Evidence Table 12

Adverse effects in short term randomized controlled trials: Proton pump inhibitor compared with proton pump inhibitor

Author
Year
Setting
DiseaseInterventionControlNumber EnrolledNumber withdrawn due to adverse eventsAdverse effects
Johnson et al.
2002
UK & Ireland
Multicenter
Crossover
Chronic PPI treatment for benign ulcers or GERDomeprazole 20 mg/dayrabeprazole 20 mg/day24030/240 (12.5%)(o) = 115 (51%) reported 114 mild, 117 moderate, and 30 serious treatment-emergent AEs.
(r) = 120 (52.6%) reported 97 mild, 118 moderate, and 28 severe treatment-emergent AEs.
No significant differences in AEs between groups.

No difference in general preference for (o) or (r).
- More patients prefer (r) for “absence of side effects” (p=.047), among those with any preference (46%).
- More patients prefer (r) for “unexpected positive side effects” (p=.019), among those with any preference (28%).
- More patients prefer tablet form of (r) as “easy to swallow” (p=.0001), among those with any preference (52%).
- More patients prefer capsule form of (o) as “easy to pick up and hold” (p=.0003), among those with any preference (47%).
Beker
1995
European
Multicenter
Duodenal ulcerpantoprazole 40mgomeprazole 20mg270 enrolled (135 each group)0.74% (p)2.9% (o)21 patients reported adverse events (10, 7% (p), 11, 8% (o)), with a total of 23 events reported. Diarrhea was the most common adverse event reported. 5 were considered serious (1 (p), GI hemorrhage and 4 (o), angina pectoris, hypertension, vertigo and abdominal pain. These patients were withdrawn from study. Serum gastrin levels rose in both groups at both 2 and 4 weeks, the change was statistically significant within but not between groups.
Capruso
1995
Italy
Multicenter
Duodenal ulcerlansoprazole 30mgomeprazole 20mg107 enrolled, (52 (l), 55(r))Not reported8 adverse effects reported: 3 (r), 3 (l), and 2 (o). No significant difference between therapies for changes in gastrin levels or changes in endocrine cells from biopsies
Chang
1995
Taiwan
Single center
Duodenal ulcerlansoprazole 30mg once a day × 4 weeksomeprazole 20mg a day × 4 weeks111 enrolled (57 (l), 54 (o)Not stated in abstractHypergastrinemia with both agents. A few occurrences of reversible skin rash and constipation.
Chang
1995
Taiwan
Single-center
Duodenal ulcerlansoprazole 30mgomeprazole 20mg83 enrolled (42 (l), 41 (o))None reportedSerum PGA was elevated in both groups (NS), and had returned to baseline at 8 weeks. In both groups, the elevation in PGA was significantly higher in those found to have H. pylori eradication
Dekkers
1999
European
Multicenter
Duodenal ulcerrabeprazole 20mgomeprazole 20mg205 enrolled (102 (r), 103 (o))1.9% (o)
0% (r)
43 patients reported at least one adverse event. (21 (r), 22 (o)). The most common was headache. 2 (o) withdrew due to adverse events (evaluated as unrelated to study)The mean elevations in serum gastrin levels at 4 weeks were 39.8 pg/ml (r) and 18.9 pg/ml (o).
Dobrilla
1999
Italy
Multicenter
Duodenal ulcerlansoprazole 30mg, then those with healed ulcer randomized to 15 or 30mg lansoprazole × 12 monthsomeprazole 40mg, then those with healed ulcer switched to omeprazole 20mg × 12 months251 eligible (167 (l), 84 (o)) Maintenance phase: 243 enrolled (164 (l), 79(o))Treatment:2.3% (o), 9% (l)Maintenance:4% (l15), 2.8% (l30), 1.4% (o)16 during phase I (healing): 10 (6%, l), 6 (7.1%, o) 21 during Phase 2 (maintenance): 9 (12.2%, l15), 4 (5.6%, l30), and 8 (11%, o) Most common adverse event was diarrhea. 8 patients withdrew due to adverse events (3 (l15), 2 (l30), 3 (o))Serum gastrin levels were elevated in both groups at 4 weeks (increase of 23.8pg/ml (l30), 35.8pg/ml (o) NS), and continued to be elevated at 6 and 12 months of maintenance therapy. The (l15) had the least and the (l30) had the highest elevation at 6 and 12 months. At 6 months all values were returning to baseline.
Ekstrom
1995
Sweden
Multicenter
Duodenal ulcerlansoprazole 30mgomeprazole 20mg279 enrolled (143 (l), 136 (o))Not reported68 adverse events occurred in 57 patients (23 (l), 34 (o)) (NS). A statistically significant difference was found in the mean change in ALT concentration, but the change was minor (0.05 unit increase (l), 0.03 unit decrease (o).
Fanti
2001
Italy
Single center
Duodenal ulcer and H. pylorilansoprazole 30mg once a day × 4 weeks
Plus clarithromycin 500 and tinidazole 1gm × 7 days
omeprazole 20mg a day × 4 weeks
Plus clarithromycin 500 and tinidazole 1gm × 7 days
43 enrolled (22 (l) and 21 (o))None“Mild and self-limiting” Total number not reported.1 (l) stomatitis and 1 (o) mild diarrhea
Kovacs
1999
USA
Multicenter
Duodenal ulcer maintenancelansoprazole 15 or 30mg once daily for up to 12 monthsplacebo once daily for up to 12 months56 enrolled19 (pl), 18 (l15), 19 (l30)21.5%(pl)17% (l15)5.3% (l30)40 patients reported adverse events (11 (pl), 15 (l15), 14 (l30)). Adverse events possibly or probably related to study drug: 2 (pl), 2 (l15), 6 (l30). None were severe. Serum gastrin levels increased significantly in both (l) groups compared to (pl) (P<0.001). Elevations occurred within 1 month of starting study. 8 patients (3(l15), 5 (l30)) had levels >200pg/ml during study. All returned to baseline within 1 month of stopping study drug.
Lanza
1997
USA
Multicenter
Duodenal ulcer maintenancelansoprazole
15mg once daily × 12 months or until ulcer recurrence
placebo
once daily × 12 months or until ulcer recurrence
186 enrolled
88 (pl),
92 (l))
4.5% (pl)
2.2% (l)
9 adverse events possibly or probably related to study drug. The most common was diarrhea. No significant differences between groups. Serum gastrin levels were significantly higher in (l) group than (pl), median 92pg.ml vs 52 pg/ml (P0.001). Values reached a plateau after one month of treatment and returned to baseline one month after treatment stopped. Gastric biopsies: significant increase in Gastrin cell density in (l) group compared to (pl) group (707cells/mm2 vs 556 cells.mm2), no other differences found.
Russo
1997
Italy
Multicenter
Duodenal ulcer maintenanceIf (l30) during healing trial:
Lansoprazole
15 mg or
Placebo once daily × 12 months or until recurrence
If (r) during healing trial:
Ranitidine or placebo 150mg once daily × 12 months or recurrence
108 enrolled 30
(l30/l15)28 (l30/p), 24
(ran/ran),26 (ran/p)
Not reportedMaintenance: 3% (l/l), 18% (l/pl), 0% (ran/ran). (ran/pl) not reported.
Dekkers
1998
European
Multicenter
Gastric ulcerrabeprazole
20mg
omeprazole
20 mg
227 enrolledNot reported60 patients reported at least one adverse event. (25 (r), 35 (o)). The most common was headache. No difference by sex, age, race.Slightly elevated creatine phosphokinase at 6 weeks was found in 6 (o) patients. The mean elevations in serum gastrin levels at 6 weeks were 12.7 pg/ml (r) and 10.0 pg/ml (o).
Adachi, 2003GERDrabeprazole 20 mgomeprazole 20 mg or lansoprazole 30 mg85Not reportedNot reported
Bardhan, 2001GERDpantoprazole 20 mgomeprazole 20 mg328Not reported57% of pantoprazole vs 50% omeprazole experienced adverse events. Severe in 10% pantoprazole and 13% omeprazole patients.
Most events judged unrelated or unlikely to be related to the study drug.
Most common adverse events (pantoprazole vs omeprazole): nausea (8% vs 7%), diarrhea (5% vs 6%), and headache (6% vs 3%).
Castell
1996
US
Multicenter
GERDlansoprazole
15 mg or 30 mg
omeprazole
20 mg
1070(o20): 2%
(l30): 1.7%
(l15): 0.9%
Any adverse event:(l15) 44.5%, (l30) 55.7%, (o20) 53.4%.
Most commonly reported events headache, diarrhea, nausea.
More patients in (ll5) reported nausea (p<0.05).
6 severe events possibly or probably related to medication (4 in (o20), 1 in (l15), 1 in (l30).
Chen et al 2005GERDesomeprazole 40mgomeprazole 20 mg48 (25 esomeprazole, 23 omeprazole)Not reportedNo treatment related serious AEs reported. 7 esomeprazole and 6 omeprazole patients reported non-serious AEs, most commonly constipation (6.3% of all patients) and dry skin (8.3% of all patients.)
Corinaldesi
1995
European
Multicenter
GERDpantoprazole
40 mg
omeprazole
20 mg
241(p40): 0.8%
(o20): 1.7%
Adverse events reported by 15% of patients in (p40), 12% in (o20).
Diarrhea, abdominal pain, hyperlipemia and constipation most frequently reported in (p40), diarrhea most frequently (o20).
Dekkers
1999
European
Multicenter
GERDrabeprazole
20 mg
omeprazole
20 mg
202(r20): 1%
(o20): 0
32% (r20) and 28% (o20) reported at least one adverse event. Headache, diarrhea, flatulence most common. Flatulence more common (o20) gr (4% vs 0%). One serious event (r20) (t wave changes).
Delchier
2000
European
Multicenter
GERDrabeprazole
20 mg or
ransoprazole 10 mg
omeprazole
20 mg
300(r10): 5%
(r20): 5%
(o20): 2%
21% (r20), 26% (r10), and 23% (o20) reported at least one event. Abdominal pain, pharyngitis, bronchitis, headache, diarrhea most common. Four serious events, none related to medication. At week 4, incidences of elevated serum gastrin levels 16% (r20), 27% (r10), 20% (o20) (NS)
Dupas
2001
France
Multicenter
GERDpantoprazole
40 mg
lansoprazole
30 mg
461(p40): 1.3%
(l30): 2.5%
Adverse events reported in 28% in p40 group, 17% in l30. Most common headache, diarrhea, elevation of hepatic enzymes, abdominal pain, skin disorders. 11 serious events (5 (p40) 6 (l30)).
Fennerty, 2005GERDesomeprazole 40 mglansoprazole
30 mg
10015/499 (1%) esomeprazole vs 9/472 (2%)
lansoprazole.
33.1% esomeprazole vs 36.9% lansoprazole reported an adverse event. Most were mild or moderate. No treatment-related adverse events reported. Most common adverse events (occurring in >2% of patients) were Barrett’s esophagus, gastritis, diarrhea, and headache. Most common adverse event leading to study withdrawal was abdominal pain (2 in each group).
Gillessen, 2004GERDpantoprazole 40 mgesomeprazole
40 mg
2276 patients overall, not reported by group.23/113 (20%) pantoprazole vs 20/114 (18%) esomeprazole had an adverse event. None judged definitely related to study medication, 9% pantoprazole, 28% esomeprazole likely related. Two serious adverse events in one patient in pantoprazole group (icterus and malignant hepatic neoplasm (not related to medication). Most frequent adverse event was dizziness (2%).
Hatlebakk
1993
Norway/Sweden
Multicenter
GERDlansoprazole
30 mg
omeprazole
20 mg
229(o20): 0.9%(l30):032.8% (l30), 29.2% (o20) reported adverse event, One (o20) withdrawn for severe diarrhea. Headache in 4 pts (o20), none (l30).2 severe events (l30) (1 pharyngitis, 1 nausea, vomiting).
Holtmann, 2002GERDrabeprazole 20 mgomeprazole 20 mg2514/125 (3%) rabeprazole vs 2/126 (2%) omeprazoleAbout 25% of patients in both groups experienced any adverse event. Most frequent were gastrointestinal system in 25 patients (10%) and nervous in 11 patients (4.4%). Seven GI events judged drug-related. Most events mild to moderate; 10 of 90 rated as “severe.” No obvious differences in tolerability between treatments (data not reported by group).
Howden et al.
2002
GERDlansoprazole
30 mg
esomeprazole
40 mg
2842/143 (1.4%) lansoprazole vs 5/141 (3.5%)
esomeprazole
Lansoprazole vs esomeprazole: Incidence of all adverse events 46.2% vs 52.5% Of these, 16.1% vs 19.1% considered “possibly”, “probably”, or “definitely” treatment-related. Most frequently reported treatment-related effects: diarrhea (5% vs 5%), headache (2% vs 5%), eructation (5% vs 2%), abdominal pain (2% vs 4%), flatulence (1% vs 4%), nausea (2% vs 2%). Most events mild to moderate. Esomeprazole one severe case each of eructation, dizziness, and paresthesia; lansoprazole one severe case each of abdominal pain, diarrhea, eructation, rectal disorder, and somnolence.
Kahrilas
2000
US
Multicenter
GERDesomeprazole 40 mg or 20 mgomeprazole
20 mg
1960(e40): 2%
(e20): 2.6%
(o20): 2%
Total or per group not reported. Most common:
headache 8.6% (e40), 8.7% (e20), 6.9% (o20)
abdominal pain 3.7% (e40), 3.7% (e20), 4.2% (o20)
diarrhea (4.6% (e40), 4.7% (e20), 3.9% (o20)
flatulence (1.8% (e40), 3.5% (e20), 4.0% (o20)
gastritis 2.5% (e40), 3.5% (e20), 2.5% (o20)
nausea 3.8% (e40), 2.9% (e20), 3.1% (o20).
No differences observed according to gender, age, or race. No serious drug-related events reported.
Kao, 2003GERDesomeprazole 40 mgomeprazole 20 mg100Not reportedNot reported
Korner et al.
2003
GERDpantoprazole 40 mgomeprazole MUPS
40 mg
6694/337 (1%) pantoprazole,
7/332 (2%) omeprazole
MUPS
Pantoprazole vs omeprazole 6% vs 7%, mostly mild or moderate. 2.1% vs 1.2% severe. Most frequently reported adverse event headache for pantoprazole (1%), diarrhea for omeprazole (2%).
Labenz
2005
Multinational, Multicenter
GERDesomeprazole 40 mgpantoprazole 40 mg315133/1562 (2.1%)
esomeprazole vs 29/1589
(1.8%) pantoprazole
Serious adverse events: 1.5% esomeprazole vs 1.3% pantoprazole.
Most commonly reported in esomeprazole group: nausea (6 patients), dizziness (5 patients);
In pantoprazole group: headache (5 patients), diarrhea (4 patients).
Mee
1996
UK and Ireland
Multicenter
GERDlansoprazole
30 mg
omeprazole
20 mg
604Not reported51% of all patients had at least one event, not broken down by treatment group. Most frequent events:
headache (12% (l30), 11% (o20)
diarrhea (9.4% (l30), 8% (o20)
nausea (4.3% (l30), 4.7% (o20).
2 serious events (o20) (esophageal cancer (pre-existing) and vasovagal syncope and loose stools)
Mulder
1996
Netherlands
Multicenter
GERDlansoprazole
30 mg
omeprazole
40 mg
211None19% (l), 21% (o) No difference in change in gastrin levels between groups. No other events reported.
Richter
2001
US
Multicenter
GERDesomeprazole
40 mg
omeprazole
20 mg
24251% in each groupAt least one adverse event reported in 32.2% in(e40), 34.3% in (o20). Most common:
headache 6.2% (e40), 5.8% (o20)
diarrhea 3.9% (e40), 4.7% (o20)
nausea 3.0% (e40), 3.0% (o20)
abdominal pain 2.6% (e40) 2.7% (o20)
< 1% in each group had a serious event (0 considered treatment related)
Richter 2001bGERDlansoprazole 30 mgomeprazole
20 mg
341040/1754 (2%)
lansoprazole 33/1756
(2%) omeprazole.
44% in both groups, most mild or moderate. Lansoprazole vs omeprazole significant differences in incidence of diarrhea (10% vs 8%), increased appetite (0.3% vs 0%), melena (0.1% vs 0.7%), asthma (0.4% vs 0%).
Scholten et al.
2003
GERDpantoprazole 40 mgesomeprazole
40 mg
2173 (groups not reported)14% of patients reported an adverse event, most assessed as “not related” to the study drug. Three patients in each group had an event assessed as “likely” or “definitely” related to study drug. No significant differences between groups in frequency or type of adverse events.
Caos et al, 2005GERD relapse preventionrabeprazole 10 or 20 mgplacebo497rabeprazole 10 mg 11% (n=18)
rabeprazole 20 mg 12% (n=19)
placebo 4% (n=7)
8%(n=42) of patients experienced AE judged to be drug related, only serious AE occurred in placebo patient. Most common non- serious AEs 20 mg rabeprazole v 10 mg rabeprazole v placebo respectively were: rhinitis (33%, 32%, 12%); diarrhea (28%, 27%, 12%); flu syndrome (23%, 20%, 8%); headache (21%, 25%, 12%); pharyngitis (21% for both treatment groups, 9% for placebo); surgical procedure (20%, 19%, 4%); back pain (19% for both treatment groups, 8% for placebo); abdominal pain (17%,19%,6%); nausea (18%,16%, and 8%) and pain (18%,25%,6%). p ≤ 0.018 v placebo for all comparisons.
Richter et al 2004GERD relapse preventionpantoprazole 20 or 40 mgranitidine 150 mg349Not reportedSpecific serious AEs not reported, however 6.5% or pantoprazole patients and 3.4% of ranitidine patients are reported as having serious AEs. Other AEs were headache (13% of pantoprazole and 6% of ranitidine patients; p=0.093) Pantoprazole patients also reported as having abdominal pain (11%) diarrhea (10%) and infection (11%.)
Tsai et al, 2004GERD relapse preventionAcute phase: esomeprazole 20 mg/day

Maintenance phase:
esomeprazole 20 mg on-demand
lansoprazole 15 mg/dayAcute phase: 774
Maintenance phase:
622
Acute phase: 18
Maintenance phase:40–10 (3%) esomeprazole and 30 (10%) lansoprazole
17 patients reported 24 serious AEs, including 3 AEs during the acute phase. During the maintenance phase, 9 esomeprazole patients reported 14 serious AEs and 5 lansoprazole patients reported 6 serious AEs. All but one AE (anaphylaxis in a lansoprazole patient) considered unrelated.
AEs reported (serious and non-serious) by 42% of acute phase patients and 71% of maintenance phase patients, most commonly headache and diarrhea. Lansoprazole patients were more likely to discontinue due to AEs than esomeprazole patients (7% v 2%, p=0.0028) and more likely to have diarrhea (14% v 5%, p<0.001)
Armstrong et al., 2004NERDesomeprazole 20 mg or 40 mgomeprazole 20 mg2645 (in 3 trials)Not reportedNot reported: “Overall, esomeprazole 40 mg and 20 mg, and omeprazole 20 mg were well-tolerated and the proportions of patients experiencing AEs were similar between treatment groups during the study period.”
Fock et al., 2005NERDrabeprazole 10 mgesomeprazole 20 mg1341 esomeprazole (headache)AEs considered related to study drug: 22% rabeprazole, 18.2% esomeprazole (NS).
Elevation in ALT: 1 rabeprazole, 4 esomeprazole
Increase in AST: 1 rabeprazole, 2 esomeprazole
(not clinically significant)
Monikes et al., 2005NERDpantoprazole 20 mgesomeprazole 20 mg529Not reportedNot reported: “Both therapies were well tolerated and safe.”
Peura et al., 2004NERDlansoprazole 15 mg, or 30mgplacebo921Not reportedDiarrhea: 6 lansoprazole 15mg, 8 lansoprazole 30mg, 4 placebo
Headache: 5 lansoprazole 15mg, 7 lansoprazole 30mg, 9 placebo
van Zyl et al., 2004NERDpantoprazole 20 mgranitidine 300 mg3389/338 (2.6%)Diarrhea: 1 pantoprazole, Constipation: 1 pantoprazole, 1 ranitidine
Urticaria: 1 pantoprazole, 1 ranitidine
Nausea: 2 ranitidine, Pruritus: 1 ranitidine
Vertigo: 1 ranitidine
Lower abdominal pain: 1 ranitidine

From: Evidence Tables

Cover of Drug Class Review: Proton Pump Inhibitors
Drug Class Review: Proton Pump Inhibitors: Final Report Update 5 [Internet].
McDonagh MS, Carson S, Thakurta S.
Portland (OR): Oregon Health & Science University; 2009 May.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

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