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Letters

Administering Proton Pump Inhibitors

I am writing with regard to the article "Alternative Methods of Proton Pump Inhibitor Administration" by Anthony Zimmerman et al. (Consult Pharm 1997;9:990–8).

The relative oral bioavailability of the proton pump inhibitors lansoprazole and omeprazole significantly affect their ability to increase intragastric pH and promote mucosal healing and symptom relief in patients with acid-related disorders. Several studies published to date have confirmed that upon first dose administration the bioavailability of lansoprazole approaches 85% while that of omeprazole is only 35%, increasing to only 63% upon repeat administration.^1–4 The poor bioavailability of omeprazole may be due to the degradation of the compound by acid in the stomach.⁵ Therefore, maintaining the integrity of the enteric coated contents of these agents, especially omeprazole, is critical to their clinical efficacy.

Given this, we found the recently published manuscript by Zimmerman et al. to contain several misleading statements. First, lansoprazole delayed-release capsules have been cleared by the Food and Drug Administration (FDA) to be opened and the intact granules sprinkled on applesauce for patients with swallowing difficulties. In addition, for patients who have a nasogastric tube in place, the labeling of lansoprazole states that the intact granules can be mixed in 40 ml of apple juice and injected through the nasogastric tube into the stomach. The integrity of the enteric coating of lansoprazole granules is maintained for at least 30 minutes when mixed with apple juice. On the basis of pharmacokinetic studies performed by Chun and colleagues, both the applesauce and apple juice methods of lansoprazole granule administration have been found to produce a total bioavailability of lansoprazole similar to that of the intact capsule dosage form.^6,7 While these two studies were presented by the authors in the text, they were not cited in Table 2 under the studies performed using opened lansoprazole capsules.

Second, while the authors cited numerous studies performed using extemporaneous preparations of omeprazole, they failed to mention that omeprazole has not received clearance by the FDA for any extemporaneous mixing of the capsule granules into any liquid or soft food. Furthermore, the labeling of omeprazole states that the capsules should not be opened, chewed, or crushed and should be swallowed whole.

Clearly, maintaining the integrity of the proton pump enteric coated granules in the acidic contents of the stomach is critical to their bioavailability and clinical efficacy. However, there is a need to establish effective alternative methods of administration in patients who are unable to swallow the intact capsules. Currently, lansoprazole is the only proton pump inhibitor that has been cleared by the FDA for administration of the capsule contents via mixing with applesauce and given orally or mixing with apple juice and injecting through a nasogastric tube into the stomach.

Robert A. Blum, PharmD
The Clinical Pharmacokinetics Laboratory
Millard Fillmore Hospital
Buffalo, New York

References

1. Delhotal-Landes B, Flouvat B, Duchier J et al. Pharmacokinetics of lansoprazole in patient with renal or liver disease of varying severity. Eur J Clin Pharmacol 1993;45:367–71.
2. Gerloff J, Mignot A, Barth H et al. Pharmacokinetics and absolute bioavailability of lansoprazole. Eur J Clin Pharmacol 1996;50:293–7.
3. Andersson T, Anden K, Cederberg C et al. Pharmacokinetics and bioavailability of omeprazole after single and repeated administration in health subjects. Br J Clin Pharmacol 1990;29:557–63.
4. Andersson T, Regardh C-G. Pharmacokinetics of omeprazole and metabolites following single intravenous and oral doses of 40 and 80 mg. Drug Invest 1990;2:255–63.
5. Dammann HG, Fuchs W, Richter G et al. Lansoprazole versus omeprazole: influence on meal-stimulated gastric acid secretion. Aliment Pharmacol Ther 1997;11:359–64.
6. Chun AHC, Shi HH, Achari R et al. Lansoprazole: administration of the contents of a capsule dosage formulation through a nasogastric tube. Clin Ther 1996;18:833–42.
7. Chun AHC, Easton CJ, Shi HH et al. Lansoprazole: an alternative method of administration of a capsule dosage formulation. Clin Ther 1995;17:441–6.

In reply: Your letter contains several misleading and potentially inaccurate statements that I would like to clarify. The increased bioavailability of omeprazole between the first dose and steady state may be explained by a decreased first-pass elimination during repeated treatment and/or by a reduced degradation of omeprazole in the stomach secondary to the profound decrease in intragastric acidity caused by the drug. It is most likely due to decreased first-pass elimination.¹

The acid-labile nature of proton pump inhibitors emphasizes the need for solid clinical data to ensure optimal patient outcomes. Studies must measure clinically relevant pharmacodynamic endpoints, such as intragastric pH, prevention of stress-related mucosal disease, and healing of esophagitis. The reports should verify that the expected endpoints have been achieved. These have all been documented and described with omeprazole, not lansoprazole, administered by methods other than intact capsules.²

I agree that omeprazole has not been "cleared" by the FDA for administration by methods other than intact capsules, but 12 of 14 published studies conducted with omeprazole contain pharmacodynamic information about the effectiveness and tolerability of various administration methods.² The two studies published with lansoprazole are only single-dose bioequivalence studies conducted in normal, healthy volunteers.^3,4 This information may or may not be transferable to patients in a clinical setting. The product being "cleared" by the FDA allows for information to be included in the labeling, not a formal indication by the FDA. My intent was to review the published information and provide guidance to clinicians to achieve optimal clinical outcomes.

The methodology section of the paper by Chun et al. describing nasogastric tube administration of lansoprazole states that intact granules can be mixed with 40 ml of apple juice and administered by the nasogastric tube. The tube is then flushed twice more with 40 ml of apple juice.

Thus, a total of 120 ml of apple juice is required to administer the contents of one 30 mg lansoprazole capsule, if one were to accurately follow the published information.³ Importantly, the healthy volunteers in this study were sitting upright, not supine as is far more common in the critical care or long-term care setting.

Table 2 in our paper does detail and describe both the applesauce and apple juice administration papers by Chun et al.^3,4 Reference 17 (Fruit Juices) accurately represents and cites the nasogastric tube study. Reference 20, not 21, accurately represents and cites the applesauce study. The information in Table 2 is correct; however the reference number is not. I and my co-authors take full responsibility for this error.Lastly, there is an Internet Web site discussing simplified omeprazole solution. For those interested, the address is: www.surgery.missouri.edu/tops/omepflav.shtml.

Anthony E. Zimmermann, PharmD
Department of Pharmacy
Baystate Medical Center
Springfield, Massachusetts

References

1. Andersson T, Anden K, Cederberg C et al. Pharmacokinetics and bioavailability of omeprazole after single and repeated administration in health subjects. Br J Clin Pharmacol 1990;29:557–63.
2. Zimmerman A, Walters JK, Katona B et al. Alternative methods of proton pump inhibitor administration. Consult Pharm 1997;12;990–8.
3. Chun AHC, Shi HH, Achari R et al. Lansoprazole: administration of the contents of a capsule dosage formulation through a nasogastric tube. Clin Ther 1996;18:833–42.
4. Chun AHC, Easton CJ, Shi HH et al. Lansoprazole: an alternative method of administration of a capsule dosage formulation. Clin Ther 1995;17:441–6.