CLINICAL PHARMACOLOGY
`
`Proton Pump Inhibitors: An Update
`
`BRUCE T. VANDERHOFF, M.D., and RUNDSARAH M. TAHBOUB, M.D.
`Grant Medical Center, Columbus, Ohio
`
`Since their introduction in the late 1980s, proton pump inhibitors have demonstrated
`gastric acid suppression superior to that of histamine H2-receptor blockers. Proton
`pump inhibitors have enabled improved treatment of various acid-peptic disorders,
`including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal anti-
`inflammatory drug–induced gastropathy. Proton pump inhibitors have minimal side
`effects and few significant drug interactions, and they are generally considered safe for
`long-term treatment. The proton pump inhibitors omeprazole, lansoprazole, rabepra-
`zole, and the recently approved esomeprazole appear to have similar efficacy. (Am Fam
`Physician 2002;66:273-80. Copyright© 2002 American Academy of Family Physicians.)
`
`Richard W. Sloan,
`M.D., R.PH.,
`coordinator of this
`series, is chairman
`of the Department
`of Family Medicine at
`York (Pa.) Hospital and
`clinical associate pro-
`fessor in family and
`community
`medicine at the
`Milton S. Hershey
`Medical Center,
`Pennsylvania State
`University, Hershey, Pa.
`
`P roton pump inhibitors (PPIs) are
`
`one of the most commonly pre-
`scribed classes of medications in
`the primary care setting and are
`considered a major advance in
`the treatment of acid-peptic diseases. Since
`the introduction of omeprazole (Prilosec) in
`1989, several other PPIs have become available
`in the United States. The intravenous form of
`pantoprazole (Protonix I.V.) is now available,
`and the U.S. Food and Drug Administration
`(FDA) approved the newest PPI, esomepra-
`zole (Nexium), in 2001.
`
`Basic Pharmacology
`PPIs are substituted benzimidazoles and are
`generally administered as enteric-coated tablets
`or capsules that pass through the stomach
`intact and are absorbed in the proximal small
`bowel. Once absorbed, all PPIs have a rela-
`tively short plasma half-life (about one to two
`hours). Their duration of action is much
`longer because of their unique mechanism of
`action. PPIs are lipophilic weak bases that
`cross the parietal cell membrane and enter the
`acidic parietal cell canaliculus. In this acidic
`environment, the PPI becomes protonated,
`producing the activated sulphenamide form
`
`The frequency of adverse effects associated with proton
`pump inhibitors is similar to that of placebo, with an overall
`incidence of less than 5 percent.
`
`of the drug that binds covalently with the
`H+/K+ ATPase enzyme that results in irre-
`versible inhibition of acid secretion by the pro-
`ton pump.1-3 The parietal cell must then pro-
`duce new proton pumps or activate resting
`pumps to resume its acid secretion.1,2
`In contrast to the other PPIs, rabeprazole
`(Aciphex) forms a partially reversible bond
`with the proton pump and is activated at a
`broader range of gastric pH. Therefore, it may
`have a more sustained acid-suppressing effect
`than the other PPIs.1,2,4 Table 12 outlines the
`pharmacokinetic profiles of
`four orally
`administered PPIs.
`
`Side Effects and Precautions
`PPIs are generally well tolerated. The fre-
`quency of adverse effects associated with PPIs
`is similar to that of placebo, with an overall
`incidence of less than 5 percent.5 The type and
`frequency of adverse effects are similar to
`those observed with histamine H2-receptor
`blockers. The most common adverse effects
`are headache, diarrhea, abdominal pain, and
`nausea. Except for diarrhea, the adverse effects
`of PPIs do not appear to be related to age,
`dosage, or duration of treatment.5,6 The diar-
`rhea seems to be related to the profound acid
`suppression, which has been shown to alter
`the bacterial content of the gut. Nevertheless,
`the overall incidence of diarrhea is less than
`5 percent, and this effect appears to be dosage-
`and age-related.5
`Short-term safety (less than 12 weeks of
`treatment) of the oldest agents, omeprazole
`
`JULY 15, 2002 / VOLUME 66, NUMBER 2
`
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`
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`TABLE 1
`Pharmacokinetic Profiles of Four Orally Administered PPIs
`
`Characteristic
`
`Bioavailability (%)
`
`Time to peak plasma
`concentration (hours)
`
`Plasma elimination
`half-life (hours)
`
`Protein binding (%)
`
`Urinary excretion
`of oral dose (%)
`
`Omeprazole
`(Prilosec)
`
`Lansoprazole
`(Prevacid)
`
`Rabeprazole
`(Aciphex)
`
`Pantoprazole
`(Protonix)
`
`30 to 40
`
`0.5 to 3.5
`
`80 to 85
`
`52
`
`77
`
`1.7
`
`1.0 to 2.0
`
`1.1 to 3.1
`
`0.5 to 1.0
`
`1.3 to 1.7
`
`1.0 to 2.0
`
`1.0 to 1.9
`
`95
`
`77
`
`97
`
`96
`
`98
`
`14 to 23
`
`30 to 35
`
`71 to 80
`
`PPIs = proton pump inhibitors.
`Adapted with permission from Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole,
`and rabeprazole in the treatment of acid-related diseases. J Am Pharm Assoc 2000;40:53.
`
`and lansoprazole (Prevacid), has been well
`established.2 The safety profiles of the newer
`agents, rabeprazole and pantoprazole, appear
`to be similar to those of the older agents.2,5,7
`PPIs are only contraindicated if the patient
`has a known history of hypersensitivity to
`them, and they should be used with caution in
`patients with severe hepatic disease. Omepra-
`zole is a pregnancy category C agent; the oth-
`ers are pregnancy category B medications.
`PPIs are not recommended for use in breast-
`feeding mothers.8-12
`
`Drug Interactions
`PPIs cause significant increases in gastric
`pH, which may alter the absorption of weak
`acids or bases. They may inhibit the absorp-
`tion of drugs such as griseofulvin (Grisactin),
`ketoconazole (Nizoral), itraconazole (Spora-
`nox), iron salts, vitamin B12, cefpodoxime
`(Vantin), and enoxacin (Penetrex), many of
`which are weak bases and require acid for
`absorption.2,5,6,13 Coadministration with these
`agents should be approached cautiously
`because it may result in clinical treatment fail-
`ure.2 PPIs are metabolized to varying degrees
`
`by the hepatic cytochrome P450 enzymatic
`system and may alter drug metabolism by
`induction or inhibition of the cytochrome P
`enzymes.2,5 This is an important considera-
`tion in patients taking medications with a nar-
`row therapeutic window, such as diazepam
`(Valium), phenytoin (Dilantin), and warfarin
`(Coumadin). Omeprazole has the greatest
`potential for altering cytochrome P activity;
`the other PPIs are less likely to cause clinically
`significant drug interactions with these
`agents.5,13 Table 22,5 illustrates the effects of
`PPIs on several medications.
`
`PPIs in Acid-Peptic Diseases
`GASTROESOPHAGEAL REFLUX DISEASE
`Gastroesophageal reflux disease (GERD)
`can be diagnosed on the basis of the history
`alone in patients presenting with typical
`symptoms of heartburn, regurgitation, or
`both, especially after meals. These symptoms
`may be exacerbated by recumbency or bend-
`ing, and relieved by antacids. It is appropriate
`to empirically treat patients with classic
`GERD symptoms with lifestyle modification
`and patient-directed antacid or acid suppres-
`
`274 AMERICAN FAMILY PHYSICIAN
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`

`PPIs
`
`sion therapy.14 PPIs are extremely effective
`acid suppressants, and it is likely that patients
`with GERD will respond to them. Physicians
`generally may assume that patients with typi-
`cal symptoms who respond to PPI therapy
`have GERD.14,15
`There is some debate about how to initiate
`treatment for GERD. There are two common
`approaches, but neither has been proved supe-
`rior. It is left to the treating physician to deter-
`mine which approach is most appropriate.
`Step-up therapy starts with over-the-counter
`or standard-dosage H2 blockers and titrates to
`symptom control. Step-down therapy starts
`with once- or twice-daily PPI therapy and
`decreases the dosage or changes to the lowest
`form of acid suppression that will control the
`patient’s symptoms.14 In considering which
`approach would be best for a patient, the
`
`It is appropriate to empirically treat patients with symptoms
`of classic gastroesophageal reflux disease with lifestyle modi-
`fication and acid suppression therapy.
`
`physician should consider that PPIs have been
`shown to be more effective and quicker to
`eliminate symptoms and heal esophagitis than
`H2 blockers.
`Regardless of treatment, certain patients
`with long-term symptoms are at increased
`risk for the development of Barrett’s esopha-
`gus. There is no evidence that acid suppres-
`sion therapy with PPIs causes regression of
`Barrett’s esophagus or prevents progression to
`adenocarcinoma of the esophagus.2,14 Thus,
`the duration of symptoms, rather than the
`
`TABLE 2
`Effects of PPIs When Coadministered with Other Drugs
`
`Drug
`
`Carbamazepine (Tegretol)
`
`Clarithromycin (Biaxin)
`
`Diazepam (Valium)
`
`Digoxin
`
`Ketoconazole (Nizoral)
`
`Methotrexate
`
`Nifedipine (Procardia)
`
`Oral contraceptives
`
`Phenytoin (Dilantin)
`
`Warfarin (Coumadin)
`
`Theophylline
`
`Omeprazole
`(Prilosec)
`↓ Metabolism
`*
`↓ Metabolism
`↑ Absorption
`↓ Absorption
`↓ Renal excretion
`↑ Absorption
`None
`↓ Metabolism
`↓ Metabolism
`None
`
`Lansoprazole
`(Prevacid)
`
`Pantoprazole
`(Protonix)
`
`Rabeprazole
`(Aciphex)
`
`Unknown
`
`None
`
`None
`
`Unknown
`↓ Absorption
`Unknown
`
`Unknown
`
`None
`
`None
`
`None
`↑ Metabolism
`
`None
`
`Unknown
`
`None
`↑ Absorption
`Unknown
`
`Unknown
`↑ Absorption
`None
`
`None
`
`None
`
`None
`
`Unknown
`
`Unknown
`
`None
`↑ Absorption
`↓ Absorption
`Unknown
`
`Unknown
`
`Unknown
`
`None
`
`None
`
`None
`
`PPIs = proton pump inhibitors; ↓ = decreased; ↑ = increased.
`*—Omeprazole increases gastric mucous concentration of clarithromycin, and clarithromycin inhibits
`cytochrome P450 metabolism of omeprazole.
`Information from Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabepra-
`zole in the treatment of acid-related diseases. J Am Pharm Assoc 2000;40:52-62, and Reilly JP. Safety profile
`of the proton-pump inhibitors. Am J Health Syst Pharm 1999;56(23 suppl 4):S11-7.
`
`JULY 15, 2002 / VOLUME 66, NUMBER 2
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`symptom complex or type of treatment, is a
`more important consideration in determining
`the need for an endoscopic evaluation to rule
`out Barrett’s esophagus.14,15 While most
`patients with typical symptoms of GERD
`responsive to empiric therapy do not require
`endoscopy, patient whose symptoms do not
`respond to PPI therapy most likely do not
`have GERD, and further evaluation of their
`symptoms is needed.14,15
`
`PEPTIC ULCERS
`Peptic ulcers usually occur in patients with
`normal acid secretion and gastroduodenal
`mucosal defenses disrupted because of Heli-
`cobacter pylori infection or therapy with non-
`steroidal anti-inflammatory drugs (NSAIDs).
`Studies of PPIs have demonstrated superior
`healing rates, shorter healing time, and faster
`symptom relief than are obtained with H2
`blockers in these patients.2-4 PPIs have been
`shown to heal peptic ulcers that may be refrac-
`tory even to high-dose H2-receptor blockers,
`and they also exhibit antimicrobial activity
`against H. pylori in vitro. While the mecha-
`nism of this antimicrobial activity is unclear, it
`is probably related to inhibition of the urease
`enzyme produced by H. pylori.
`PPIs only suppress H. pylori in vivo, and
`antibiotics alone are ineffective in eradicating
`H. pylori. A combination of adequate acid sup-
`pression and antibiotic therapy is necessary
`for the successful eradication of H. pylori.2-4
`The recurrence rate of peptic ulcers after one
`
`The Authors
`BRUCE T. VANDERHOFF, M.D., is chairman of the department of family practice and
`associate director of the family practice residency program at Grant Medical Center,
`Columbus, Ohio, and clinical assistant professor of family medicine at Ohio State Uni-
`versity, also in Columbus. He received his medical degree from the University of Penn-
`sylvania School of Medicine, Philadelphia, and completed a residency in family practice
`at York (Pa.) Hospital.
`
`RUNDSARAH M. TAHBOUB, M.D., received her medical degree from the University of
`Jordan College of Medicine, Amman, Jordan, and completed a residency at Grant
`Medical Center.
`
`Address correspondence to Rundsarah M. Tahboub, M.D., 4160 Mumford Ct., Colum-
`bus, OH 43220 (e-mail: rund.s@lycos.com). Reprints are not available from the authors.
`
`year is less than 10 percent when the combi-
`nation of a PPI and antibiotics is used for
`H. pylori eradication.2,6
`
`NSAID–INDUCED GASTROPATHY
`NSAIDs cause peptic ulcers by inhibiting
`prostaglandin synthesis and weakening gastro-
`duodenal mucosal defenses. Uncomplicated
`ulcers usually heal after discontinuation of
`NSAIDs and treatment with standard dosages
`of PPIs, H2 blockers, or sucralfate (Carafate).
`PPIs are the treatment of choice for large or
`complicated ulcers,2,16 and they may also be
`used for prevention of NSAID–induced ulcers.
`Omeprazole at a dosage of 20 mg daily has
`been shown to be better tolerated and associ-
`ated with a lower relapse rate than misoprostol
`(Cytotec) at a dosage of 200 mcg twice
`daily.2,16,17 Omeprazole and misoprostol
`appear to be equally effective in preventing
`NSAID–induced ulcers.16
`
`Dosage and Administration
`PPIs are inactivated by exposure to gastric
`juice and are delivered in delayed-release
`gelatin capsules containing enteric-coated
`granules (omeprazole and lansoprazole) or in
`delayed-release enteric-coated tablets (rabe-
`prazole and pantoprazole).2,8-11 Omeprazole is
`supplied in doses of 10, 20, and 40 mg, and
`lansoprazole is supplied in doses of 15 and
`30 mg. Both of these agents should be taken
`30 minutes before meals, and their capsules
`should not be opened, chewed, or crushed,
`but should be swallowed whole.
`Other methods of administering omepra-
`zole, lansoprazole,2,8,9 or esomeprazole12 have
`been recommended for patients who are
`unable to swallow intact capsules. The cap-
`sules may be opened and the granules sprin-
`kled over a tablespoon of applesauce, pud-
`ding, yogurt, or cottage cheese; the food must
`be swallowed immediately without stirring,
`crushing, or chewing. In patients with naso-
`gastric or gastrostomy tubes, the granules in
`one capsule may be mixed with 40 mL of
`apple juice and injected through the tube,
`
`276 AMERICAN FAMILY PHYSICIAN
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`
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`PPIs
`
`Proton pump inhibitors may be more cost effective than
`H2 blockers because of their less frequent dosing
`requirements and shorter duration of required therapy.
`
`Esomeprazole is indicated for the short-
`term (four to eight weeks) treatment and
`healing of erosive esophagitis. If needed, an
`additional four to eight weeks of therapy may
`be considered. It is also indicated for mainte-
`nance therapy of erosive esophagitis; however,
`studies do not extend beyond six months of
`use. Esomeprazole, used as part of triple ther-
`apy,
`is indicated for the eradication of
`H. pylori to reduce the risk of duodenal ulcer
`recurrence.12 Table 32,6,8-10 compares indica-
`tions and dosages of omeprazole, lansopra-
`zole, and rabeprazole.
`
`Recommendations
`Although H2 blockers are less expensive
`than PPIs, PPIs provide superior acid suppres-
`sion, healing rates and symptom relief. There-
`fore, PPIs may be more cost-effective than
`H2 blockers, especially in patients with more
`severe acid-peptic disorders, because of their
`lower and less frequent dosing requirements
`and their comparatively shorter duration of
`required therapy.20 When deciding which PPI
`to use, physicians should consider the patient’s
`age, medications, and diagnosis, as well as the
`expense of therapy.
`All five PPIs appear to have similar efficacy
`in the treatment of various acid-peptic disor-
`ders. The newer agents, rabeprazole and
`pantoprazole, seem to have fewer drug interac-
`tions. This is a particularly important consid-
`eration in older patients who are already tak-
`ing several other medications. While the
`average wholesale prices of all agents in this
`class are similar, pantoprazole is the least
`expensive.
`Some controversy remains regarding the
`need to endoscopically evaluate patients
`before prescribing PPIs. It would be prudent
`
`which should be flushed with additional juice
`to clear the tube.
`Rabeprazole is supplied in one dose of
`20 mg, and pantoprazole (Protonix) is sup-
`plied in one dose of 40 mg. Both agents must
`be swallowed whole without crushing, chew-
`ing, or splitting. Rabeprazole should be taken
`after meals, but pantoprazole may be taken
`without regard to meals. Antacids may be
`administered concomitantly with all PPIs.
`Dosage adjustments for PPIs are not necessary
`in elderly patients or those with renal failure
`or mild hepatic impairment. Lansoprazole,
`rabeprazole, and pantoprazole should be used
`with caution in patients with severe hepatic
`impairment.2,8-12
`The FDA has not approved pantoprazole for
`maintenance therapy because safety has not
`been established beyond 16 weeks. At this time,
`pantoprazole is indicated by the FDA only for
`the treatment of erosive esophagitis in a dosage
`of 40 mg daily for eight to 16 weeks.11 It is the
`only PPI available for intravenous administra-
`tion and has recently been approved by the
`FDA for the short-term intravenous treatment
`(seven to 10 days) of GERD in hospital inpa-
`tients who are unable to take an oral PPI. The
`intravenous dosage is the same as the oral
`dosage (40 mg) and should be administered
`slowly over two to 15 minutes.1,2,18
`Esomeprazole is the s-isomer of omepra-
`zole. It is more bioavailable than omeprazole as
`the result of a lesser first-pass effect and slower
`plasma clearance. Esomeprazole in dosages of
`20 and 40 mg produces higher 24-hour intra-
`gastric pH levels than omeprazole, thus possi-
`bly resulting in superior acid control. The
`incidence and types of adverse effects appear
`to be similar to those of omeprazole.19
`Esomeprazole is supplied as delayed-release
`capsules containing enteric-coated pellets and
`is available in doses of 20 and 40 mg. It should
`be taken one hour before meals, and dosage
`adjustment is not necessary in elderly patients
`or those with mild to moderate hepatic impair-
`ment. Daily dosages should not exceed 20 mg
`in patients with severe hepatic impairment.
`
`JULY 15, 2002 / VOLUME 66, NUMBER 2
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`TABLE 3
`Indications and Recommended Dosages for Omeprazole, Lansoprazole, and Rabeprazole
`
`Indication
`
`Short-term
`treatment of
`active duodenal
`ulcer
`
`Helicobacter pylori
`eradication for
`reduction of
`duodenal ulcer
`recurrence
`
`Omeprazole (Prilosec)
`
`Lansoprazole (Prevacid)
`
`Dosage
`
`20 mg daily
`
`Duration of
`treatment
`
`4 weeks; another
`4 weeks may
`be required
`
`Dosage
`
`15 mg daily
`
`Triple therapy: omeprazole,
`20 mg, clarithromycin,
`500 mg, and amoxicillin,
`1,000 mg, each
`taken twice daily
`Dual therapy: omeprazole,
`40 mg daily, and
`clarithromycin, 500 mg,
`each three times daily
`
`Triple therapy: 10 days, plus
`18 days of omeprazole
`therapy if an ulcer is
`present at initiation of
`treatment
`Dual therapy: 14 days, plus
`14 days of omeprazole
`therapy at 20 mg daily if
`an ulcer is present at
`initiation of treatment
`
`Triple therapy: lansoprazole,
`30 mg, amoxicillin, 1,000 mg,
`and clarithromycin, 500 mg,
`each taken twice daily
`Dual therapy: lansoprazole,
`30 mg, and amoxicillin,
`1,000 mg, each taken
`three times daily
`
`Duration of
`treatment
`
`4 weeks
`
`Triple therapy:
`10 to 14 days
`Dual therapy:
`14 days
`
`Maintenance
`therapy for healed
`duodenal ulcer
`
`NA
`
`NA
`
`15 mg daily
`
`NA
`
`Short-term
`treatment of
`gastric ulcer
`
`Short-term
`symptomatic
`gastroesophageal
`reflux disease
`
`Short-term erosive
`esophagitis
`
`Maintenance
`therapy of erosive
`esophagitis
`
`Pathologic
`hypersecretory
`conditions
`
`40 mg daily
`
`4 to 8 weeks
`
`30 mg daily
`
`Up to 8 weeks
`
`20 mg daily
`
`Up to 4 weeks
`
`15 mg daily
`
`8 weeks
`
`20 mg daily
`
`4 to 8 weeks
`
`30 mg daily
`
`8 weeks; another
`8 weeks of
`treatment may
`be required if
`not healed
`
`20 mg daily
`
`NA
`
`15 mg daily
`
`NA
`
`Dosages vary; recommended
`starting dosage is 60 mg
`daily; dosages of 120 mg
`three times daily may be
`needed; dosages of more
`than 80 mg daily should
`be divided
`
`Treatment for several
`years may be
`required
`
`Dosages vary; usual starting
`dosage is 60 mg daily, up to
`90 mg twice daily; dosages
`of more than 120 mg daily
`should be divided
`
`Treatment for
`years may be
`required
`
`NA = not available.
`Information from references 2, 6, and 8 through 10.
`
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`PPIs
`
`Rabeprazole (Aciphex)
`
`Dosage
`
`20 mg daily
`
`Duration of
`treatment
`
`Up to 4 weeks; most
`will heal in this period;
`some patients may
`require additional therapy
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`20 mg daily
`
`4 to 8 weeks; if not healed
`after 8 weeks, another
`8 weeks of treatment
`may be considered
`
`20 mg daily
`
`NA
`
`Treatment for several
`years may be required
`
`Dosages vary; usual
`starting dosage is
`60 mg daily, and
`dosages of 60 mg
`twice daily may
`be required
`
`to consider endoscopic evaluation before ini-
`tiating PPI therapy in patients 45 years or
`older and in those with atypical symptoms
`because pre-endoscopy treatment with a PPI
`could mask gastric cancer. While some
`authorities recommend that the H. pylori sta-
`tus of all patients requiring long-term PPI
`therapy be determined and that those who are
`positive for H. pylori receive appropriate treat-
`ment to eradicate the infection, the FDA’s gas-
`trointestinal drug advisory committee has
`issued assurances regarding the absence of the
`risk of atrophic gastritis and gastric carcinoma
`in these patients.6,21-24 Esomeprazole may have
`increased bioavailability when compared with
`omeprazole, but otherwise it appears to be
`similar; omeprazole will soon be available in
`generic form.
`
`The authors indicate that they do not have any con-
`flicts of interest. Sources of funding: none reported.
`
`REFERENCES
`
`1. Playford RJ, Podas T, Modlin I. Pantoprazole, Prout
`and the proton pump. Hosp Med 1999;60:500-4.
`2. Welage LS, Berardi RR. Evaluation of omeprazole,
`lansoprazole, pantoprazole, and rabeprazole in the
`treatment of acid-related diseases. J Am Pharm
`Assoc 2000;40:52-62.
`3. Williams MP, Pounder RE. Review article: the phar-
`macology of rabeprazole. Aliment Pharmacol Ther
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