Topic 32: Proton Pump Inhibitors – How much for how long?

The considerable benefits and perceived safety of proton pump inhibitors (PPIs) in the management of acid-related gastrointestinal (GI) disorders means they are often used for long periods without ongoing review.

Topic 32: Proton Pump Inhibitors – How much for how long? Sep 2012.Veterans’ Medicines Advice and Therapeutics Education Services

Inside

Key pointsIn the treatment of GORD, review patients:

• afterfourtoeightweeksofinitialfull-dosePPItreatment

• ifPPImedicineswereinitiatedinhospital

Considerastep-downapproachforthe maintenanceofsymptoms:

• reducethedose

• adoptintermittentsymptom-drivenuse

• trialcessation

DuetohighprevalenceofextendeduseofPPIs,rarebutpotentiallyseriousadverseeffectsareoftenobserved.

Prescribing for gastro-oesophageal reflux disease (GORD)

Step-down strategies and PPI withdrawal plan

What to discuss with your patient

Adverse effects

When is long term treatment appropriate?

Further information

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The initial course of treatment usually involves the prescribing of a full-dose PPI (see table 1) for four to eight weeks, after which treatment should be reviewed.3,4 If response is adequate, consider ‘stepping-down’ to maintenance dose, switching to intermittent dosing or trialling cessation (see table 1). For many patients symptoms will have resolved and extended treatment may be unnecessary. If response is inadequate after two to four weeks, check adherence.

Prescribing for gastro-oesophageal reflux disease (GORD)

If adherence to the PPI is satisfactory, then endoscopy may be required to exclude other conditions.3,5 If after endoscopy no underlying cause is found, it may be necessary to double the dose for four weeks before ‘stepping-down’ to the lowest effective dose or trialling cessation.4 Patients initiated on PPIs in hospitals should be reviewed as they may not require ongoing treatment following discharge. Ongoing use of PPIs may expose patients to adverse effects.

In Australia the use of PPIs increased 1318% between 1995 and 2006.1 Currently there are enough PPIs dispensed to treat seven percent of the Australian population every day.2 This translates to 1.6 million Australians taking a PPI daily.

Despite their perceived safety, emerging evidence suggests PPIs are associated with a range of rare but serious adverse effects. These include osteoporosis and fractures, hypomagnesaemia, interstitial nephritis, enteric infection and community acquired pneumonia. This therapeutic brief advocates the benefits of a step-down approach: reducing the dose, adopting intermittent use or trialling cessation, while maintaining adequate symptom control.

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Reduce the doseA recommended approach is to prescribe either half the daily dose or alternate daily dosing, depending on patient preference. At least 80% of patients with GORD presenting with healed oesophagitis can achieve symptomatic remission with lower (maintenance) doses of PPIs.6 Refer to Table 1 for dosing advice.

Intermittent symptom-driven PPI

As an example, use omeprazole 10mg or equivalent on days when symptoms occur. This dosage controls symptoms in most people with endoscopy negative GORD.7

Topic 32: Proton Pump Inhibitors – How much for how long? Sep 2012.Veterans’ Medicines Advice and Therapeutics Education Services

In patients who have had an adequate response to initial full-dose PPI therapy, it is appropriate to cease or reduce PPI therapy using a ‘step down’ approach:

Step-down strategies and PPI withdrawal plan

Table 1: Initial and maintenance proton-pump inhibitors therapy for gastro-oesophageal reflux disease

(Losec®, Acimax®, Meprazol®, Ozmep®, Omepro®, Omepral®, Maxor®, Pemzo®, Probitor®) tablet, capsule

(Zoton FasTabs®, Zopral®, Lanzopran®) tablet, capsule

(Somac®, Ozpan®, Gastenz®, Salpraz®, Pantofast®, Pantoloc®, Panto®, Sozol®, Suvacid®) tablet, granules

(Pariet®) tablet

(Nexium®) tablet

Initialtherapy(full-dosePPI)3,4 20mg 30mg 40mg 20mg 20mg *

Maintenancetherapy(lowerdosePPI)

10mg 15mg 20mg 10mg See note**

Omeprazole Lansoprazole Pantoprazole Rabeprazole Esomeprazole

Not all strengths and formulations of PPIs are included in the Table. Table excludes injections.* While many patients may be initially treated with esomeprazole 40mg, 20mg is recommended initial therapy3,4; esomeprazole 40mg is appropriate if endoscopy reveals severe erosive disease or ulceration in previously untreated patient3 or response to esomeprazole 20mg is inadequate after initial 4 weeks.4 The advantage of starting on 20mg esomeprazole is that it reduces the number of steps required in the step-down process. ** Step-down strategy: 10mg omeprazole is appropriate step-down therapy from 20mg esomeprazole.

Trial cessationIn a significant minority of patients (up to 30%) symptoms will not return after cessation of PPI therapy.5 The decision to cease therapy should be guided by symptom control and each patient’s ability to report return of symptoms.

If the initial attempt to step-down or discontinue PPI therapy is unsuccessful, the PPI may be continued for a few weeks before considering another attempt to reduce the dose or cease treatment.8

Following cessation, antacids, histamine H2 receptor antagonists (H2RAs) or PPIs at the lowest effective dose may be used as needed for the relief of mild, occasional reflux symptoms.3

ReboundactivationofprotonpumpsresultinginreboundacidhypersecretionmayoccurfollowingcessationofPPIs.9,10Gradualdosetaperingorswitchingtoalternate daytherapyforonetotwoweeksbeforecessationmaypreventreboundsymptoms.11

Veterans’ Medicines Advice and Therapeutics Education Services Topic 32: Proton Pump Inhibitors – How much for how long? Sep 2012.

Patients with mild or infrequent symptoms can often be managed with simple non-drug measures. Advisepatientsaboutlifestylemodificationsasappropriate,suchasweightloss,moderationofalcoholconsumption, smokingcessation,elevationofbedheadandavoidanceofprecipitatingfoods.3

What to discuss with your patient

Adverse effectsThe high prevalence of extended use of PPIs means that rare but potentially serious adverse effects are being seen more often.

FracturesRecent meta-analyses and regulatory agencies have identified an association between use of PPIs and fractures, including hip and spinal fractures.13,14 This may be due to impaired calcium absorption.13 Patients at risk of osteoporotic fractures are advised to maintain an adequate intake of calcium and vitamin D. Bone mineral density tests are recommended for high-risk patients using a high-dose PPI on a long-term basis.15 These may include older patients and postmenopausal females.

Acute interstitial nephritisAcute interstitial nephritis (AIN) is a rare adverse event (approximately 8 cases per 100,000 patient years in one study).16 The TGA has warned that PPIs are now a leading cause of AIN in Australia.17

HypomagnesaemiaClinicians should be alert to the possibility of PPI-associated hypomagnesaemia. Patients may present with clinical symptoms such as nausea and vomiting, anorexia, weakness and fatigue, dizziness, decreased mobility, paraesthesia or severe muscle cramps.18 Use of magnesium supplements may be insufficient to correct a magnesium deficiency associated with long-term PPI use, and the PPI may need to be discontinued.19

Enteric infectionPPIs may increase susceptibility to enteric bacterial infection, including Clostridium difficile infection due to the reduction in gastric acidity.20 The use of probiotics for the prevention or treatment of Clostridium difficile is not warranted.4 TheUSFoodandDrugAdministrationrecommendspatientsusingPPIscontacttheirhealthprofessionaliftheydeveloppersistentdiarrhoea.21 Patients using PPIs may be at increased risk of traveller’s diarrhoea, and the ongoing need for PPI therapy in patients travelling to high risk areas should be reviewed.20

PneumoniaEpidemiological studies suggest an association between use of PPIs and both community and hospital-acquired pneumonia, possibly due to the reduction in gastric acidity which allows bacterial colonization. The greatest risk of developing pneumonia happens shortly after initiating treatment.22

Vitamin B12 deficiencyLong-term use of PPIs may decrease the absorption of Vitamin B12, although the clinical relevance is uncertain.4

PPIs and clopidogrelRegulatory agencies have warned that PPIs, particularly omeprazole and esomeprazole, may reduce the antiplatelet effect of clopidogrel.23,24

However, a recent meta- analysis has not found strong evidence to suggest that the interaction is clinically significant.25

Patients achieving good symptom control may be hesitant to trial dose reduction or cessation. For these patients it may be worthwhile highlighting that by using a step-down approach it is often possible to maintain symptom relief while avoiding potential adverse effects.12

Encourage patients to try again if attempt to step-down PPI therapy is unsuccessful.

Advise patients to adopt symptom-driven use of antacids, antacid/alginate combination, H2RAs or low-dose PPIs for the relief of mild, occasional acid-related GI disorders.3,5 Patients should also be informed of the need for assessment in the case of recurrent symptoms.

Provided by: University of South Australia Quality Use of Medicines and Pharmacy Research CentreIn association with: Discipline of General Practice, The University of Adelaide Discipline of Public Health, The University of Adelaide Repatriation General Hospital, Daw Park NPS – Better choices, Better health Australian Medicines Handbook Drug and Therapeutics Information Service

References12. NPS - Better Choices, Better Health. NPS

Prescribing Practice Review 45: Proton pump inhibitors: step-down to symptom control. 2009 [accessed 25 June 2012]; Available from: http://www.nps.org.au/__data/assets/pdf_file/0016/70711/PPR45_PPIs_ulcer_0509.pdf

13. Eom CS, Park SM, Myung SK, et al. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med 2011; 9(3): 257-67.

14. European Medicines Agency (EMA). Pharmacovigilance Working Party (PhVWP) Monthly report on safety concerns, guidelines and general matters - Proton-pump inhibitors – Risk of bone fracture. 2012 [accessed 25 June 2012]; Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2012/04/WC500124972.pdf

15. Talley NJ, Jung HK, Jiang X, Locke GR. Is there an increased risk of hip fracture in patients on long-term PPI therapy? Nat Clin Pract Gastroenterol Hepatol 2007; 4:420-1.

16. Simpson IJ, Marshall MR, Pilmore H, et al. Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases. Nephrology (Carlton) 2006; 11(5): 381-5.

17. Therapeutic Goods Administration (TGA). Proton pump inhibitors and acute interstitial nephritis. Medicines Safety Update 2011 [accessed 25 June 2012]; Available from: http://www.tga.gov.au/hp/msu-2011-06.htm

18. Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM 2010; 103(6): 387-95.

19. Therapeutic Good and Administration (TGA). Risk of hypomagnesaemia with proton pump inhibitors. Medicines Safety Update 2011 [accessed 25 June 2012]; Available from: http://www.tga.gov.au/hp/msu-2011-03.htm

20. Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther 2011; 34(11-12): 1269-81.

21. Food and Drug Administration (FDA). Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). 2012 [accessed 25 June 2012]; Available from: http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm

22. Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ 2011; 183:310-9.

23. Food and Drug Administration (FDA). Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). 2009 [accessed 25 June 2012]; Available from: http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatients andProviders/DrugSafetyInformationfor HeathcareProfessionals/ucm190787.htm?utm _campaign=Google2&utm_source=fdaSearch &utm_medium=website&utm_term= ppisandclopidogrel&utm_content=1

24. European Medicines Agency (EMA). Interaction between clopidogrel and proton-pump inhibitors CHMP updates warning for clopidogrel-containing medicines. 2010 [accessed 25 June 2012]; Available from: http://www.prescriber.org.uk/2010/03/ema-updates-clopidogrel- ppi-advice/

25. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Can J Gastroenterol 2010; 31(8): 810-23.

1. Hollingworth S, Duncan EL, Martin JH. Marked increase in proton pump inhibitors use in Australia. Pharmacoepidemiol Drug Saf 2010; 19(10): 1019-24.

2. OECD (2011), “OECD Health Data: Pharmaceutical market", OECD Health Statistics (database). doi: 10.1787/data-00545-en [accessed 07 June 2012]

3. Therapeutic Guidelines. Gastrointestinal Version 5. Melbourne; 2011.

4. Rossi S (Editor). Australian Medicines Handbook. Australian Medicines Handbook Pty Ltd. Adelaide; 2012.

5. Gastroenterological Society of Australia. Gastro-Oesophageal Reflux Disease in Adults. 2011 [accessed 25 June 2012]; Available from: http://www.gesa.org.au/professional.asp?cid=9&id=121

6. Tytgat GN. Review article: treatment of mild and severe cases of GERD. Aliment Pharmacol Ther 2002; 16 Suppl 4:73-8.

7. Dent J, Talley NJ. Overview: initial and long-term management of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2003; 17 Suppl 1:53-7.

8. Zarowitz BJ. The challenge of discontinuing proton pump inhibitors. Geriatr Nurs 2011; 32(4): 276-8.

9. Reimer C, Sondergaard B, Hilsted L, et al. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137(1): 80-7.

10. Niklasson A, Lindstrom L, Simren M, et al. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebo-controlled trial. Am J Gastroenterol 2010; 105(7): 1531-7.

11. Vakil N. Prescribing proton pump inhibitors: is it time to pause and rethink? Drugs 2012; 72(4): 437-45.

When is long term treatment appropriate?Some patients may require long term treatment with PPIs. This includes patients with severe oesophagitis, oesophageal stricture or scleroderma, Zollinger-Ellison syndrome or Barrett’s oesophagus.12 Patients who require long-term treatment with a NSAID, including low-dose aspirin, may be co-prescribed a low-strength PPI for ulcer prophylaxis in some circumstances.3 Prophylaxis with a PPI may also be clinically appropriate in other patients at high risk of bleeding.

• Gastroenterological Society of Australia www.gesa.org.au

Further information: