INDICATION

MEDICATIONS

Duration

GERD/reflux/dyspepsia/heartburn

Pantoprazole 40 mg OD

Omeprazole 20/40 mg OD

Esomeprazole 20/40 mg OD

Lansoprazole 30mg OD

Dexlansoprazole 30 mg OD*

Up to 12 weeks

*Up to 4 weeks (FUKKM)

oesophagitis

Pantoprazole 40 mg OD

Omeprazole 20/40 mg OD

Esomeprazole 20/40 mg OD

Lansoprazole 30mg OD

Dexlansoprazole 60 mg OD*

For treatment : up to 12 weeks

For maintenance : may be Continued if clinically indicated

*step down to Dexlansoprazole  30mg for maintenance

Peptic ulcer (duodenal ulcer, gastric ulcer)

Pantoprazole 40 mg OD

Omeprazole 20/40 mg OD

Lansoprazole 30mg OD

For treatment : up to 12 weeks

For maintenance : may be Continued if clinically indicated

H pylori eradication

Pantoprazole 40 mg BD

Omeprazole 20/40 mg BD

Esomeprazole 40 mg OD

Lansoprazole 30mg BD

Up to 2 weeks

PPI

DOSE (MG)

HIGH DOSE (MG)

Omeprazole

20

40

Pantoprazole

40

-

Lansoprazole

-

30

Esomeprazole

20

40

Dexlansoprazole

30

60

Risk factors:

• Previous peptic ulcer
• Previous GI bleed
• Co-prescription of anticoagulant drugs
• Co-prescription of corticosteroids
• Concurrent NSAIDs, selective serotonin reuptake inhibitors (SSRIs)
• Chronic renal failure
• Age > 65
• Previous long term NSAID use
• Diabetes
• Baseline anaemia haemoglobin (Hb)

              Male <120g/L, Female <110g/L

• Alcohol excess

               Male >21 units/week, Female >14 units/week

People are considered at:

High risk if they have a history of previously complicated ulcer, or multiple (more than two) risk factors

Moderate risk if they have 1-2 risk factors

Low risk if they have no risk factors

Clinical indication

Recommended duration of PPI therapy

Step-down strategy appropriate?

Uninvestigated GERD/dyspepsia

4-8 weeks.

Yes

Endoscopically confirmed peptic ulcer disease

up to 8 weeks - if confirmed H.pylori positive and successfully treated with eradication therapy

Yes

Investigated non-ulcer dyspepsia

up to 12 weeks

Yes

Endoscopy-negative reflux disease

up to 12 weeks

Yes

Mild to moderate oesophagitis

up to 12 weeks

Yes

Severe oesophagitis

long term PPI therapy

No

Barrett’s oesophagus

Zollinger-Ellison syndrome

Scleroderma

Stricture

long term PPI therapy

No

Prophylaxis of NSAID-induced dyspepsia/ulceration

long term PPI therapy

No

Yes-if NSAID treatment is stopped

AE

Explaination

Incidence/Prevalence

Acute interstitial nephritis

serious hypersensitivity reaction reported with all PPIs. Symptoms are non-specific eg weight loss, fatigue, nausea vomiting and onset may be delayed by as much as 12 months. Renal function typically improves after withdrawal of the PPI, but there may be residual chronic kidney disease.

(0.32 vs. 0.11 per 1000 person-years; HR 3.00, 95% CI 1.47 to 6.14) were higher among patients given PPIs than among controls.

Antoniou, T., Macdonald, E. M., Hollands, S., Gomes, T., Mamdani, M. M., Garg, A. X., Paterson, J. M., & Juurlink, D. N. (2015). Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open, 3(2), E166–E171. https://doi.org/10.9778/cmajo.20140074

Hip fracture

reduction in calcium absorption due to increased gastric pH

PPIs therapy was associated with a statistically significant increase of hip fracture risk (pooled odds ratio=1.24; 95% confidence interval: 1.15–1.34; P<0.00001) under a random model.

Ye, Xiaofeia,*; Liu, Hongb,*; Wu, Chenga,*; Qin, Yingyia; Zang, Jiajiea; Gao, Qingbina; Zhang, Xinjia; He, Jiaa. Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. European Journal of Gastroenterology & Hepatology 23(9):p 794-800, September 2011. | DOI: 10.1097/MEG.0b013e328348a56a

Pooled risk ratio showed a statistically significant association between PPI use and hip fracture risk (RR 1.26 [95% CI 1.17–1.35], p < 0.00001).

Hussain, S., Siddiqui, A.N., Habib, A. et al. Proton pump inhibitors’ use and risk of hip fracture: a systematic review and meta-analysis. Rheumatol Int 38, 1999–2014 (2018). https://doi.org/10.1007/s00296-018-4142-x

Clostridium difficile infection

PPIs therapy profoundly inhibits gastric acid production leading to the proliferation of spores and their ability to convert to a vegetative form of C. difficile . Moreover, PPIs impair leukocyte function by inhibiting phagocytosis and acidification of phagolysosome.

Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users.

Trifan A, Stanciu C, Girleanu I, Stoica OC, Singeap AM, Maxim R, Chiriac SA, Ciobica A, Boiculese L. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis. World J Gastroenterol. 2017 Sep 21;23(35):6500-6515. doi: 10.3748/wjg.v23.i35.6500. PMID: 29085200; PMCID: PMC5643276.

Community Acquired Pneumonia

Decreased gastric acidity is associated with alteration of gut flora. Micro-aspiration of the altered gut flora is one hypothesized mechanism for the increased CAP risk observed in the setting of elevated gut pH. More recently, proton pumps have been localized to the upper and lower respiratory tract, suggesting that pH dysregulation may additionally alter respiratory flora, thereby directly inducing infection.

The incidence of CAP was higher in PPI users than non -PPI users [OR = 1.37 (95% CI = 1.22-1.53)]

Xun X, Yin Q, Fu Y, He X, Dong Z. Proton Pump Inhibitors and the Risk of Community-Acquired Pneumonia: An Updated Meta-analysis. Ann Pharmacother. 2022 May;56(5):524-532. doi: 10.1177/10600280211039240. Epub 2021 Aug 23. PMID: 34425689.

In current PPI users, pooled OR for CAP was 1.86 (95% confidence interval (CI), 1.30-2.66)

Nguyen PA, Islam M, Galvin CJ, Chang CC, An SY, Yang HC, Huang CW, Li YJ, Iqbal U. Meta-analysis of proton pump inhibitors induced risk of community-acquired pneumonia. Int J Qual Health Care. 2020 Jun 17;32(5):292-299. doi: 10.1093/intqhc/mzaa041. PMID: 32436582.

MEDICATIONS

RIGHT TIME OF ADMINISTRATION

SUGGESTION FOR PATIENT WITH GI SYMPTOMS

• Anticholinergic effect drugs (eg, Tricyclic antidepressants, antipsychotics, oxybutinin)

Before or After Meal

Take After Meal

• Beta blockers

Before or After Meal

Take After Meal

• Biphosphonates (eg Alendronate)

Before Meal

Before Meal

• Calcium channel blocker

After Meal

Take After Meal

• Clopidogrel

Before or after meal

Take after meal

• Corticosteroids

After Meal

After Meal

• Dopaminergic drugs

Before meal

-

• Iron

Before meal

Take after meal

• Nitrates

Before meal

Before meal

• NSAIDs

After meal

After meal

• Slow released potassium

After meal

After meal

• Tetracyclines (eg doxycycline)

Before or after meal

After meal

• Theophylline

Before or after meal

After meal

INTERACTIONS

MECHANISMS

MANAGEMENT

SEVERITY (Reference: Lexicomp)

Azole antifungals

eg. Ketoconazole,Itraconazole

PPIs increase gastric pH, causing decreased absorption of antifungals leading to decrease concentration of antifungals.

Avoid combination when possible

Administer ketoconazole with an acidic beverage

Administer PPI at least 2 hours before or 2 hours after itraconazole.

Moderate (Ketoconazole)

Major (Itraconazole)

Clopidogrel

Omeprazole & Esomeprazole reduce the antiplatelet effect of clopidogrel.

Switch to pantoprazole

Major

Citalopram

Phenytoin

Omeprazole & Esomeprazole Inhibits elimination, potentially increasing drug concentration.

Switch to pantoprazole

Major

Diazepam

Omeprazole & Esomeprazole Inhibits elimination of diazepam, potentially increasing diazepam concentration.

Switch to pantoprazole

Minor

Digoxin

PPIs increase gastric pH, causing increase absorption of digoxin, leading increased digoxin concentration

Separate time of administration

Minor

Methotrexate

PPIs inhibit excretion of methotrexate  in renal tubules, caused increase concentration of MTX

Monitor for sign and symptoms of methotrexate toxicity.

Use in antirheumatic doses (<20 mg) is  less significant.

Moderate

Protease inhibitors

eg. Atazanavir, Ritonavir, Lopinavir

PPIs increased gastric pH, causing decreased absorption, leading to low concentration of these medications.

Avoid combination

Separate dose by 12 hours

Dose should not exceed the equivalent 20 mg omeprazole.

Major (Atazanavir only- malaysian consensus guideline antiretroviral therapy 2022)

Warfarin

Decreased metabolism of warfarin, increasing accumulation of warfarin, leading to increase INR.

Monitor INR

Adjust dose of warfarin accordingly

Moderate