Clinical Reviews

Alternative Methods of Proton Pump Inhibitor Administration

Anthony Zimmermann J. Ken Walters Brian Katona Paul Souney

Data Sources: Search of MEDLINE and its backfiles, Science Citation Index, abstracts from gastrointestinal and critical care meetings reported between 1985-1997, and product manufacturers' information on file.

Study Selection: There were 14 studies describing the administration of proton pump inhibitors in ways other than intact capsules: 12 with omeprazole, and two with lansoprazole. All reports from indicated data sources describing alternative oral administration methods were included.

Data Extraction: Target criteria were method of administration and measures of effectiveness of therapy with the proton pump inhibitor.

Data Synthesis: Four main methods of administering proton pump inhibitors (PPI) to patients with swallowing obstacles were identified: (1) simple flushing of the intact granules with water; (2) preparation of a sodium bicarbonate-based suspension which allows the granules to dissolve; (3) administration of the intact granules in acidic fruit juices, or (4) sprinkling intact granules on applesauce and yogurt.

Conclusion: All four methods of proton pump inhibitor administration seem to be effective. Currently, the majority of published trials and reports describing the utility of all four options have involved the PPI, omeprazole. Experience with lansoprazole is currently limited to administration of intact granules in apple juice or applesauce in healthy volunteers. The method used to administer the medication should be tailored to the clinical situation.

Key Words: Omeprazole, Lansoprazole, Nasogastric Tube, Jejunal Tube, ph, Pharmacokinetics, Stability, Granules.

Abbreviations Used: ng = Nasogastric; J Tube= Jejunal Tube; sos = Simplified Omeprazole Solution; SRMD = Stress-Related Mucosal Disease.

Consult Pharm: 1997; 12:990-98.

There are clinical situations where proton pump inhibitors represent optimal therapy, but the patients are unable to swallow the medication. Common examples include: patients with nasogastric, jejunal, or feeding tubes; patients with swallowing disorders; critically ill patients; geriatric patients; and pediatric patients.

The purpose of this review is to identify clinical reports describing alternative methods of administering proton pump inhibitors to patients who preclude the use of intact capsules, to describe criteria used to measure the clinical benefit of these methods, and to provide guidance for clinicians when recommending these alternative methods.

Methods

Results

Author/year	Drug	Tube	Vehicle	Outcome
Opening Capsule
Larson (1996)5	Omeprazole	NG	Water	Bioequivalence
Hassal (1997)21	Omeprazole	None	Water	Symptom improvement and healing of esophagitis
Balaban (1997)6	Omeprazole	NG	Water	Prevention of SRMD, 40 mg superior to 20 mg in maintaining intragastric pH > 4.0
Sodium Bicarbonate Solutions
Naesdal (1984)7	Omeprazole	NG	Sodium bicarbonate (8 mmol/50ml)	Dose ranging, bioavailability
Pilbrandt (1985)4	Omeprazole	None	Sodium bicarbonate (50 ml/ 8mmol)	Pilot bioavailability study
Carroll (1994)8	Omeprazole	NG	25 ml sodium bicarbonate (1 mEq/ml)	Prevention of SRMD and elevation of intragastric pH
Phillips (1996)9	Omeprazole	NG	10-20 ml sodium bicarbonate 8.4% solution	Prevention of SRMD and elevation of intragastic pH
Mohiuddin (1996)11	Omeprazole	None	2 Alka-Seltzer Gold in 240 ml water	Therapeutic equivalence and intragastric pH comparison
Fruit Juices
Mohiuddin (1996)11	Omeprazole	None	240 ml orange juice	Therapeutic equivalence and intragastric pH
Gunasekaran (1993)17	Omeprazole	None or gastrostomy or J-tube	Orange juice, cranberry juice or yogurt	Improvement in GERD/esophagitis, intragastric pH
Sharma (1997)19	Omeprazole	Gastrostomy	Orange juice	Therapeutic equivalence and intragastric pH
Chun (1996)16	Lansoprazole	NG	Apple juice	Bioequivalence
Applesauce
Mohiuddin (1996)11	Omeprazole	None	One teaspoon applesauce	Therapeutic equivalence and intragastric pH
Hassall (1997)21	Omeprazole	None	Sprinkled on applesauce	Symptom improvement and healing of esophagitis
Chun (1995)20	Lansoprazole	None	Sprinkled on one tablespoon of applesauce	Bioequivalence
Yogurt
Gunasekaran (1993)18	Omeprazole	None or gastrostomy or J-tube	Yogurt	Improvement in GERD/esophagitis, intragastric pH
Hassall (1997)21	Omeprazole	None	Sprinkled on yogurt	Symptom improvement and healing of esophagitis
Unspecified
Barie (1992)22	Omeprazole	NG	Not described	Treatment of SRMD

NG= nasogastric
J-tube= jegunal tube
GERD= gastroesophageal reflux disease

Four basic methods were described for administering proton pump inhibitors to patients unable to ingest intact capsules: (1) opening capsules and simply flushing intact granules with water; (2) preparing a sodium bicarbonate-based suspension; (3) administering intact granules in acidic fruit juices; and (4) sprinkling intact granules on applesauce and yogurt.

Table 2: Methods and Vehicles for Proton Pump Inhibitor Administration

	Omeprazole	Lansoprazole
Opening Capsule5,6	1. Open capsule and place granules in a small cup. Flush 6-10 granules with 10-20 ml of water. Total volume 120-140 ml. 2. Open capsule and place granules in a bowel containing 30 ml of water. Pour 1/3 to 1/2 of the granules in water into a 30 ml syringe with plunger removed and flush through nasogastric tube. Repeat until all complete then flush with 15 ml of water. A total of 45 ml of water is required.	No information published
Sodium Bicarbonate9-13	1. Simplified Omeprazole Suspension (SOS) Empty 1-2 capsules into a 10 ml or 20 ml syringe with needle in place. Add 10-20 ml, respectively, of 8.4 % (1mEq/ml) sodium bicarbonate (based on 20 mg or 40 mg omeprazole) solution. Let stand for more than 30 minutes, with agitation. The final omeprazole concentration should be 2mg/ml. Flush with 5-10 ml of tap water and clamp tube for one hour. The total volume administered is 15-30 ml depending on dose. 2. Open five omeprazole 20 mg capsules and empty into a 60 ml syringe. Withdraw 50 ml, of 8.4 % sodium bicarbonate from a vial into the syringe, replace the needle with a fluid-dispensing connector while adding a second 60 ml syringe to the fluid-dispensing connector. Gently transfer between syringes until completely dissolved. Place solutions back into the empty sodium bicarbonate vial and label with an expiration date of 14 days if stored at room temperature or 30 days if frozen or refrigerated. 3. Sodium bicarbonate solution can be extemporaneously prepared by placing 1/2 to one teaspoon of baking soda (sodium bicarbonate) into 240 ml of warm water.	No information published
Yogurt17,21	1. Open capsule and sprinkle granules onto one teaspoon of applesauce	No information published
Fruit Juices11,14-19	1. Open capsule and add granules to apple, cranberry, grape, grapefruit, orange, pineapple, prune, tomato, or V-8 juice and give orally. DO NOT CHEW.	1. Open capsule and add granules to apple, cranberry, grape, grapefruit, orange, pineapple, prune, tomato, or V-8 juice and give orally. DO NOT CHEW. 2. Open capsule and place granules in a 60ml syringe with plunger removed. Add 40 ml apple juice. Shake carefully and push through nasogastric tube over 3-5 minutes. Rinse syringe twice with 40 ml of apple juice. The total volume administered is 120 ml
Applesauce11,18,21	1. Open capsule and sprinkle granules onto one teaspoon of applesauce.	1. Open capsule and sprinkle granules onto one tablespoon of applesauce.

Opening Capsules

Larson et al. compared the bioavailability and efficacy of a single dose of 40 mg omeprazole given either orally as an intact capsule or the granules via nasogastric tube in 10 healthy subjects in a randomized, crossover design, with subjects serving as their own control.⁵ When administered through the nasogastric tube, the omeprazole capsules were opened, and the granules were placed in a small cup. Each 6 to 10 granules were then flushed with 10-20 ml of water. A total of 140 ml of water was administered. Peak acid output, area under the curve, volume of distribution and plasma half-life were determined. There were no significant differences in gastric acid suppression (85.5% versus 79.6%), area under the curve (2.02 mcg/hr/liter versus 1.74 mcg/hr/liter), and volume of distribution (135.7 liters versus 140.9 liters) between the oral and nasogastric route. Statistically, the mean plasma half-life was significantly longer after nasogastric administration than after oral delivery (1.4 hours versus 1.9 hours, p < 0.03).

Balaban et al. administered omeprazole, either as a 20 or 40 mg dose, through a nasogastric tube to 10 critically ill patients.⁶ The objective of the study was to determine if omeprazole administered in this manner could achieve and maintain an intragastric pH > 4.0. The granules from each capsule were placed in a bowl containing 30 ml of water. A 30 ml syringe, with the plunger removed, was attached to the nasogastric tube. One-third to one-half of the granules with water were poured into the syringe and flushed through the tube. The process was repeated until all granules were administered. The tube was then flushed with 15 ml of water. A total of 45 ml of water was used.

Three of the four patients in the 20 mg treatment group demonstrated an intragastric pH > 4.0 during the course of therapy. Only one patient sustained this effect over a 24-hour period. The mean intragastric pH rose from 2.4 ± 1.1 to 3.7 ±1.6 (p = 0.013). Only 12 of 35 (34%) intragastric pH measurements were greater than 4.0 However, in the six patients in the 40 mg group, the mean intragastric pH rose from 2.8 ± 0.8 to 5.7 ± 1.1 (p < 0.001). Additionally, 39 of 46 (86%) of the intragastric pH measurements were greater than 4.0, with only one measurement 20 hours post-dose less than 4.0. There were no bleeding events, deaths, or adverse events reported in either treatment group.

Both studies administered divided portions of granules since the granules become soft and sticky on contact with water. Thus, liberal flushing with water was needed for proper delivery of medication. Omeprazole 40 mg, rather than 20 mg, was required to maintain intragastric pH > 4.0 over the study period.^5,6 This process is simple but time and labor intensive. Fluid restricted patients might be excluded from use of this method.

Sodium Bicarbonate Solutions

Of the 65 patients receiving SOS as initial prophylaxis, none developed SRMD. In four of five patients who had developed bleeding before study entry, a decreased presence of occult blood within 18 hours of receiving SOS was noted, with complete cessation of hemorrhage by 36 hours. There were no deaths attributed to bleeding or use of SOS. Mean gastric pH before SOS was 3.5 and increased significantly to 7.1 (p < 0.001) within four hours of SOS administration. Mean and lowest gastric pH measurements were also significantly different than mean pre-omeprazole pH (6.8 and 5.6 versus 3.5, p < 0.001).

SOS was prepared by emptying the contents of one or two 20 mg omeprazole capsules into an empty 10 or 20 ml syringe with the needle in place (plunger removed). The plunger was replaced and the needle uncapped. A total of 10 or 20 ml, respectively, of 8.4 % (1 mEq/ml) sodium bicarbonate (based on 20 or 40 mg omeprazole) solution was withdrawn from the bicarbonate vial. The resultant preparation was allowed to stand for a minimum of 30 minutes, with intermittent agitation, to allow the omeprazole granules to suspend. The preparation formed a milky white suspension with a final omeprazole concentration of 2 mg/ml. The SOS was administered via nasogastric tube, which was then flushed with 5-10 ml tap water and clamped for one hour.⁹ The total volume administered was 15-20 ml for omeprazole 20 mg doses and 25-30 ml for omeprazole 40 mg doses. The SOS maintained greater than 90% potency at room temperature for seven days and remained free of bacterial and fungal contamination for 30 days, also at room temperature.⁸ Quercia et al. reported that extemporaneously prepared SOS, 2 mg/ ml, is stable for 14 days at 24ºC and 30 days at 5ºC and -20ºC.¹⁰

Practical preparation of sodium bicarbonate solution in the outpatient setting can be easily accomplished by placing 1/2 to 1 teaspoon of baking soda (sodium bicarbonate) into 240 ml of warm water and allowing the baking soda to dissolve. The administration procedure decribed above can then be followed, with the unused solution stored in the refrigerator. A second possibility is to prepare a 50 ml stock solution (2 mg /ml) weekly using the procedure described by Quercia et al.¹⁰ The solution was prepared by adding the contents of five omeprazole 20 mg capsules to a 60 ml syringe, withdrawing 50 ml from a 8.4 % sodium bicarbonate vial into the syringe, replacing the needle with a fluid-dispensing connector while adding a second 60 ml syringe to the fluid-dispensing connector. The solution is gently transferred between syringes until completely dissolved, transferred back into the empty sodium bicarbonate vial, and labeled with an expiration date of 14 days if stored at room temperature or 30 days if stored in the refrigerator or freezer.

Mohiuddin et al. described a third type of bicarbonate mixture administered to seven human volunteers in a crossover design.¹¹ The subjects were randomly assigned to either omeprazole 20 mg capsules administered with water, or to omeprazole 20 mg granules mixed in 240 ml of water containing two Alka-Seltzer Gold tablets (958 mg sodium bicarbonate, 832 mg citric acid, and 312 mg potassium bicarbonate per tablet) for seven days to assess the effect on gastric acid suppression. An eight hour pH study was done to compare the total percentage of time that intragastric pH > 4.0, and time until intragastric pH < 4.0. The total percent of time the intragastric pH > 4.0 and time to intragastric pH < 4.0 were not statistically different between intact capsule and Alka-Seltzer administration (68.7% versus 65.1%, NS and 327.5 minutes versus 310.5 minutes, NS), suggesting equivalence of these two methods of administration.

Utilization of sodium bicarbonate-based suspensions is the option most widely described to date. Several recent articles advocate this method.^12,13 There are advantages to this approach, especially in patients with NG tubes, J-tubes or feeding tubes (i.e. it is the method least likely to clog tubes and the suspensions can be efficiently administered through the tubes). This approach also eliminates the problems of intact granules adhering to syringes or tubes during administration with water or fruit juices. However, when given by nasogastric or feeding tubes to naïve patients, two bolus doses are required before administering the usual dose. If Alka-Seltzer is used, it must be the Gold formulation, which does not contain aspirin.

Fruit Juices

Woods and McClintock, in a letter to the editor, described opening the omeprazole capsule and administering the enteric-coated granules with an acidic beverage (pH < 5.3), as a method to deliver a fraction of the adult dose to a pediatric patient.¹⁴ The manufacturer of omeprazole has tested the integrity of the enteric-coated granules mixed with various juices: apple, cranberry, grape, grapefruit, orange, pineapple, prune, tomato, and V-8. The integrity of the granules was maintained for a minimum of 30 minutes.¹⁵

Mohiuddin et al. compared omeprazole 20 mg capsules administered with water to omeprazole 20 mg granules mixed in 240 ml of orange juice given orally in seven human volunteers each for seven days to assess effectiveness on gastric acid suppression.¹¹ An eight hour pH study was done to compare the total percent of time intragastric pH > 4.0, and time until intragastric pH < 4.0. The total percent of time the intragastric pH > 4.0 and time to intragastric pH < 4.0 was not significantly different between intact capsule and orange juice administration (68.7% versus 68.5%, NS and 327.5 minutes versus 308.5 minutes), suggesting equivalence of the two regimens.

Chun et al. compared lansoprazole 30 mg swallowed as an intact capsule to iansoprazole 30 mg granules mixed in apple juice, administered via nasogastric tube to 22 healthy human volunteers.¹⁶ The objective was to evaluate the bioavailability and bioequivalence of the two administration methods. This was a single-dose, randomized, crossover design study, with patients serving as their own controls. Pharmacokinetic parameters calculated were peak concentration (Cmax), time to peak concentration (Tmax), area under the curve (AUC) and mean plasma half-life (T1/2).

The granules were placed in a 60 ml catheter-tipped, plastic syringe with the plunger removed. Apple juice was added through the plunger end. The plunger was replaced and the volume adjusted to 40 ml. The granules were carefully shaken and slowly pushed through the nasogastric tube over three to five minutes, with the patient in the seated position. The syringe was then rinsed twice with 40 ml of apple juice and the juice was transferred into the nasogastric tube. The total apple juice volume administered was 120 ml. There were no statistically significant differences in Cmax (660 ng/ml versus 728 ng/ml), Tmax (1.5 hour versus 1.8 hour), AUC (1,388 ng/h/ml versus 1,468 ng/h/ml), and T1/2 (0.99 hour versus 0.93 hour) between the oral and nasogastric routes of administration, indicating similar bioavailability. The manufacturer of lansoprazole has tested the integrity of the enteric-coated granules mixed with various juices: apple, cranberry, grape, orange, prune, and V-8. The integrity of the enteric coating was maintained for 30 minutes.¹⁷

Gunasekaran et al. administered omeprazole in orange juice, cranberry juice or yogurt to 15 children between the ages of 10 months and 17 years (mean 8.1 years) in whom histamine₂ receptor-antagonists and prokinetic agents failed to heal esophagitis.¹⁸ This was an open-label study. Children older than three years of age began with omeprazole 20 mg in the morning while those less than three years of age started on omeprazole 10 mg; one patient recieved a sodium bicarbonate solution. Patients were studied by 24-hour pH monitoring after five days. The therapeutic endpoint was to achieve a pH < 4.0 for less than 6% of the study period time. The dose was titrated upward to reach this goal. Patients had follow-up visits at three months, six months, and then every six months for up to 26 months.

The dosage required to control esophageal reflux was 20-40 mg (0.7-3.3 mg/kg) in 11 children, 10 mg (0.7 mg/kg) in one child, and 60 mg (1.9-2.4 mg/kg) in three children. All were free of symptoms by the second follow-up visit. The children received omeprazole continuously for periods ranging from 5.5 to 26 months. Seven children developed elevated AST and/or ALT (two times the normal maximum) that stabilized with continued therapy and returned to baseline when discontinued. One child developed alopecia after 12 months. There were 11 patients with hypergastrinemia: two had an elevated fasting gastrin before starting; three developed hypergastrinemia within six months of beginning omeprazole; and six exhibited this symptom after more than six months of therapy. Helicobacter pylori status was not determined in any patient.

Sharma et al. studied the effect of omeprazole 20 mg daily for seven days on 24-hour intragastric pH in 14 patients with gastrostomy.¹⁹ This was an open-label study, with patients serving as their own controls. Patients' tube feedings were discontinued for two hours before and one hour after omeprazole administration. The gastrostomy tube was first flushed with 15 ml of orange juice using a catheter-tipped syringe. The omeprazole granules were poured into the catheter-tipped syringe while connected to the gastrostomy tube and gently flushed with small amounts of orange juice until all granules were out of the syringe. The gastrostomy tube was then flushed with 15 ml of orange juice.

The mean 24-hour intragastric pH was significantly elevated compared to baseline (4.9 ± 0.8 versus 1.8 ± 0.7, p < 0.0001). The proportion of time that the intragastric pH exceeded 3.0 (19.2 hours versus 5.1 hours, p < 0.0001) and 4.0 (17.4 hours versus 3.6 hours, p < 0.001) was also statistically significant.

Applesauce

Chun et al. administered lansoprazole 30 mg either as intact gelatin capsules or enteric-coated granules from opened capsules in one tablespoon of applesauce to 24 healthy males in a randomized, single-dose, open-label, crossover study.²⁰ Pharmacokinetic parameters calculated were peak concentration (Cmax), time to peak concentration (Tmax), area under the curve (AUC), and mean plasma half-life (T1/2). There was no significant difference in any pharmacokinetic parameter when taken with applesauce or as an intact capsule, indicating similar bioavailability.

In the largest proton pump inhibitor study in children to date, 51 children (27 reflux, 17 neurologically impaired, 7 esophageal atresia) ages one to 16 years with grade two or higher esophagitis were enrolled in a dose-finding, healing, and maintenance study of omeprazole.²¹ There were 18 previously untreated and 28 treatment failures to prokinetics and/or histamine₂-receptor antagonists. The starting dose was 0.7 mg/kg omeprazole and was increased every 5 to 14 days to achieve a therapeutic goal of an esophageal pH < 4.0 less than 6% of total time. The maximum total daily dose was 3.5 mg/kg, with no child receiving greater than 80 mg daily. Granules were mixed in yogurt or applesauce, or the capsules opened and the granules swallowed immediately with water.

At entry, 42 (82%) children had moderate-to-severe symptoms. After esophageal healing occurred, the children were entered into the maintenance phase, where treatment consisted of 50% of the healing dose. They were re-evaluated after three months and, if relapse occurred, were given the dose that achieved initial healing then re-evaluated at seven, 12, 17, and 21 months after entry into the maintenance phase. Forty-nine of 51 children had esophageal healing; three required a second course of therapy. The proportion of children requiring greater than 1.4 mg/kg/day was higher in those with more severe esophagitis. Healing occurred with the following dosage regimens: 0.7 mg/kg, 23/49 (47%); 1.4 mg/kg, 13/49 (27 %); 2.1 mg/kg, 7/49 (14%); 2.8 mg/kg, 4/49 (8%); and 3.5 mg/kg, 2/49 (4%). At last visit, 27% were asymptomatic, 47% had mild symptoms, 20% moderate symptoms, and 10 % severe symptoms. There were no adverse events attributable to omeprazole therapy. The Helicobacter pylori status and gastric endocrine cell data were similar at entry and at last visit for each patient.

Summary and Conclusions

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