Advances in Proton Pump Inhibitor Therapy: An Immediate-Release Formulation of Omeprazole Ralph E. Small, PharmD

Transcription

1 Advances in Proton Pump Inhibitor Therapy: An Immediate-Release Formulation of Omeprazole Ralph E. Small, PharmD PROTON PUMP INHIBITORS: AN OVERVIEW Acid-related disorders encompass a wide variety of diagnoses, including the extremely prevalent gastroesophageal reflux disease (GERD), which affects an estimated 25 million Americans, 1 duodenal and gastric ulceration, stressrelated mucosal disease, and acute upper gastrointestinal bleeding, a common medical emergency resulting in approximately 3, hospitalizations annually. 2 During the last three decades, the management of these disorders has been revolutionized by the introduction of histamine-2 receptor antagonists (H 2 RAs) and proton pump inhibitors (PPIs). Five available delayed-release PPIs include omeprazole (Prilosec, Astra- Zeneca), lansoprazole (Prevacid, TAP), pantoprazole (Protonix, Wyeth), esomeprazole magnesium (Nexium, Astra- Zeneca), and rabeprazole (Aciphex, Eisai/Janssen). These drugs are highly effective, irreversible inhibitors of H+/K+ ATPase, the final step in gastric acid secretion. Although these agents form the therapeutic cornerstone of management for a variety of acid-related disorders, there is still room for improvement in our armamentarium. For example, all PPI compounds are weak bases that are acidlabile and are rapidly degraded, usually within minutes, in the acidic environment of the stomach. Until the recent introduction of immediate-release omeprazole Dr. Small is Professor Emeritus at Virginia Commonwealth University in Richmond, Virginia. Drug Forecast is a regular department coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York. ( [Zegerid, Santarus]), this pharmacological property required the active ingredient in all delayed-release oral PPI formulations to have an enteric coating. The coating protects the active ingredient from degradation by gastric acid, but it also delays absorption, so that the peak plasma concentration (C max ) is not typically attained for up to five hours after oral administration of these formulations. In addition, patients must not chew or crush the tablets or the entericcoated granules. For patients who cannot swallow intact capsules or tablets or who have a nasogastric tube in place, various liquid formulations have been compounded extemporaneously from sodium bicarbonate solution, with omeprazole or lansoprazole granules, or crushed pantoprazole tablets. 3,4 These formulations have a limited shelf life and may adhere to the syringe and the tubing used for administration, with the result that the tubing has the potential to become clogged. 5 Limitations to enteric-coated PPI formulations also include the potential for nocturnal acid breakthrough (NAB), defined as an intragastric ph below 4 for at least one hour during the night with PPI therapy. NAB occurs in up to 7% of patients with GERD. 69 Despite adequate therapeutic dosing (including twice-daily administration), patients taking entericcoated, delayed-release PPIs may experience nocturnal gastric acidity, whether or not the agent is taken before breakfast, before dinner, or twice daily 911 and may have nighttime symptoms of heartburn. Patients with nocturnal GERD may have a higher potential for severe refluxinduced complications such as esophagitis, Barrett s esophagus, esophageal motility disorder, esophageal stricture formation, and esophageal adeno- carcinoma. 9,1217 Individuals with nocturnal heartburn also report less satisfaction with PPIs and a diminished quality of life in terms of both mental and physical components, compared with GERD patients, who do not experience nocturnal heartburn. 7,18 Strategies for managing nocturnal gastric acidity include increasing PPI administration from once to twice daily, increasing the dose, switching to another PPI, or adding an H 2 RA at bedtime Although this last strategy may provide short-term efficacy, its clinical utility may be limited by the potential for the development of tolerance to H 2 RAs as well as by the additional cost of therapy. Lapses in controlling gastric ph during PPI therapy may impair the ability of PPIs to adequately protect against stressrelated intestinal mucosal disease, a significant clinical problem that occurs in 7% to 9% of critically ill patients 22 and portends increased morbidity as well as extended hospital stays Among patients who are not given prophylactic pharmacological therapy, overt upper gastrointestinal (GI) bleeding has been documented in 17% of critically ill patients. 23 More than a decade ago, investigators found that various degrees of acid suppression produced different physiological effects in the gastric milieu. 23 At a ph of 4.5 or above, pepsin begins to be inactivated; at a ph of 5 or above, it becomes completely inactivated; and at a ph of 7 or above, there is a potential for a decreased incidence of peptic ulcer rebleeding in patients who have already achieved hemostasis. 23 Some investigators suggest that a gastric ph of 6.5 or higher is optimal for preventing stress ulceration; at this value, pepsin is inactivated and blood coag- 698 P&T December 25 Vol. 3 No. 12

2 Table 1 Uses and Dosages of Immediate-Release Omeprazole () Powder for Suspension Indication ulation parameters are maintained, 22 although other authors consider a ph of 3.5 to 4 or above to be sufficient. 23,27,28 H 2 RAs can be effective in attaining these levels, but tachyphylaxis is a frequent occurrence. 29 More recent studies support the clinical efficacy of PPI therapy in the management of these critically ill patients; 333 a recent Cochrane Collaboration found that the ability of PPI therapy to raise gastric ph is independent of the route of administration; 31 however, this effect must be sustainable. Therefore, although significant progress has been made in treating acidrelated disorders, patients would benefit from advances in PPI therapy. Specifically, an acid-suppressing agent that shows more rapid absorption; that can be administered orally, even in patients who cannot swallow intact capsules or tablets; that provides better nocturnal acid control; and that sustains gastric ph above a critical threshold would be a welcome addition to the PPI class. THE ADVENT OF IMMEDIATE- RELEASE OMEPRAZOLE Approximately one year ago, the U.S. Food and Drug Administration (FDA) approved a unique IR formulation of omeprazole (Zegerid ) to treat a variety of acid-related disorders and to reduce the Dose 1. Short-term treatment of active 1. 2 mg once daily for four weeks; duodenal ulcer some patients may require an additional four weeks of therapy. 2. Gastric ulcer 2. 4 mg once daily for four to eight weeks. 3. GERD; symptomatic, no 3. 2 mg once daily for up to four esophageal lesions weeks 4. GERD; symptomatic with confirmed 4. 2 mg once daily for four to eight erosive esophagitis weeks 5. Maintenance of healing of 5. 2 mg once daily; controlled studies erosive esophagitis do not extend beyond 12 months. 6. Reduction in risk of upper 6. 4 mg initially, followed by 4 mg gastrointestinal bleeding in critically ill patients GERD = gastroesophageal reflux disease. after six to eight hours as a loading dose on the first day, then 4 mg once daily for up to 14 days; the use of in critically ill patients for longer than 14 days has not been evaluated. risk of upper gastrointestinal bleeding in critically ill patients (Table 1). This compound was developed by combining a highly effective PPI (omeprazole) with an antacid buffer (sodium bicarbonate), which neutralizes gastric acid and protects the PPI from gastric acid degradation. Studies have found that the degradation half-life of nonenteric-coated omeprazole is approximately seven hours at a ph of 6, compared to less than three minutes at a ph of In an in vitro model, the sodium bicarbonate buffer in rapidly increases the ph to greater than 6 within one minute and sustains this ph environment for approximately 3 minutes. 41 This pharmacological synergy protects omeprazole from gastric acid degradation, allows it to be rapidly absorbed, and eliminates the need for an enteric coating. PHARMACOKINETICS The pharmacokinetic profile of IR- OME differs significantly from that of a delayed-release PPI plus an antacid. Specifically, the C max of the IR formulation is achieved in 1 to 9 minutes (mean, 3 minutes) after single or multiple oral doses are taken on an empty stomach. 35 In contrast, several investigators, studying the pharmacokinetics of delayed-release omeprazole or rabeprazole, coadministered with antacids, found no significant change in the C max, the mean time to peak plasma concentration (T max ), or the area under the curve (AUC) One study of delayed-release lansoprazole, given with an antacid, revealed a slight decrease in the AUC and a significant decrease in the C max with no change in the T max. 4 In an open-label, randomized, twoperiod crossover comparator trial with a 1- to 14-day washout period between treatments, in strengths of 4 and 2 mg was compared with delayedrelease 4- and 2-mg omeprazole capsules. 35,41 During each treatment period, healthy subjects received seven consecutive single daily doses of each dosage strength one hour before they ate a standardized high-fat breakfast. As illustrated in Figure 1, the T max observed with each dosage strength of the IR formulation occurred much sooner (P <.1) (at approximately 3 minutes with each dose) than that of the respective dose of the enteric-coated formulation (at 1.8 and 1.4 hours, respectively) with delayed-release omeprazole 4 mg and 2 mg (Table 2). The AUC of 4 mg is about three-fold higher than that of the 2-mg dose, and repeated exposure to the IR form results in increased bioavailability. The observed increase in the AUC is almost doubled from a single dose, compared with the steady state (Table 2A). 35 Because taking one hour after a meal decreases the AUC by approximately 26% at steady state, optimal pharmacokinetic parameters are achieved when patients take this drug on an empty stomach. However, the AUC associated with a postprandial 4-mg dose of is still substantial (3,862 ng hour/ml) in the range associated with a 7% reduction in baseline gastric acidity. 35 Approximately 95% of omeprazole is protein-bound. In healthy subjects, its plasma half-life is about one hour (range,.43.2 hours) and the plasma clearance averages between 5 and 6 ml/ minute. Most of the omeprazole (77%) is excreted as metabolites in the urine, and the remainder is eliminated in the feces. 35 Elderly Populations Older age produces a slight decrease in the elimination rate of omeprazole and Vol. 3 No. 12 December 25 P&T 699

3 Table 2 Mean Pharmacokinetic Parameters after Administration of Omeprazole on Days One and Seven A, Immediate-Release Omeprazole Day One Day Seven Parameter 4 mg 2 mg 4 mg 2 mg AUC (ng hour/ml) 2, ,64 1,446 C max (ng/ml) 1, , T max (minutes) Half-life (hours) B, Delayed-Release Omeprazole Day One Day Seven Parameter 4 mg 2 mg 4 mg 2 mg AUC (ng hour/ml) 2, ,591 1,351 C max (ng/ml) 1, , T max (hours) Half-life (hours) AUC = area under the curve; C max = maximum concentration; T max = time to maximum concentration. increases its bioavailability. Compared with a bioavailability of 58% in younger subjects, the bioavailability of a single 4-mg dose of in healthy older subjects was 76%. 35 The extent of metabolite excretion in the urine (7%) was similar to that observed in younger subjects. The plasma half-life was also similar at approximately one hour. 35 Hepatic Impairment In patients with chronic hepatic disease, the bioavailability of increases, reflecting a decrease in firstpass metabolism. The plasma half-life increases to approximately three hours, and plasma clearance decreases to about 7 ml/minute. 35 Renal Impairment In patients with chronic renal impairment (the creatinine clearance is between 1 and 62 ml/minute per 1.73 m 2 ), the bioavailability of omeprazole is slightly increased and urinary elimination is decreased. The reduced elimination is related to the decrement in creatinine clearance. 35 PHARMACODYNAMICS A gastric ph of greater than 4 has long been established as the target for effective mucosal healing. 42 Studies in healthy subjects have found that once-daily dosing of 4 mg and 2 mg of maintains the gastric ph above 4 for 77% and 51%, respectively, of a 24-hour period. 35,43 In these two studies, maintained a median gastric ph of 5.2 with the 4-mg dose and 4.2 with the 2-mg dose. 35,43 The median 24-hour gastric ph exceeded 4 for 18.6 hours with 4 mg and 12.2 hours with 2 mg. The decrease from baseline for integrated gastric acidity (or total accumulated gastric acid) with 4 mg was 84%; with 2 mg, the decrease was 82%. Although no head-to-head studies have compared with delayed-release esomeprazole, lansoprazole, or rabeprazole, the duration of time that 4 mg and 2 mg maintain the gastric ph above 4 is slightly longer than the values reported in the product labeling for these delayed-release compounds (Table 3). 35,4447 In all cases, given the relatively short plasma half-lives of these medications (about one hour), the extended durations of antisecretory effects probably reflect the irreversible binding to the parietal cell H+/K+ ATPase enzyme by the PPIs. CLINICAL TRIALS Efficacy Nocturnal Acid Control One trial has confirmed the effectiveness of a bedtime dose of in controlling nocturnal gastric acidity. Goldlust and colleagues 43 presented data from an open-label study. 2 mg Plasma Concentration (ng/ml) A 1,8 1,6 1,4 1,2 1, Immediate-release omeprazole suspension 4 mg Immediate-release omeprazole suspension 2 mg Delayed-release omeprazole capsule 4 mg Delayed-release omeprazole capsule 2 mg 1,8 1,6 1,4 1,2 1, I I I I I I I I I Day 1 Hours B Day 7 Plasma Concentration (ng/ml) Immediate-release omeprazole suspension 4 mg Immediate-release omeprazole suspension 2 mg Delayed-release omeprazole capsule 4 mg Delayed-release omeprazole capsule 2 mg I I I I I I I I I Hours Figure 1 A, B, Mean plasma concentrations of immediate-release omeprazole () suspension and delayed-release omeprazole capsules on days one and seven. Both compounds were administered one hour before mealtime. The mean time to peak plasma concentration (T max ) with these doses occurred significantly sooner (at approximately 3 minutes) (Table 2A) on days one and seven than that of delayed-release omeprazole (range, hours) on day one (Table 2B) and with a repeated administration (range, hours) on day seven (Table 2B). (Data from Santarus. 35,41 ) 7 P&T December 25 Vol. 3 No. 12

4 Table 3 Pharmacodynamic Parameters of Proton Pump Inhibitors by Product Labeling Esomeprazole Lansoprazole Rabeprazole (Zegerid ) (Nexium ) (Prevacid ) (Aciphex ) (Protonix ) 4 mg 2 mg 4 mg 2 mg 3 mg 15 mg 2 mg 4 mg 2 mg Time gastric NA NA ph > 4 (hours) Percentage of time 77% 51% 7% 53% 66% 49% 6% NA NA with gastric ph > 4 Median gastric ph * 4.1* 4.9* 4.* = immediate-release omeprazole; NA = not available. * Mean. Data from package inserts. 35, 4447 was administered once a day one hour before breakfast for seven days to 17 healthy subjects. On the eighth day, the participants received 2 mg twice daily, one hour before breakfast and at bedtime (1 p.m., or 22 hours). Twenty-four-hour gastric ph monitoring was performed on days seven and eight. Figure 2 depicts the 24-hour median gastric ph profiles of patients taking at the steady state with 4 mg once daily in the morning, 2 mg once daily in the morning, and 2 mg twice daily, in the morning and at bedtime. As shown in Figure 2C, the bedtime dose of rapidly raised the gastric ph and sustained this effect for approximately eight hours. The median percentage of nighttime hours during which the gastric ph was above 4 was 87% with twice-daily dosing of 2 mg and 39% with once-daily morning dosing of 2 mg of (P <.1). 43 Twice-daily administration of 2 mg of also significantly reduced the percentage of patients with NAB, compared with 2 mg administered once daily in the morning, namely, 29% (five of 17 patients) versus 76% (13 of 17 patients) (P =.5). 43 Castell and colleagues compared the nighttime gastric ph control of suspension with that of delayed-release pantoprazole tablets. 48 ( is currently the only PPI that is FDAapproved to treat nighttime symptoms of GERD.) In the first period of the openlabel, two-period crossover trial, patients with a history of nocturnal GERD symptoms were randomly assigned to receive either or pantoprazole. 4 mg (n = 32) was taken at bedtime (1 p.m.) for six days. On day seven, 15 patients were randomly selected to receive 2 mg twice daily, one hour before breakfast and at bedtime; 17 patients received 4 mg twice daily, also one hour before breakfast and at bedtime. 4 mg was administered at 1 p.m. on day one and before dinner on days two through six. On day seven, this dose was given twice: one hour before breakfast and at bedtime). After a 1- to 14-day washout period, patients crossed over to the alternate treatment in the second period. As illustrated in Figure 3, statistically significant differences (P <.1) were observed between the once-daily and twice-daily suspensions and the comparative pantoprazole regimen in the median percentages of time that the gastric ph was maintained above 4 during the eight-hour nighttime interval (from 1 p.m. to 6 a.m.). For each paired comparison, the median values were as Fig 2A. Trial 1 4 mg q AM Day 7 (Dose 7) Dose Meal Meal Meal Fig 2B. Trial 2 2 mg q AM Day 7 (Dose 7) Dose Meal Meal Meal Fig 2C. Trial 2 2 mg q AM and HS Day 8 (Doses 8 and 9) Dose Meal Meal Meal Dose Gastric ph Gastric ph Gastric ph Hours (24-hour Clock) n = Hours (24-hour Clock) Figure 2 A, B, Twenty-four-hour gastric ph profiles of immediate-release omeprazole (). Repeated administration of in the morning produces a gastric acidity profile similar to other proton pump inhibitors (PPIs). C, Adding a second bedtime dose of abruptly raises the gastric ph and sustains this level throughout the nighttime interval. HS = at bedtime. (From Goldlust B, Hepburn B, Hardiman Y. Am J Gastroenterol 24;99:S ) n = 17 1 Hours (24-hour Clock) n = 17 Vol. 3 No. 12 December 25 P&T 71

5 % Time ph > % 4 mg q.d. (n = 32) P < % 4 mg q.d. (n = 32) shown in Figure 3. The median nighttime gastric ph values were 4.7 with 4 mg and 2 with pantoprazole 4 mg on day six (P <.1). 48 The percentage of patients who experienced NAB was also significantly smaller during therapy than with pantoprazole on days six and seven (P <.5 for each comparison) (Figure 4). On day six, significantly fewer patients treated with 4 mg (53.1%) experienced NAB than when they had used pantoprazole 4 mg (78.1%) (P =.5). Twice-daily produced a significantly higher median percentage of time during which the gastric ph was maintained above 4, compared with twice-daily pantoprazole during the 24-hour interval (1 p.m. to 1 p.m.). A median gastric ph level greater than 4 was maintained for 87.8% of the 24-hour interval with twice-daily 4 mg, compared with 56.9% (P <.1) observed during twice-daily therapy with pantoprazole 4 mg. 48 At steady state, the median percentage of time with the gastric ph above 4 during the 24-hour interval was similar for paired patients taking once-daily 4 mg and twice-daily pantoprazole 4 mg (Figure 5). 48 Reduction in Risk of Upper GI Bleeding in Critically Ill Patients Conrad and colleagues established the efficacy of in reducing the risk of 72 P&T December 25 Vol. 3 No % 2 mg b.i.d. (n = 15) P < % 4 mg b.i.d. (n = 15) 92.% 4 mg b.i.d. (n = 17) P < % 4 mg b.i.d. (n = 17) Figure 3 Median percentage of time that gastric ph stayed above 4 during the nighttime interval (from 1 p.m. to 6 a.m.) following repeated dosing with immediaterelease omeprazole () and pantoprazole. For this eight-hour interval, the median time that gastric ph stayed above 4 was significantly greater with once daily (q.d.) or twice daily (b.i.d.), compared with pantoprazole once daily (P <.1 for each comparison). (Data from Castell D, et al. Aliment Pharmacol Ther 25;21: ) upper GI bleeding in critically ill patients in a multicenter, randomized, doubleblind, double-dummy, parallel-group study of 359 patients. 49 These patients, who were undergoing mechanical ventilation in the intensive care unit (ICU) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 11 or higher and one additional risk factor for upper GI bleeding, were enrolled at 47 sites in the U.S. The patients were assigned to receive either suspension via nasogastric or orogastric tube at a dose of 4 mg twice daily on day one (six to eight hours apart) and 4 mg once daily thereafter (and continuous intravenous [IV] Percentage of Patients % 4 mg q.d. at bedtime (n = 32) P = % 4 mg q.d. before dinner (n = 32) placebo) or IV cimetidine (Tagamet, GlaxoSmithKline), given as a 3-mg bolus. This dose was followed by an infusion of 5 mg/hour thereafter (and placebo oral suspension). Each regimen was administered for up to 14 days. Gastric aspirates were sampled for upper GI bleeding every two hours on the first and second days, then every six hours for the remaining study days. Gastric aspirates were also used to measure ph every two hours on the first and second days and immediately before and one hour after administration of the suspension on days 3 to 14. The dose of or cimetidine was doubled for patients with two successive gastric aspirates of a ph of 4 or less. A second daily dose of 4 mg was administered to patients only on the day when they had two successive gastric aspirates of a ph of 4 or less, whereas the dose of cimetidine was doubled to 1 mg/hour for the duration of the study. Patients were permitted enteral feedings after the third day. Feedings were held for three hours before and for one hour after administration of the suspension. The primary efficacy endpoint of this non-inferiority study was the occurrence of clinically significant upper GI bleeding. This was defined as bright-red blood via a nasogastric or an orogastric tube that had not cleared after 5 to 1 minutes of lavage or as persistent Gastroccult - positive coffee-ground material for at least eight consecutive hours on days one and two or for two to four hours on days 11.8% 4 mg b.i.d. (n = 17) P =.2 7.6% 4 mg b.i.d. (n = 17) Figure 4 Percentage of patients with nocturnal acid breakthrough (NAB) during treatment with immediate-release omeprazole () and pantoprazole. once daily (q.d.) and twice daily (b.i.d.) produced significantly smaller percentages of patients with NAB (P <.5), compared with pantoprazole once or twice daily. (Data from Castell D, et al. Aliment Pharmacol Ther 25;21: ) continued on page 711

6 continued from page 72 % Time ph > % 4 mg q.d. (n = 18) 56.2% 4 mg b.i.d. (n = 18) Figure 5 Median percentage of time that the gastric ph stayed above 4 during the 24-hour interval following repeated dosing with immediate-release omeprazole () and pantoprazole. A median gastric ph above 4 was maintained for 61.1% of the 24-hour interval for once-daily (q.d.) 4 mg, compared with 56.2% for pantoprazole 4 mg twice daily (b.i.d). (Data from Castell D, et al. Aliment Pharmacol Ther 25;21: ) 3 through 14 that had not cleared with 1 ml or more of lavage. Because this was a non-inferiority study, the primary efficacy analysis was conducted on the per-protocol population at the one-sided α =.25 level of significance. Secondary endpoints included the percentage of patients with any evidence of bleeding and the percentage of patients with a gastric ph of 4 or below on two consecutive gastric aspirates. The safety and tolerability of each regimen were also assessed. The mean patient age was 55.7 years (range, 1691 years). These patients, 58.5% of whom were men and 64% of whom were white, were treated for a mean of 6.8 days. Patient characteristics were similar between the treatment groups. 49 The rates of clinically significant bleeding were 4.5% with and 6.8% with cimetidine. These results satisfied the criteria for the non-inferiority of in preventing upper GI bleeding in critically ill patients compared with IV cimetidine. was more effective than IV cimetidine in maintaining a median gastric ph above 4. in critically ill patients. The effects of on gastric ph were consistent regardless of patients baseline ph values. Median gastric ph values greater than 6 were observed in almost all patients following the first dose of. A median gastric ph above 6 was sustained on all days for patients receiving but persisted on only 5% of the days for patients receiving cimetidine (Figure 6). After three days of cimetidine administration, the median gastric ph began to decline, suggesting the development of tachyphylaxis. After day eight, at least 25% of the cimetidine patients had a median gastric ph below 4. During the entire trial, failure of ph control (two consecutive gastric aspirates of ph of 4 or below at least one hour apart on the same day) was observed in 58% of the cimetidine patients but in only 18% of the IR- OME patients (P <.1). The incidence and type of adverse drug events (ADEs) reported with and cimetidine were similar. For instance, nosocomial pneumonia occurred at a rate of 11.2% with and at a rate of 9.4% with IV cimetidine (P =.61). 49 All currently available PPIs, including, are effective in relieving GERD symptoms, healing gastroduodenal ulcers, providing treatment of erosive esophagitis, and maintaining healing of lesions. Unlike the other PPIs, may control nocturnal gastric acidity when it is given at bedtime. is the only PPI that has been subjected to clinical study and carries an FDA indication for reducing the risk of upper GI bleeding in critically ill patients. Safety Adverse Effects In the U.S. trial of omeprazole, the most frequently reported ADEs in 465 patients that were considered possibly, probably, or definitely treatment-related were headache (in 2.4% of patients), diarrhea (in 1.9%), rash (in 1.1%), nausea (in.9%), constipation (in.9%), dizziness (in.6%), vomiting (in.4%), abdominal pain (in.4%), and asthenia (in.2%). Occasional cases of atrophic gastritis have been noted in gastric corpus biopsies of patients receiving long-term omeprazole therapy. A symptomatic response to omeprazole does not preclude the presence of gastric malignancy. 35 Median Gastric ph No. of patients No. of patients Immediate-Release Omeprazole Cimetidine Trial Day Figure 6 Gastric ph in critically ill patients, by treatment. A median gastric ph above 6 was sustained on all days in patients receiving immediate-release omeprazole () compared with 5% of the days in patients receiving cimetidine. (Adapted from Conrad S, Gabrielli A, Margolis B, et al. Crit Care Med 25;33[4]:76765, Lippincott Williams & Wilkins. 49 ) Vol. 3 No. 12 December 25 P&T 711

7 Sodium Bicarbonate Each 4-mg and 2-mg dose packet of contains 46 mg of sodium in the form of sodium bicarbonate (1,68 mg, 2 meq). This fact should be taken into consideration for patients who are following sodium-restricted diets. The use of is contraindicated in patients with metabolic alkalosis and hypocalcemia. Sodium bicarbonate should also be used with caution in patients with Bartter s syndrome, hypokalemia, respiratory alkalosis, and acidbase imbalances. The long-term administration of sodium bicarbonate with calcium or milk can induce the milk-alkali syndrome. 35 DRUG INTERACTIONS Like the delayed-release, entericcoated, oral PPI formulations, may prolong the elimination of drugs that are metabolized by oxidation in the liver, such as diazepam (Valium, Roche), warfarin (Coumadin, Bristol-Myers Squibb), and phenytoin (Dilantin, Pfizer). Increased International Normalized Ratios (INRs) and prothrombin times have been reported in patients receiving concomitant warfarin and omeprazole therapy. These increases may lead to abnormal bleeding and possibly death. Therefore, patients taking warfarin and omeprazole concomitantly should be monitored closely for INRs and prothrombin times. 35 In studies of once-daily omeprazole 4 mg and clarithromycin (e.g., Biaxin, Abbott) 5 mg every eight hours administered to healthy men, the steadystate plasma concentrations of omeprazole were increased: the C max by 3%, the AUC 24 by 89%, and the half-life by 34%). 35 INDICATIONS As summarized in Table 1, is indicated for the short-term treatment (four to eight weeks) of active duodenal ulcer, heartburn, and other symptoms associated with GERD; the short-term treatment of erosive esophagitis, as diagnosed by endoscopy; the maintenance of healing of erosive esophagitis (studies do not extend beyond 12 months); and the short-term treatment of active benign gastric ulcer. 35 This is the only PPI to date that is indicated for lowering the risk of upper GI bleeding in critically ill patients and for nasogastric and/or orogastric tube administration. 35 DOSAGE AND ADMINISTRATION The recommended dose of is 4 mg or 2 mg, based upon the indication, to be taken once daily on an empty stomach at least one hour before a meal. When taken at bedtime, it reduces nocturnal gastric acidity to an extent that has not been observed with once-daily dosing of delayed-release PPIs. Dosage modification is generally not needed in elderly patients or in those with mild-to-moderate renal or hepatic impairment. The IR formulation is currently available as a peach-mint flavored powder for oral suspension in 4- and 2-mg packets. Because of this product s unique pharmacokinetic profile, there are no therapeutic equivalents, and it is not AB-rated compared with delayed-release omeprazole (Prilosec, Prilosec OTC). 5 The oral suspension offers an alternative for patients (e.g., elderly people and children) who require PPI therapy for acid-related conditions but who have difficulty swallowing tablets or capsules. Absorption is optimized when patients take this product on an empty stomach at least one hour before a meal. For the control of nighttime gastric acidity, however, the effect is greatest when it is taken at bedtime on an empty stomach. Patients should be instructed to pour a packet of the powder for oral suspension into a small cup containing one to two tablespoons (153 ml) of water, to stir well, and to drink immediately. No other liquids or foods should be mixed with the powder. The cup should be refilled with an additional small amount of water, and this should also be consumed right away to ensure that a complete dose is ingested. 35 For patients with nasogastric or orogastric tubes, the powder should be constituted with approximately 15 to 3 ml of water (.51. fluid ounce). Other liquids or foods should not be used. The suspension should be stirred well and administered immediately, and a syringe of the appropriate size should be used to instill the suspension in the tube. The suspension should be washed through the tube with an additional 2 ml of water. 35 The FDA is currently reviewing 4-mg and 2-mg capsules and chewable tablets. CONCLUSION The unique non-enteric formulation of provides more rapid absorption and decreased time to peak plasma concentrations than do enteric-coated, delayed-release PPIs. These pharmacokinetic properties may confer advantages for patients with acid-related disorders, as suggested by emerging data about the product s effectiveness in controlling nocturnal gastric ph in symptomatic GERD patients and its ability to control gastric acidity in critically ill patients. Oral, when taken on an empty stomach at bedtime, is effective in controlling nocturnal gastric acidity. It is an alternative to the use of IV acidsuppressant therapy for attaining and sustaining a gastric ph above 6 and for lowering the risk of upper GI bleeding in critically ill patients. REFERENCES 1. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 22;122: Longstreth G. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: A population based study. Am J Gastroenterol 1995;9: Ferron GM, Ku S, Abell M, et al. Oral bioavailability of pantoprazole suspended in sodium bicarbonate solution. Am J Health Syst Pharm 23;6: DiGiacinto JL, Olsen KM, Bergman KL, et al. Stability of suspension formulations of lansoprazole and omeprazole stored in amber-colored plastic oral syringes. Ann Pharmacother 2;34: Welage LY. Overview of pharmacologic agents for acid suppression in critically ill patients. Am J Health Syst Pharm 25; 62(Suppl 2):S4S1. 6. Tutuian R, Katz PO, Castell DO. A PPI is a PPI is a PPI: Lessons from prolonged intragastric ph monitoring. Gastroenterology 2;118:A Hammer J, Schmidt B. Effect of splitting the dose of esomeprazole on gastric acidity and nocturnal acid breakthrough. 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