subjects posaconazole dose with 240ml of in healthy volunteers after given high-fat (~50g) and nonfat nutritional supplement or 15ml of 240ml of a nutritional meals, respectively. A low-fat meal canola oil. If patient is unable to supplement (Boost Plus) 81-85 Posaconazole (14g) resulted in a ~3-fold increase in tolerate supplement or canola oil, resulted in 19% decrease in C and a 2.1-fold increase in AUC use alternative antifungal due to C and ~24% decrease in max max as compared to fasting. inadequate posaconazole AUC compared to oral absorption. administration. Canola oil (15mls) gives 15G of fat. Giving posaconazole via (Class IIb, Level of Evidence B) NGT in surgical intensive care unit patients receiving continuous enteral nutrition leads to inadequate plasma drug concentrations. The median fat intake was only 1.3 (range, 0-4.1) g/hour.

Greater than 90% of Suggest no dose adjustment ranitidine tablets and syrup necessary. 88,89 Ranitidine was recovered at 24 hours No interaction. after mixing with 8 different enteral feedings. (Class IIa, Level of Evidence C)

No data available with enteral Suggest no dose adjustment feedings required if enteral tube ends in the stomach. A 29% and 56% decrease in Doses up to 10 mg rivaroxaban had AUC and Cmax was reported high oral bioavailability taking with or when rivaroxaban was (Class IIa, Level of Evidence B) 90,91 Rivaroxaban without food. Rivaoxaban 15 mg and released in the proximal 20 mg need to be taken with food to small intestine compared to Recommend using alternative achieve high bioavailability (>=80%). the stomach. Exposure is anticoagulant if enteral tube ends further reduced when drug is distal to the stomach. released in the distal small intestine. (Class III, level of evidence B)

Manufacturer does not Recommend change to recommend administering suspension. Suggest scheduling Sevelamer tablets through feeding tubes 4-6 times per day for maximum as contents expand in water effect. If a combination of Therapeuticeffect of drug requires 92,93 and result in tube occlusion. phosphate binders is needed, that it be taken with food. May use suspension they should be scheduled at formulation. different times.

(Class IIb, Level of Evidence C)

High-fat meals alter bioavailability of oral Rapamune® solution. When compared to fasting, a 34% decrease in C , a 3.5-fold increase in T , max max Suggest no dose and a 35% increase in AUC was adjustments.Monitor sirolimus observed. After administration of levels. 96 Sirolimus No data available. Rapamune® tablets with a high-fat meal, Cmax, Tmax, and AUC showed increases of 65%, 32%, and 23%, (Class IIb, Level of Evidence C) respectively. To minimize variability, the oral solution and tablets should be taken consistently with or without food.

Binds to protein in tube feedings. Insoluble Use not recommended with Sucralfate may bind to the protein in complexes form with tube enteral feedings.Alternative: use food and reduce efficacy; therefore, it 21,97 Sucralfate feeding. PPI or H RA. is recommended to give sucralfate 1 2 hour before or 2 hours after meals. No activation due to alkaline (Class III, Level of Evidence C) pH of tube feeding.

Good bioavailability with food. High Suggest no dose adjustment fat may decrease AUC and C by max required. Enteral feedings through a 37% and 72%, respectively; Tmax was nasojejunal feeding tube did lengthened 5-fold. 98,99 Tacrolimus Monitor tacrolimus levels. not interfere with tacrolimus capsule absorption. High carbohydrate foods decreased mean AUC and mean C by 28% max (Class IIa, Level of Evidence B) and 65%, respectively.

Suggest holding enteral nutrition Absorption decreases by 1 hour before and 1 hour after >30% when given with dose.Use rapid release enteral nutrition have been theophyline products/solutions. reported. Absorption of an Food does not cause clinically Take total daily dose and divide extended-release preparation 2,101,102 Theophylline significant changes in absorption from into 3-4 doses per day. with enteral feedings given immediate-release dosage forms. orally did not differ from Monitor theophylline levels. absorption when administered on an empty stomach. (Class IIa, Level of Evidence B)

Suggest no dose adjustment No clinical significance when mixed required 103 Topiramate No data with food (Class IIb, Level of Evidence C)

Suggest no dose adjustment required. 104,105 Valacyclovir No data available. No interactions.

(Class IIb, Level of Evidence C)

Suggest administering same total Administration with food may delay daily dose, but use valproic acid the rate of absorption, but does not solution dosed every 6-8 hours. Valproic acid / 108 No data available. alter systemic exposure. Difference Monitor valproate levels. Divalproex should be of minor clinical importance under steady state conditions. (Class IIb, Level of Evidence C)

Suggest no dose adjustment required. 109 Vancomycin No data available. No interactions.

(Class IIb, Level of Evidence C)

Crushed voriconazole tablets delivered via a NGT (enteral feeding interrupted only for duration of dose administration) was associated with adequate Suggest holding tube feeds 1 Bioavailability of twice-daily 200mg plasma levels in 88% of hour before and 1 hour after voriconazole is reduced by ~22% as study patients. administration. 110,111 Voriconazole measured by AUC after multiple dosing when taken with food as Infectious disease physicians Monitor voriconazole levels. compared to fasting. concerned with inadequate (Class IIb, Level of Evidence C) levels when given concurrently with enteral nutrition and would prefer that enteral nutrition be held around dose.

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 Table 1: Documented interaction Medications Recommendation: with continuous enteral Interacting with Documented Food Interaction Adjustments with regards to Reference feedings / site of enteral Continuous Enteral continuous enteral feedings access FeedingsMedication Possible sequestering of Suggest no dose adjustment. warfarin in the Alternatively, suggest holding macromolecular fraction of feeds 1 hour before and 1 hour the formulas. Current enteral No interactions. 21,112- after administration. Either Warfarin formulations have minimal method requires close INR 115 amounts of Vitamin K to monitoring. Avoid formulas interact with warfarin. containing soy protein. Proteins in formula may bind (Class IIb, Level of Evidence B) to warfarin.

Suggest no dosing adjustment Food delays time to Cmax, however required 116 Zonisamide No data bioavailability is unchanged (Class IIb, Level of Evidence C)

Abbreviations: AUC: Area under the curve; Cmax: Intravenous maximum concentration; H2RA: Histamine-2 receptor antagonists; INR: International Normalized Ratio; IV: Intravenous; NGT: Nasogastric tube; NJT: Nasojejunal tube; PPI: Proton pump inhibitor; Tmax: Time to maximum concentration

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 09/2015 UW Health Implementation Benefits/Harms of Implementation 1. Appropriately dosing medications in patients receiving enteral nutrition will improve patient outcomes. 2. Standardizing dosing of medications in patients receiving enteral nutrition will provide consistency in patient treatment.

Implementation Strategy – The guideline will be posted electronically.

Implementation Tools/Plan – Education: Information will be sent to nurses, pharmacists and physicians regarding the updated guideline.

Disclaimer This Clinical Practice Guideline provides an evidence-based approach for the dosing of medications in patients receiving continuous enteral feedings. It is understood that occasionally patients will not match the conditions considered in the guideline.

Table 2. Evidence Grading system of the American Society for Parenteral and Enteral Nutrition (ASPEN)1

The evidence supporting each statement is classified as follows: Class A There is good research-based evidence to support the guideline (prospective, randomized trials). Class B There is fair research-based evidence to support the guideline (well-designed studies without randomization). Class C The guideline is based on expert opinion and editorial consensus

Figure 1. Quality of Evidence and Strength of Recommendation Grading Matrix4

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