Recommendations for the Use of Medications with Continuous Enteral Nutrition

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 (C_max) 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 (t_max) 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 C _max 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 C _max 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 t_max but a decreased C_max 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 C_max.^[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 C_max and AUC by approximately 50%,^[35] and the t_max 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 C_max 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 t_max by one hour and decreases the C_max 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.^[43] For 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 t _max of linezolid from 1.5 to 2.2 hours and result in a 17% decrease in the C _max; 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 C_max 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 t _max 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 C_max 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 C_max 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 t_max 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 C_max 3.4-fold and AUC 2.6-fold in healthy volunteers.^[63] A 4-fold and 2.6-fold increase in the C _max 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 C_max, a 3.5-fold increase in the t_max, and a 35% increase in the AUC were observed.^[68] After administration of sirolimus tablets with a high-fat meal, the C_max, t_max, 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 C_max by 37% and 72%, respectively, and increase the t_max by fivefold. High-carbohydrate foods decreased the mean AUC and mean C_max 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 C_max 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 ≈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).

Am J Health Syst Pharm © 2009  American Society of Health-System Pharmacists

Cite this: Recommendations for the Use of Medications with Continuous Enteral Nutrition - Medscape - Aug 15, 2009.