TY - JOUR
AU - Fish, Jeffrey, T.
AB - Abstract Purpose. Recommendations for the use of medications with continuous enteral nutrition are provided. Methods. A literature review was conducted to identify primary literature reporting medication interactions with continuous enteral nutrition. For medications without supporting literature, manufacturers were contacted for information. Package inserts for specific medications were also investigated for any information to help guide recommendations. If no specific recommendations were made by the pharmaceutical manufacturer or the package insert concerning administration of products with continuous enteral nutrition, a tertiary database was consulted. Recommendations were generated by a consensus of clinicians for those medications that lacked specific recommendations in the primary literature or from the pharmaceutical manufacturer. Documentation of medication interactions with continuous enteral nutrition and food was then collated along with specific recommendations on how to administer the medication with regard to continuous enteral nutrition. Recommendations were classified as strong (grade 1) or weak (grade 2). The quality of evidence was classified as high (grade A), moderate (grade B), or low (grade C). Results. Forty-six medications commonly given to hospitalized patients were evaluated. Twenty-four medications had recommendations based on available data, and the remaining 22 medications had recommendations based on a consensus of clinicians. Conclusion. There was a lack of published data regarding drug–nutrient interactions for a majority of the drugs commonly administered to patients receiving continuous enteral nutrition. Clinicians should recognize potential drug–nutrient interactions and use available evidence to optimize patients’ drug therapy. Drug interactions, Nutrition Enteral nutrition has been used for more than 400 years.1 Over the past 40 years, advances in administration techniques and product formulations have made nutrition support possible for many patients. Although interactions between medications and nutrients have been appreciated for many years,2 specific recommendations on how to administer the majority of medications to patients receiving continuous enteral nutrition are lacking. This issue has become more problematic with the recent emphasis on i.v.-to-oral conversion, when appropriate, in order to decrease costs. Ensuring that the medications delivered to a patient will be adequately absorbed is often the responsibility of the pharmacist. However, the complex nature of enteral nutrition combined with the variety of drug dosage forms, active and inactive ingredients, and metabolites of these medications make this task more difficult. Earlier initiation of continuous enteral nutrition and the routine use of multiple medications may further complicate how to optimally administer necessary medications. By recognizing the severity of potential drug–nutrient interactions, practitioners may prevent possible complications, improve patient outcomes, and decrease costs. To aid practitioners in this task, we developed recommendations on how best to administer medications to patients receiving continuous enteral nutrition. The recommendations were derived from published clinical data or, in cases where supporting literature was lacking, opinions from experienced pharmacy clinicians. Literature review A review of the English-language medical literature from 1949 to 2008 was conducted to identify primary literature based on the controlled vocabulary of the U.S. National Library of Medicine. The medical subject heading (MeSH) term enteral nutrition was cross-referenced with the MeSH term for specific medications commonly used in hospitalized patients. The references of these articles and of secondary literature on enteral nutrition were manually searched for more articles for inclusion. If the primary literature did not identify any interactions with continuous enteral nutrition for a medication, two investigators contacted the manufacturers of medications lacking sufficient information regarding the interaction. Package inserts for specific medications were also investigated for any information to help guide recommendations. If no specific recommendations were made by the pharmaceutical manufacturer or the package insert concerning the administration of products with continuous enteral nutrition, a keyword search was conducted for each medication using the Drugdex database (Thomson Healthcare, Greenwood Village, CO). The pharmacokinetic section for each medication was consulted, and documented food interactions were recorded. Finally, eight unit-based clinical pharmacists, one clinical dietitian, and one nutrition-support pharmacist at the University of Wisconsin Hospital and Clinics were asked to provide recommendations based on food and drug interactions that they have noted in practice. All recommendations were assigned a grade of evidence based on a modified approach of the Grading of Recommendations Assessment, Development and Evaluation group.3 Recommendations were classified as strong (grade 1) or weak (grade 2). The quality of evidence was classified as high (grade A), moderate (grade B), or low (grade C). One of the following recommendations was made for commonly administered oral medications: (1) adjust the dose of the oral medication, (2) no medication administration changes are needed, (3) give the medication with enteral nutrition, (4) hold enteral nutrition around the administration of the medication, (5) hold the oral medication while the patient is on enteral nutrition, or (6) use an alternative administration route for the medication. Holding enteral nutrition was the last option chosen due to concerns about adjusting enteral nutrition and patients not meeting their nutritional goals. Evidence and recommendations for interactions between medications and enteral nutrition Forty-six oral medications communly used in hospitalized patients were evaluated. Study investigators identified these medications as the formulary medications most frequently prescribed in the medical–surgical intensive care unit at the University of Wisconsin Hospital. Listed below are the data compiled for these oral medications, including information on relevant interactions (or the lack thereof) with continuous enteral nutrition and food, along with recommendations for use and the grade of evidence for each recommendation. Acyclovir None of the available data indicated a drug–nutrient interaction between acyclovir and continuous enteral nutrition. Furthermore, the manufacturer reported that the absorption and bioavailability of acyclovir are unaffected by the administration of food.4 Therefore, no medication administration changes are needed (grade 2C). Aminophylline Aminophylline solution given with concurrent enteral nutrition resulted in a mean relative difference of 2.18% in drug absorption between the i.v. and enteral route, a nonsignificant difference.5 Food does not affect drug’s AUC, but extremes in dietary protein and carbohydrate intake when taking aminophylline should be avoided. Changes in diet may affect the elimination of theophylline (aminophylline).5 Charbroiled foods may increase drug elimination, reducing the drug’s half-life by 50%.5 No medication administration changes are needed (grade 1A). Amiodarone None of the available data indicated a drug–nutrient interaction between amiodarone and continuous enteral nutrition. The manufacturer reported that food may increase the rate and extent of absorption of oral amiodarone.6 The pharmacokinetics of a single 600-mg dose of oral amiodarone was evaluated in 30 healthy subjects after fasting overnight and immediately after consuming a high-fat meal via an open-labeled, crossover study.6 In the presence of food, amiodarone’s area under the plasma concentration–time curve (AUC) increased by 2.3 times the fasting value (range, 1.7–3.6 times), and the peak plasma concentration (Cmax) increased 3.8 times the fasting value (range, 2.7–4.4 times). The rate of absorption increased in the presence of food, while the time to peak plasma concentration (tmax) was decreased by 37%.6 No medication administration changes are needed; however, the drug should be administered consistently with regard to meals (grade 2C). Amoxicillin–clavulanate None of the available data indicated a drug–nutrient interaction between amoxicillin–clavulanate potassium and continuous enteral nutrition. Amoxicillin–clavulanate potassium is optimally administered at the beginning of a standardized meal. The absorption rate of amoxicillin is decreased in the fasting state, and high-fat meals decrease the absorption of the clavulanate potassium component.7 Therefore, no medication administration changes are needed (grade 2C). Atovaquone The mean AUC of atovaquone suspension in serum after concomitant administration with an enteral nutrient supplement (Sustacal Plus) was significantly greater than the mean AUC found with fasting.8 Food significantly increases the drug’s bioavailability. Therapeutic plasma concentrations may not be achieved if atovaquone is administered during fasting. Therefore, atovaquone should be administered with enteral nutrition for maximal absorption (grade 1A). Azithromycin None of the available data indicated a drug–nutrient interaction between azithromycin and continuous enteral nutrition. The manufacturer reported that coadministration of food with azithromycin does not result in a clinically significant change in bioavailability.9 For the tablet form, a high-fat meal resulted in a 23% increase in the Cmax but had no effect on the AUC in 12 healthy subjects who received a single 500-mg dose of azithromycin. Coadministration of azithromycin suspension with food resulted in a 56% increase in the Cmax but did not affect the AUC. Therefore, no medication administration changes are needed (grade 2C). Carbamazepine When the suspension is administered through a nasogastric tube, carbamazepine adheres to the polyvinyl chloride walls of feeding tubes, resulting in inadequate drug delivery.10,–12 The bioavailability of carbamazepine suspension with enteral feeding administration was 90.1% of that during fasting.13 Although absorption of the suspension was generally slower and slightly diminished during nasogastric tube feeding, this interaction may lessen unwanted adverse effects of the drug. Carbamazepine should be diluted with an equal amount of diluent (e.g., sterile water, 0.9% sodium chloride injection, 5% dextrose injection) to prevent the significant loss of drug seen when given undiluted.12 Coadministration of carbamazepine with food results in increased drug bioavailability.10,–13 However, in vitro data suggest that the mean recovery of carbamazepine mixed with an enteral nutrient supplement was significantly reduced.14 Nevertheless, the same total daily dose can be administered but in four equally divided doses of the suspension or tablets. The suspension should be diluted with an equal amount of diluent, and the dosage should be adjusted based on serum carbamazepine levels (grade 2B). Cimetidine No data are available regarding drug–nutrient interactions for oral cimetidine formulations. I.V. cimetidine mixed with enteral nutrition retained over 90% of the initial drug concentration at 48 hours, and no interactions have been reported when coadministered with meals.15 No medication administration changes are needed (grade 2B). Ciprofloxacin Coadministration of ciprofloxacin tablets with continuous enteral nutrition resulted in an increased tmax but a decreased Cmax and decreased bioavailability.16,–20 In order to achieve approximately equivalent levels, a higher enteral dose of ciprofloxacin tablets must be administered (i.e., 750 mg enterally ≃ 400 mg i.v.). Enteral nutrition contains sufficient concentrations of calcium, aluminum, magnesium, and zinc ions, resulting in chelation of the drug and decreased absorption. Absorption may also be decreased if given by jejunostomy tube. Because of its physical characteristics, the suspension should not be given through feeding tubes.20 Coadministration of ciprofloxacin with food resulted in decreased bioavailability (31–82% of fasting-state values). Therefore, for severe infections, administer the drug intravenously initially and consider change to 750 mg enterally twice a day when the patient improves. For mild–moderate infections, administer 750 mg enterally twice daily (approximately equivalent to 400 mg i.v. twice daily). Enteral nutrition may be held for one hour before and two hours after ciprofloxacin administration. Because maximum serum drug levels may not be obtained when the drug is administered through a jejunostomy tube, ciprofloxacin should be administered i.v. if no other enteral route is available. Ciprofloxacin suspension should not be administered through feeding tubes (grade 2B). Clindamycin None of the available data indicated a drug–nutrient interaction between clindamycin and continuous enteral nutrition. Furthermore, the manufacturer reported that food does not affect the bioavailability or absorption of the drug.21 Therefore, no medication administration changes are needed (grade 2C). Cyclosporine None of the available data indicated a drug–nutrient interaction between any formulation of cyclosporine and continuous enteral nutrition. The manufacturer reported that high-fat meals (45 g of fat) administered 30 minutes before cyclosporine administration resulted in a 13% decrease in the AUC and a 33% decrease in the Cmax.22 Similar results were reported with coadministration of a low-fat meal (15 g of fat).22 Therefore, no medication administration changes are needed; however, serum cyclosporine levels should be monitored (grade 2C). Diazepam Administration of diazepam solution through an enteral tube is not recommended, as the solution binds to plastic tubing.23 Coadministration of diazepam tablets with a moderate-fat meal results in delayed and decreased absorption. However, food has a minimal effect on bioavailability.24 Therefore, diazepam tablets should be used instead of diazepam solution (grade 2B). Diltiazem None of the available data indicated a drug–nutrient interaction between diltiazem and continuous enteral nutrition. Food increases absorption by 28% (maximal plasma concentrations were 73 ± 19 ng/mL versus 130 ± 82 ng/mL in the fasting and nonfasting states, respectively).25,26 Coadministration of the tablets with a high-fat meal does not affect systemic exposure. Diltiazem tablets may be administered without regard to food. However, extended-release formulations may not be crushed or chewed.25,26 Therefore, the same total daily dose should be administered with continuous enteral nutrition, but immediate-release tablets should be administered every six to eight hours (grade 2C). Esomeprazole None of the available data indicated a drug–nutrient interaction between esomeprazole and continuous enteral nutrition. According to the manufacturer, esomeprazole should be taken at least one hour before meals, as coadministration with food may decrease the AUC by 43–53% when compared with the fasting state.27 Therefore, enteral nutrition should be held at least one hour before and one hour after dose administration. The delayed-release capsules may be opened and the intact granules emptied into a syringe for administration into a nasogastric tube. The delayed-release suspension may be added to 15 mL of water in an oral syringe, shaken, allowed to sit for two to three minutes, and then given through a nasogastric or gastric tube (grade 2C). Famotidine None of the available data indicated a drug–nutrient interaction between famotidine and continuous enteral nutrition. The manufacturer indicated that food may slightly increase the bioavailability of famotidine, but this does not result in a substantial clinical effect.28,29 Therefore, no medication administration changes are needed (grade 2C). Fluconazole When administered with continuous enteral nutrition, the mean AUC of fluconazole tablets did not significantly differ from that of the i.v. form.30,–32 The concentrations of fluconazole capsules reached via enteral administration were lower than those when the i.v. form was used but were adequate to treat most cases of deep mycoses. Coadministration of fluconazole with meals has minimal effect on the drug’s bioavailability. Therefore, no medication administration changes are needed (grade 1A ). Hydralazine Coadministration of hydralazine with enteral nutrition results in decreased drug absorption and decreased serum concentrations of the medication.33 However, hydralazine has good bioavailability when given with food. Therefore, no medication administration changes are needed; however, blood pressure levels should be monitored for changes (grade 2B). Itraconazole None of the available data indicated a drug–nutrient interaction between itraconazole and continuous enteral nutrition. The capsule formulation is maximally absorbed when administered with a “full meal.”34 The oral solution is maximally absorbed when administered in a fasting state and, therefore, no medication administration changes are needed. However, the liquid formulation should be used for patients who are concomitantly prescribed a proton-pump inhibitor (PPI) or histamine H2-receptor antagonist.34 Conversely, patients not concomitantly receiving a PPI or H2-receptor antagonist should receive the capsule form and not the liquid formulation of itraconazole (grade 2C). Lansoprazole Crushing the contents of the delayed-release capsule can result in tube clogging.10,35,–38 Dissolving the enteric-coated granules in water before administration through a nasogastric tube can diminish the efficacy of the drug before it reaches its site of absorption in the small intestine.36 Lansoprazole is available as a granule packet to be reconstituted with water to form a suspension that may be administered via a feeding tube; however, this formulation contains xanthan gum and has been reported to clog feeding tubes.37 A recipe for a simplified oral suspension made with sodium bicarbonate is available.38 The administration of lansoprazole 30 minutes after ingestion of food will reduce both the Cmax and AUC by approximately 50%,35 and the tmax can be delayed for up to 3.7 hours.35 However, the serum pharmacokinetics is not altered if lansoprazole is administered before the ingestion of food.35 Therefore, intact granules of the delayed-release capsule can be mixed with an acidic medium (e.g., apple or orange juice) and flushed with the acidic medium after administration through gastric feeding tubes. If a small-bore feeding tube is used, the oral alkaline suspension should be used. Use of the granule packet and the orally disintegrating tablet may also be tried. Enteral nutrition should be held at least one hour before and one hour after the administration of lansoprazole (grade 2B). Lanthanum None of the available data indicated a drug–nutrient interaction between lanthanum and continuous enteral nutrition. Nevertheless, lanthanum is not water soluble and would be difficult to administer through a feeding tube. Lanthanum should be administered with food to reach its maximal therapeutic effect.39 Therefore, use with enteral nutrition is not recommended, since it will likely result in a clogged feeding tube. Alternatively, calcium carbonate suspension can be used (grade 2C). Levetiracetam The overall rate and extent of absorption of levetiracetam tablets were not significantly impaired after mixing the tablet with enteral nutrition.40 The Cmax may be slightly reduced after mixing, though the difference was not significant when compared with a control substance. The rate and extent of absorption of the oral levetiracetam solution were not significantly impaired when the drug was mixed with food.40 Therefore, no medication administration changes are required (grade 1B). Levofloxacin None of the available data indicated a drug–nutrient interaction between levofloxacin and continuous enteral nutrition. Oral administration of levofloxacin 500 mg with food prolongs the tmax by one hour and decreases the Cmax by 14% after tablet administration and by approximately 25% after oral solution administration.41 Therefore, levofloxacin tablets can be administered without regard to food. It is recommended that levofloxacin oral solution be taken one hour before or two hours after eating. If the patient’s infection is considered severe, levofloxacin should be administered i.v. If enteral administration is required, hold the enteral nutrition for one hour before and two hours after administration (grade 2C). Levothyroxine sodium When combined with continuous enteral nutrition, levothyroxine sodium may bind to enteral feeding tubes, resulting in decreased drug efficacy. Manessis et al.42 found that the use of percutaneous endoscopic gastrostomy tubes may result in significant levothyroxine adsorption. However, the extent of the adsorption is likely clinically insignificant and may be attributed to drug lost during crushing and transfer. Coadministration with food may decrease absorption and increase fecal elimination.43For use for less than seven days, no medication administration changes are needed. For use for seven days or longer, tube feedings should be held one hour before and after administration of a dose. Thyroid function should be monitored weekly (grade 2B). Linezolid Linezolid oral suspension is rapidly and completely absorbed when administered via the enteral route.44,45 The bioavailability of linezolid remains unaltered in the presence of continuous enteral nutrition. Administration with a high-fat meal may delay the tmax of linezolid from 1.5 to 2.2 hours and result in a 17% decrease in the Cmax; however, the AUC remains relatively unaffected. Therefore, no medication administration changes are needed (grade 1A). Lorazepam No data are available indicating a drug–nutrient interaction between lorazepam and continuous enteral nutrition. No interactions have been documented when coadministering lorazepam with meals.46 Therefore, no medication administration changes are needed (grade 2C). Metoprolol None of the available data indicated a drug–nutrient interaction between metoprolol and continuous enteral nutrition. Metoprolol should be taken with food or directly after a meal.47 No medication administration changes are needed (grade 2C). Metronidazole None of the available data indicated a drug–nutrient interaction between metronidazole and continuous enteral nutrition. No interactions have been documented when coadministering metronidazole with meals.48 Therefore, no medication administration changes are needed (grade 2C). Moxifloxacin When a single tablet of moxifloxacin 400 mg was given to healthy volunteers in a crossover fashion, the drug’s AUC was slightly decreased when coadministered with enteral nutrition through a nasogastric tube compared with oral administration; however, the difference was not deemed clinically significant.49 Moxifloxacin 400 mg has demonstrated bioequivalence with respect to the Cmax and AUC when given in fasting and nonfasting states.50 The consumption of high-fat foods may delay the drug’s rate of absorption; however, the extent of absorption is unaffected. The tmax is similar in non-fasting and fasting conditions. No medication administration changes are needed (grade 1C). Mycophenolate mofetil None of the available data indicated a medication–nutrient interaction between mycophenolate mofetil and continuous enteral nutrition. A recipe to compound a 100-mg/mL suspension is available.51 Food has no effect on mycophenolic acid’s AUC but has been shown to decrease mycophenolic acid’s Cmax by 40%.52 Administration with iron has no change in the AUC.51,52 Therefore, no medication administration changes are needed (grade 2C). Omeprazole Crushing the capsule granules destroys the enteric coating, allowing gastric acid to inactivate the medication.53 The manufacturer recommends the powder for oral suspension for patients receiving nutrition through a nasogastric or an orogastric tube.54 A recipe for a simplified oral suspension made with sodium bicarbonate is available.55 Omeprazole should be taken before meals, however, the immediate-release capsules and the powder for oral suspension should be taken one hour before meals. Drug absorption is delayed by food; when omeprazole was given one hour after meals, the Cmax and AUC were reduced by 63% and 24%, respectively.56 Enteral nutrition should be held at least one hour before and one hour after the administration of each dose (grade 2B). Pantoprazole Crushing the delayed-release tablet can result in tube clogging.57 The delayed-release oral suspension should be dissolved in apple juice before administering via a nasogastric tube. A recipe to compound a 2-mg/mL suspension with sodium bicarbonate is available.58,59 Coadministration with food has no effect on pantoprazole pharmacokinetics.57,–59 Neither food nor antacids altered the bioavailability of pantoprazole. The tmax is highly variable and may increase when pantoprazole is given with meals. The manufacturer recommends administering the delayed-release oral suspension 30 minutes before a meal.57 No medication administration changes are needed when using a compounded pantoprazole suspension. For the commercially available delayed-release oral suspension, enteral nutrition should be held 30 minutes before administration. Pantoprazole delayed-release, enteric-coated tablets should not be crushed for administration via feeding tubes (grade 2B). Penicillin V Penicillin V displays unpredictable absorption when combined with continuous enteral nutrition; the bioavailability may vary from 30% to 80%.12,60 Administration of penicillin V with food reduces and prolongs peak serum levels; however, the extent of absorption remains unchanged. Enteral nutrition should be held one hour before and two hours after dose administration. Higher doses may be administered or substitute with amoxicillin (grade 2B). Phenytoin Feeding tubes and enteral nutrition may decrease absorption of phenytoin suspension by up to 80% via protein binding, poor solubility, or binding to feeding tubes.12,61 Food has no effect on the absorption of the brand-name extended-release capsule formulation; however, food decreases the absorption of generic phenytoin extended-release capsules.62 Enteral nutrition should be held at least one hour before and one hour after dose administration. Alternatively, the phenytoin dose can be increased to overcome the interaction with enteral feedings. I.V. phenytoin or fosphenytoin can also be continued. The total daily dose should preferably be divided into two daily doses to minimize the time that enteral nutrition is held (grade 2B). Posaconazole Administration of posaconazole suspension with a nutritional supplement increased the Cmax 3.4-fold and AUC 2.6-fold in healthy volunteers.63 A 4-fold and 2.6-fold increase in the Cmax and AUC was observed in subjects given high-fat (≃ 50 g) and nonfat meals, respectively. Therefore, the drug should be given with enteral nutrition for adequate absorption (grade 1B). Ranitidine Greater than 90% of ranitidine in tablets and syrup was recovered at 24 hours after mixing with eight different enteral feedings.64 No interaction with food was noted.65 Therefore, no medication administration changes are needed (grade 2B). Sevelamer The manufacturer does not recommend putting the drug in feeding tubes, as it may clog the tubes.66 An 80-mg/mL suspension has been developed and given to pediatric patients through gastric tubes.67 The phosphate-binding effect of the drug requires that it be taken with food;66 however, the drug should not be given with enteral nutrition. A compounded suspension of the drug may be given through a gastrostomy tube in certain situations, or calcium carbonate suspension may be tried as a substitution (grade 2C). Sirolimus None of the available data indicated a medication–nutrient interaction between sirolimus and continuous enteral nutrition. High-fat meals alter the bioavailability of the oral solution; when compared with fasting, a 34% decrease in the Cmax, a 3.5-fold increase in the tmax, and a 35% increase in the AUC were observed.68 After administration of sirolimus tablets with a high-fat meal, the Cmax, tmax, and AUC increased by 65%, 32%, and 23%, respectively.68 To minimize variability, the oral solution and tablets should be taken consistently with or without food. No medication administration changes are needed for enteral feedings; however, serum sirolimus levels should be monitored (grade 2C). Sucralfate Sucralfate binds to the protein in tube feedings and forms insoluble complexes that may clog feeding tubes.12 Also, the alkaline pH of tube feedings does not allow sucralfate to become activated. For these reasons, sucralfate should be given one hour before or two hours after meals.69 Sucralfate should not be given with enteral feedings. Alternatives include PPIs or H2-receptor antagonists (grade 2C). Tacrolimus Enteral feedings through a nasojejunal feeding tube did not interfere with tacrolimus capsule absorption.70 High-fat meals may decrease the AUC and Cmax by 37% and 72%, respectively, and increase the tmax by fivefold. High-carbohydrate foods decreased the mean AUC and mean Cmax by 28% and 65%, respectively.71 Therefore, no medication administration changes are needed for enteral feedings; however, tacrolimus levels should be monitored (grade 1B). Theophylline Absorption of an extended-release preparation with enteral feedings given orally, not through a feeding tube, to healthy volunteers did not differ from absorption when administered on an empty stomach.72 Decreased theophylline levels of >30% when given with enteral nutrition have been reported.73 This interaction was overcome when the tube feedings were held one hour before and after administration of the dose. Administration of theophylline with food does not cause clinically significant changes in absorption from immediate-release dosage forms.74 Therefore, enteral nutrition should be held one hour before and one hour after dose administration. Rapid-release theophylline products or solutions should be used if possible, and theophylline levels should be monitored closely (grade 2B). Valacyclovir None of the available data indicated a drug–nutrient interaction between valacyclovir hydrochloride and continuous enteral nutrition. A recipe to compound a 50-mg/mL suspension is available.75 No drug–food interactions have been noted.76 Therefore, no medication administration changes are needed for enteral feeding (grade 2C). Valganciclovir None of the available data indicated a drug–nutrient interaction between valganciclovir hydrochloride and continuous enteral nutrition. A recipe to compound a 90-mg/mL suspension is available.77 Food enhances the bioavailability of valganciclovir hydrochloride; the AUC and Cmax increase by 30% and 14%, respectively, in the fed state.78 Therefore, valganciclovir hydrochloride should be administered with food. No medication administration changes are needed for enteral feeding (grade 2C). Valproic acid None of the available data indicated a drug–nutrient interaction between valproic acid and continuous enteral nutrition. Administration of valproic acid with food may delay the rate of absorption but does not alter total systemic exposure.79 This difference should be of minor clinical importance under steady-state conditions. No medication administration changes are needed; however, valproate levels should be monitored (grade 2C). Vancomycin None of the available data indicated a drug–nutrient interaction between vancomycin solution and continuous enteral nutrition. No interaction was noted with oral vancomycin solution and food.80 No medication administration changes are needed (grade 2C). Voriconazole Crushed voriconazole tablets delivered via a nasogastric tube, with the enteral feedings interrupted only for the duration of dose administration, were associated with adequate plasma levels in 88% of study patients.81 The AUC of multiple doses of voriconazole is reduced by ap;22% when taken with food versus the fasting state.82 Therefore, no medication administration changes are needed for enteral feeding; however, voriconazole levels for treatments given longer than seven days should be monitored (grade 1B). Warfarin Warfarin may be sequestered in the macromolecular fraction of enteral nutrition formulas.14,83,–86 Current enteral nutrition formulations have minimal amounts of vitamin K to interact with warfarin; however, the proteins in these formulas may bind to warfarin. Warfarin absorption is unaffected by food. Therefore, no medication administration changes are needed. Alternatively, enteral nutrition may be held one hour before and one hour after the administration of a warfarin dose. Formulas containing soy proteins should be avoided. With either method, the International Normalized Ratio should be monitored closely (grade 2B). Discussion Specialized nutrition support is often used in hospitalized, critically ill patients.87 Beneficial effects of nutritional support include the preservation of lean tissue mass and host defenses. “When the gut works, use it” is a common expression used to encourage the use of enteral nutrition over parenteral nutrition.88 Despite the ability of the normal, well-fed intestine to absorb nutrients and medications, clinicians frequently administer medications intravenously because of the reliability of this route and because of unknown interactions between medications and enteral nutrition. The complexity of medications and enteral nutrition formulations and devices makes predicting drug–nutrient interactions difficult for those patients receiving continuous enteral feedings. Various nutritional elements may interact with drug molecules and render the agents inactive or may decrease or increase their efficacy. For example, acidic preparations can cause clumping or precipitation of the enteral feeding, and some syrups can obstruct feeding tubes. Some medications bind to the feeding tube, resulting in decreased absorption (e.g., phenytoin, carbamazepine). Other medications may form complexes with enteral nutrition formulations, resulting in decreased absorption (e.g., fluoroquinolones).12 Some medications may be administered simultaneously with continuous enteral nutrition; for others, practitioners must decide whether to hold the enteral nutrition, find an alternative route to administer the medication, use an alternative medication, or increase the dosage of the medication to overcome the decreased absorption. Yet another choice for practitioners would be to administer the medication and check serum drug concentrations, when possible, to ensure adequate absorption. Another issue that practitioners must consider is the complexity of the feeding tubes. The location of the tip of the feeding tube can be at the gastric, duodenal, or jejunal portion of the gastrointestinal tract, which may affect the absorption of the medication. To administer medications via feeding tubes, the tubes should be flushed with 30 mL of water before and after administration. Medications should be given separately and flushed with 5–30 mL of water between medications. Liquid formulations, particularly elixirs and suspensions, are the preferred dosage form to administer through feeding tubes. These formulations should be diluted with at least 30 mL of water, especially if hyperosmolar, for administration. Unfortunately, certain medications are only available as solid dosage forms, and some may not be crushed. Immediate-release tablets should be crushed into a fine powder and mixed with 30 mL of water to form a slurry for administration. Immediate-release capsules should be opened and the contents mixed with 30 mL of water to form a slurry for administration. The contents of soft gelatin capsules can be aspirated with a needle and syringe and diluted in 30 mL of water for administration. Alternatively, the contents can also be dissolved in warm water and the entire volume administered after the undissolved gelatin portion has been removed. However, caution is recommended when giving medications with enteral nutrition, since little compatibility data are available. Medications should never be mixed directly with enteral formulas. Smaller-bore feeding tubes (i.e., jejunostomy tubes) should only have liquid formulations administered through them to avoid clogging the tube, since replacement is costly and invasive. Nasogastric tubes, when used for gastric suctioning, may suction out the medication before it is adequately absorbed, so it is preferred to clamp the tube for at least 30 minutes after medication administration if the patient can tolerate it.89 The compiled data contained herein should serve as a useful guide for clinicians on how to administer medications with tube feedings. However, the research methods were not without limitations. Unfortunately, there is an overwhelming lack of published data supporting dosage and administration recommendations for the majority of medications given to patients receiving continuous enteral nutrition. A potential limitation of the search strategy employed was the use of enteral nutrition as the only MeSH search term to cross-reference all medications evaluated. The lack of published data required the study investigators to seek recommendations from experienced pharmacy clinicians. Many of the recommendations received from clinicians were based on a combination of available information and clinical experience. These clinicians have had anecdotal success administering the medications in the recommended fashion without compromising patient care. Since several recommendations are based on clinical experience, this may be considered another limitation of the study. Therefore, the recommendations given in this article should be used as a guide, along with the clinician’s judgment, for determining the proper dose and administration technique. More medication pharmacokinetic studies are needed to improve medication therapy in patients receiving enteral nutrition. Conclusion There was a lack of published data regarding drug–nutrient interactions for a majority of the drugs commonly administered to patients receiving continuous enteral nutrition. Clinicians should recognize potential drug–nutrient interactions and use available evidence to optimize patients’ drug therapy. References 1 Kirby DF, Delegge MH, Fleming CR. American Gastroenterological Association technical review on tube feeding for enteral nutrition. Gastroenterology . 1995 ; 108 : 1282 –301. Crossref Search ADS PubMed 2 Brown RO, Dickerson RN. Drug-nutrient interactions. Am J Manag Care . 1999 ; 5 : 345 –55. PubMed 3 Guyett G, Gutterman D, Baumann MH et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest . 2006 ; 129 : 174 –81. Crossref Search ADS PubMed 4 Zovirax (acyclovir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2005 . 5 Shalansky KF, Vaughan LM, Ustad C et al. Absolute bioavailability of aminophylline liquid administered enterally in adults requiring mechanical ventilation. Clin Pharm . 1992 ; 11 : 428 –32. PubMed 6 Pacerone (amiodarone) package insert. Minneapolis: Upsher-Smith Laboratories, Inc., 2004 . 7 Augmentin (amoxicillin–clavulanate) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2005 . 8 Freeman CD, Klutman NE, Lamp KC et al. Relative bioavailability of atovaquone suspension when administered with an enteral nutrition supplement. Ann Pharmacother . 1998 ; 32 : 1004 –7. Crossref Search ADS PubMed 9 Zithromax (azithromycin) package insert. New York: Pfizer Labs; 2004 . 10 Clark-Schmidt AL, Garnett WR, Lowe DR et al. Loss of carbamazepine suspension through nasogastric feeding tubes. Am J Hosp Pharm . 1990 ; 47 : 2034 –7. PubMed 11 Sacks G. Drug-nutrient considerations in patients receiving parenteral and enteral nutrition. Pract Gastroenterol . 2004 ; 28 : 39 –48. 12 Engle KK, Hannawa TE. Techniques for administering oral medication to critical care patients receiving continuous enteral nutrition. Am J Health-Syst Pharm . 1999 ; 56 : 1441 –4. Crossref Search ADS PubMed 13 Bass J, Miles MV, Tennison MB et al. Effects of enteral tube feeding on the absorption and pharmacokinetic profile of carbamazepine suspension. Epilepsia . 1989 ; 30 : 364 –9. Crossref Search ADS PubMed 14 Kassam RM, Friesen E, Locock RA. In vitro recovery of carbamazepine from Ensure. J Parenter Enteral Nutr . 1989 ; 13 : 272 –6. Crossref Search ADS 15 Rochard EB, Barthes DM, Courtois PY. Stability of cimetidine hydrochloride in Sondalis Iso enteral nutrition formula. Am J Hosp Pharm . 1991 ; 48 : 1681 –2. 16 De Marie S, VandenBergh MF, Buijk SL et al. Bioavailability of ciprofloxacin after multiple enteral and intravenous doses in ICU patients with severe gram-negative intra-abdominal infections. Intensive Care Med . 1998 ; 24 : 343 –6. Crossref Search ADS PubMed 17 Mimoz O, Binter V, Jacolot A et al. Pharmacokinetics and absolute bioavailability of ciprofloxacin administered through a nasogastric tube with continuous enteral feeding to critically ill patients. Intensive Care Med . 1998 ; 24 : 1047 –51. Crossref Search ADS PubMed 18 Healy DP, Brodbeck MC, Clendening CE. Ciprofloxacin absorption is impaired in patients given enteral feedings orally and via gastrostomy and jejunostomy tubes. Antimicrob Agents Chemother . 1996 ; 40 : 6 –10. Crossref Search ADS PubMed 19 Cohn SM, Sawyer MD, Burns GA et al. Enteric absorption of ciprofloxacin during tube feeding in the critically ill. J Antimicrob Chemother . 1996 ; 38 : 871 –6. Crossref Search ADS PubMed 20 Cipro (ciprofloxacin) tablets/suspension package insert. Wayne, NJ: Bayer Health Care; 2008 Oct. 21 Cleocin HCl (clindamycin) package insert. Kalamazoo, MI: Pharmacia & Upjohn Company; 2003 . 22 Neoral (cyclosporine) package insert. East Hanover, NJ: Novartis Pharmaceuticals; 2001 . 23 Thomson FC, Naysmith MR, Lindsay A. Managing drug therapy in patients receiving enteral and parenteral nutrition. Hosp Pharm . 2000 ; 7 : 155 –6. 24 Valium (diazepam) tablets package insert. Nutley, NJ: Roche Pharmaceuticals; 2008 . 25 Diltiazem. In: Drugdex System [Internet database]. Version 5.1. Greenwood Village, CO: Thomson Healthcare. Updated periodically. 26 Cardizem LA (diltiazem) package insert. Cranbury, NJ: Kos Pharmaceuticals, Inc.; 2006 . 27 Nexium (esomeprazole magnesium) package insert. Wilmington, DE: Astra-Zeneca LP; 2008 . 28 Data on file for Pepcid (famotidine). Merck & Co., Whitehouse Station, NJ; 2008 . 29 Pepcid (famotidine) package insert. Whitehouse Station, NJ: Merck & Co.; 2007 . 30 Nicolau DP, Crowe H, Nightingale CH et al. Bioavailability of fluconazole administered via a feeding tube in intensive care unit patients. J Antimicrob Chemother . 1995 ; 36 : 395 –401. Crossref Search ADS PubMed 31 Buijk SL, Gyssens IC, Mouton JW et al. Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function. Intensive Care Med . 2001 ; 27 : 115 –21. Crossref Search ADS PubMed 32 Rosemurgy AS, Markowsky S, Goode SE et al. Bioavailability of fluconazole in surgical intensive care unit patients: a study comparing routes of administration. J Trauma . 1995 ; 39 : 445 –7. PubMed 33 Semple HA, Koo W, Tam YK et al. Interactions between hydralazine and oral nutrients in humans. Ther Drug Monit . 1991 ; 13 : 304 –8. Crossref Search ADS PubMed 34 Sporanox (itraconazole) package insert. Raritan, NJ: Ortho Biotech Products, LP; 2003 . 35 Prevacid (lansoprazole) package insert. Lake Forest, IL: TAP Pharmaceuticals Inc.; 2003 . 36 Barradell LB, Faulds D. Lansoprazole. A review of its pharmacodynamic and pharmacokinetic properties and its therapeutic efficacy in acid-related disorders. Drugs . 1992 ; 44 : 225 –50. Crossref Search ADS PubMed 37 Michael RC. Medication errors. Liquid lansoprazole: gumming up the works. Nursing . 2002 ; 32 : 14 . 38 Sharma VK, Vasudeva R, Howden CW. Simplified lansoprazole suspension—a liquid formulation of lansoprazole—effectively suppresses intragastric acidity when administered through a gastrostomy. Am J Gastroenterol . 1999 ; 94 : 1813 –7. PubMed 39 Data on file for Fosrenol (lanthanum). Shire US, Wayne, PA; 2007 Apr. 40 Monica AF, Raj DS, Gidal BE. Oral absorption kinetics of levetiracetam: the effect of mixing with food or enteral nutrition formulas. Clin Ther . 2005 ; 27 : 594 –8. Crossref Search ADS PubMed 41 Levaquin (levofloxacin) package insert. Raritan, NJ: Ortho-McNeil Pharmaceuticals, Inc.; 2008 . 42 Manessis A, Lascher S, Bukberg P et al. Quantifying amount of adsorption of levothyroxine by percutaneous endoscopic gastrostomy tubes. J Parenter Enteral Nutr . 2008 ; 32 : 197 –200. Crossref Search ADS 43 Smyrniotis V, Vaos N, Arkadopoulos N et al. Severe hypothyroidism in patients dependent on prolonged thyroxine infusion through a jejunostomy. Clin Nutr . 2000 ; 19 : 65 –7. Crossref Search ADS PubMed 44 Zyvox (linezolid) package insert. Kalama-zoo, MI: Pharmacia & Upjohn Company; 2003 . 45 Beringer P, Nguyen M, Hoem N et al. Absolute bioavailability and pharmacokinetics of linezolid in hospital patients given enteral feedings. Antimicrob Agents Chemother . 2005 ; 49 : 3676 –81. Crossref Search ADS PubMed 46 Ativan (lorazepam) package insert. Corona, CA: Watson Laboratories; 2004 . 47 Lopressor (metoprolol tartrate) package insert. Detroit, MI: Caraco Pharmaceutical Labortories, Ltd.; 2007 . 48 Metronidazole. In: Drugdex System [Internet database]. Version 5.1. Greenwood Village, CO: Thomson Healthcare. Updated periodically. 49 Burkhardt O, Stass H, Thuss U et al. Effects of enteral feeding on the oral bioavailability of moxifloxacin in healthy volunteers. Clin Pharmacokinet . 2005 ; 44 : 969 –76. Crossref Search ADS PubMed 50 Lettieri J, Vargas R, Agarwal V et al. Effect of food on the pharmacokinetics of a single oral dose of moxifloxacin 400mg in healthy male volunteers. Clin Pharmacokinet . 2001 ; 40 (suppl 1): 19 –25. Crossref Search ADS PubMed 51 Anaizi NH, Swenson CF, Dentinger PJ. Stability of mycophenolate mofetil in an extemporaneously compounded oral liquid. Am J Health-Syst Pharm . 1998 ; 55 : 926 –9. Crossref Search ADS PubMed 52 Cellcept (mycophenolate mofetil) package insert. Nutley, NJ: Roche Laboratories, Inc.; 2004 . 53 Omeprazole. In: Drugdex System [Internet database]. Version 5.1. Greenwood Village, CO: Thomson Healthcare. Updated periodically. 54 Zegerid (omeprazole–sodium bicarbonate) package insert. San Diego: Santarus, Inc.; 2008 . 55 Phillips JO, Metzler MH, Palmieri TL et al. A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit Care Med . 1996 ; 24 : 1793 –800. Crossref Search ADS PubMed 56 Cornish P. “Avoid the crush”: hazards of medication administration in patients with dysphagia or a feeding tube. CMAJ . 2005 ; 172 : 871 –2. Crossref Search ADS PubMed 57 Protonix (pantoprazole sodium) package insert. Philadelphia: Wyeth Pharmaceuticals, Inc.; 2008 . 58 Ferron GM, Ku S, Abell M et al. Oral bioavailability of pantoprazole suspended in sodium bicarbonate solution. Am J Health-Syst Pharm . 2003 ; 60 : 1324 –9. Crossref Search ADS PubMed 59 Dentinger PJ, Swenson CF, Anaizi NH. Stability of pantoprazole in an extemporaneously compounded oral liquid. Am J Health-Syst Pharm . 2002 ; 59 : 953 –6. Crossref Search ADS PubMed 60 McCarthy CG, Finland M. Absorption and excretion of 4 penicillins: penicillin G, penicillin V, phenethicillin and phenylmercaptomethylpenicillin. N Engl J Med . 1960 ; 263 : 315 . Crossref Search ADS 61 Au Yeung SC, Ensom MH. Phenytoin and enteral feedings: does evidence support an interaction? Ann Pharmacother . 2000 ; 34 : 896 –905. Crossref Search ADS PubMed 62 Wilder BJ, Leppik I, Hietpas TJ et al. Effect of food on absorption of Dilantin Kapseals and Mylan extended phenytoin sodium capsules. Neurology . 2001 ; 57 : 582 –9. Crossref Search ADS PubMed 63 Sansone-Parsons A, Krishna G, Calzetta A et al. Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers. Antimicrob Agents Chemother . 2006 ; 50 : 1881 –3. Crossref Search ADS PubMed 64 Crowther RS, Bellanger R, Szauter KE. In vitro stability of ranitidine hydrochloride in enteral nutrient formulas. Ann Pharmacother . 1995 ; 29 : 859 –62. Crossref Search ADS PubMed 65 Zantac (ranitidine) package insert. Research Triangle Park, NJ: GlaxoSmithKline; 2007 . 66 Data on file for Renagel (sevelamer). Genzyme Corporation, Cambridge, MA; 2005 Sep. 67 McElhiney LF. Sevelamer suspension in children with end-stage renal disease. Int J Pharm Compd . 2007 ; 11 : 20 –4. PubMed 68 Rapamune (sirolimus) oral suspension and tablets package insert. Philadelphia: Wyeth Pharmaceuticals Inc.; 2005 . 69 Giesing DH, Bighley LD, Iles HL. Effect of food and antacid on binding of sucralfate to normal and ulcerated gastric and duodenal mucosa in rats. J Clin Gastroenterol . 1981 ; 3 (suppl 2): 111 –6. PubMed 70 Murray M, Grogan TA, Lever J et al. Comparison of tacrolimus absorption in transplant patients receiving continuous versus interrupted enteral nutritional feeding. Ann Pharmacother . 1998 ; 32 : 633 –6. Crossref Search ADS PubMed 71 Prograf (tacrolimus) package insert. Deerfield, IL: Astellas Pharma US, Inc.; 2005 . 72 Plezia PM, Thornily SM, Kramer TH et al. The influence of enteral feedings on sustained-release theophylline absorption. Pharmacotherapy . 1990 ; 10 : 356 –61. PubMed 73 Gal P, Layson R. Interference with oral theophylline absorption by continuous nasogastric feedings. Ther Drug Monit . 1986 ; 8 : 421 –3. Crossref Search ADS PubMed 74 Elixophylline package insert. St. Louis: Forest Pharmaceuticals, Inc.; 2004 . 75 Fish DN, Vidaurri VA, Deeter RG. Stability of valacyclovir hydrochloride in extemporaneously prepared oral liquids. Am J Health-Syst Pharm . 1999 ; 56 : 1957 –60. Crossref Search ADS PubMed 76 Valtrex (valacyclovir) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2004 . 77 Valcyte (valganciclovir) package insert. Nutley, NJ: Roche Pharmaceuticals; 2003 . 78 Anaizi NH, Dentinger PJ, Swenson CF. Stability of valganciclovir in an extemporaneously compounded oral liquid. Am J Health-Syst Pharm . 2002 ; 59 : 1267 –70. Crossref Search ADS PubMed 79 Depakene (valproic acid) package insert. North Chicago, IL: Abbott Laboratories; 2006 . 80 Vancocin (vancomycin) package insert. Exton, PA: ViroPharma Incorporated; 2005 . 81 Purkins L, Wood N, Kleinermans D et al. Effect of food on the pharmacokinetics of multiple-dose oral voriconazole. Br J Clin Pharmacol . 2003 ; 56 (suppl 1): 17 –23. Crossref Search ADS PubMed 82 Mohammedi I, Piens MA, Padoin C et al. Plasma levels of voriconazole administered via a nagogastric tube to critically ill patients. Eur J Clin Microbiol Infect Dis . 2005 ; 24 : 358 –60. Crossref Search ADS PubMed 83 Penrod LE, Allen JB, Cabacungan LR. Warfarin resistance and enteral feedings: 2 case reports and a supporting in vitro study. Arch Phys Med Rehabil . 2001 ; 82 : 1270 –3. Crossref Search ADS PubMed 84 Kuhn TA, Garnett WR, Wells BK et al. Recovery of warfarin from an enteral nutrient formula. Am J Health-Syst Pharm . 1989 ; 46 : 1395 –9. Crossref Search ADS 85 Martin JE, Lutomski DM. Warfarin resistance and enteral feedings. J Parenter Enteral Nutr . 1989 ; 13 : 206 –8. Crossref Search ADS 86 Dickerson RN, Garmon WM, Kuhl DA et al. Vitamin K-independent warfarin resistance after concurrent administration of warfarin and continuous enteral nutrition. Pharmacotherapy . 2008 ; 28 : 308 –13. Crossref Search ADS PubMed 87 Mowatt-Larson CA, Brown RO. Specialized nutritional support in respiratory disease. Clin Pharm . 1993 ; 12 : 276 –92. PubMed 88 Kudsk KA, Croce MA, Fabian TC et al. Enteral vs parenteral feeding effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg . 1992 ; 215 : 503 –13. Crossref Search ADS PubMed 89 Williams NT. Medication administration through enteral feeding tubes. Am J Health-Syst Pharm . 2008 ; 65 : 2347 –57. Crossref Search ADS PubMed Author notes The Clinical Consultation section features articles that provide brief advice on how to handle specific drug therapy problems. All articles are based on a systematic review of the literature. The assistance of ASHP’s Section of Clinical Specialists and Scientists in soliciting Clinical Consultation submissions is acknowledged. Unsolicited submissions are also welcome. The authors have declared no potential conflicts of interest. Copyright © 2009, American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Recommendations for the use of medications with continuous enteral nutrition
JO - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp080632
DA - 2009-08-15
UR - https://www.deepdyve.com/lp/oxford-university-press/recommendations-for-the-use-of-medications-with-continuous-enteral-3zXBgPuoza
SP - 1458
VL - 66
IS - 16
DP - DeepDyve
ER -