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PROTON PUMP
INHIBITORS:
USES, MISUSES, AND THE UNKNOWN
Deborah E. Westbrook, B.S.,M.S., RPh
Pediatric Clinical Pharmacist
Vidant Medical Center
Greenville, North Carolina
Disclosure
•
I have no financial conflicts of interest
•
Off label uses of these medications will be discussed
Objectives
•
Know the approved indications for proton pump inhibitors.
•
Review uses of PPI in infants, older children and adolescents and analyze the
literature that addresses these indications.
•
Review the mechanism by which proton pump inhibitors decrease acid
production.
•
Discuss short and long term side effects which are associated with PPI use.
•
Identify important drug interactions which may occur with proton pump
inhibitors.
•
Review patient education which should be provided when a PPI is prescribed.
Proton Pump Inhibitors: FDA-Approved Indications
Erosive
Esophagitis
GERD
H pylori
Active Gastric
Ulcer
Active
NSAIDDuodenal Ulcer Associated
Gastric Ulcer
Upper GI
Bleed
Pantoprazole
(Protonix®)
√
√
Omeprazole
(Prilosec®)
√
√
√
√
√
√
Esomeprazole
(Nexium®)
√
√
√
Lansoprazole
(Prevacid®)
√
√
√
√
√
Dexlansoprazole √
(Dexilant®)
√
Rabeprazole
(Aciphex®)
√
√
√
√
√
√
√
FDA- Approved Indications for PPIs in Pediatric
Patients
Age Range (Years)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
esomeprazole
lansoprazole
omeprazole
pantoprazole
rabeprazole
Symptomatic GERD
Healing of Erosive Esophagitis
https://www.accessdata.fda.gov/drugsatfda_docs
16
17
18
Proton Pump Inhibitors Side Effects
•
Infants
Nausea
• Diarrhea
•
•
Children
Headache
• Nausea
•
•
Adolescents/Adults
•
•
•
•
•
Headaches
Diarrhea
Nausea
Dry mouth
Constipation
Proton Pump Inhibitors: New Labeling
Adverse Effects Associated with PPI Use
Rebound Hypersecretion of Acid
•
Due to hyperplasia of parietal cells
•
Occurs within first 2 months after starting therapy
•
May last for up to 2 months before resolution of symptoms
•
Abruptly stopping increases risk
• Wean dose of PPI
• Change to Histamine-2 receptor antagonist
•
Prevention
• Evaluate whether PPI is optimal for management of GERD/dyspepsia
• Use lowest dose of PPI which is effective
• Use for shortest time period possible
Adverse Effects Associated with PPI Use
Increased Risk of Bone Fractures
•
Increase in hip, wrist and spine fractures
•
Proposed Mechanism
• Decreased calcium absorption
•
Risk Factors
• Over 50 years of age
• Greater than 1 year of treatment
• Twice daily dosing
• Diabetes
• CKD
• Glucocorticoid use
Adverse Effects Associated with PPI Use
Hypomagnesemia
•
Decreased oral absorption of magnesium
•
Consequences
• Life-threatening arrhythmias
• Seizures
•
Risk Factors
• Concomitant diuretic therapy
• PPI use greater than 3 months
•
Monitoring
• Baseline magnesium prior to starting PPI in patients at risk
•
Treatment
• Often unresponsive to magnesium supplementation
• Discontinuation of PPI
Adverse Effects Associated with PPI Use
Vitamin B 12 Deficiency
•
Decreased activation of B12 to active form in stomach resulting in decreased B12 available
for absorption
•
Risk Factors
• Age
• Nutritional status
• Duration of PPI use greater than 3 years
• High dose PPI
•
Consequences
• Neurologic Consequences- paresthesias
• Cognitive and behavioral changes
Adverse Reactions Associated with PPI Use
•
Iron Deficiency
•
Iron better absorbed in acidic medium
•
Risk Factors
• Low initial iron stores
• Poor nutritional status
Adverse Effects Associated with PPI Use
Clostridium Difficile Infections (CDAD)
• Proposed mechanism
Inhibition of gastric acidity results in loss of normal defense mechanism which destroys
ingested spores and bacteria
• Higher gastric pH facilitates survival of the ingested spores
• Decreased neutralization of toxin produced by C.difficile
•
•
Risk
•
•
•
•
•
•
Hospitalized patients on PPI and antibiotics
Hospitalized patients on PPI alone
Patients on immunosuppressive therapies
Comorbidities such as cancer, cystic fibrosis
Patients in ambulatory care setting
Evidence
Observational studies have shown a 1.4-2.75 times higher risk for patients on PPI to develop
CDAD than those patients not on PPI
• Observational study in children showed 4.5 times more likely to develop CDAD on PPI
compared to children not on PPI
•
Adverse Effects Associated with PPI Use
Clostridium difficile Infections
•
Clinical Consequences
•
•
•
•
•
•
Life threatening complications
• Dehydration
• Toxic Megacolon
• Necrotic Bowel
• Colonic Perforation
Asymptomatic carriers
Increased risk of recurrent disease after treatment
Decreased response to antibiotic therapy
Death
Consequences
Poor patient outcomes
• Increase length of hospital stay
• Additional health care cost
•
Adverse Effects Associated with PPI Use
Hospital and Community Acquired Pneumonia
Proposed mechanisms
• Increase in upper GI bacterial overgrowth resulting in potential aspiration of
infected secretions
• Inhibition of Hydrogen-potassium ATPase enzymes in lungs thereby altering lung
pH resulting in bacterial growth in lung
• Evidence
• Not as strong as for C. difficile
• FDA did not add as a warning
• Expect to see revisited
•
Adverse Effects Associated with PPI Use
•
Acute Interstitial Nephritis (AIN)
•
•
•
•
•
Idiosyncratic hypersensitivity reaction
Onset can be anytime during therapy
Presents with fever, vomiting, oliguria, elevated creatinine
Discontinue therapy and do not reinitiate
Chronic Kidney Disease (CKD)
•
•
•
Several recent studies have shown increase risk of CKD in patients on PPI
May develop CKD without previous signs of or history of AKI
More common in patients on twice daily dosing
Adverse Effects Associated with PPI Use
Cutaneous and Systemic Lupus Erythematosus
•
New onset or exacerbation of known disease
•
Presentation
Most often cutaneous presenting with rash
May see arthralgia and thrombocytopenia and leukopenias
Develops weeks to years after initiation of PPI
Seen in all age groups – infants to elderly
•
•
•
•
•
•
•
Treatment
Discontinue PPI
Usually resolves in 4-12 weeks
Adverse Effects: Conclusions
•
Level of evidence for these adverse effects are limited by lack of
randomized trials
•
Best evidence supports risk of C.difficile and fractures in identified
populations
•
Case reports for lupus, hypomagnesemia, acute interstitial nephritis which
have been added as warnings
•
Other labelled adverse effects may be associated with PPI use but have not
been proven to be caused by PPI use
•
Weigh the risk versus benefits for each patient
Drug Interactions and Proton Pump Inhibitors
•
Methotrexate
•
•
•
Proton Pump Inhibitors decrease the clearance of methotrexate potentially increasing the
risk for methotrexate toxicity
Clopidogrel (Plavix®)
•
Omeprazole ,rabeprazole ,esomeprazole and lansoprazole inhibit cytochrome P450 (CYP
2C19) enzyme which is necessary to metabolize clopidogrel to active form. Use of these
agents together may decrease the antiplatelet effect of clopidogrel. This has been reported
to increase CAD complications in patients on both drugs.
•
Pantoprazole does not interfere with clopidogrel metabolism
Tacrolimus
•
Adding PPI to tacrolimus may increase tacrolimus level
Drug Interactions and Proton Pump Inhibitors
•
Drugs dependent on acidic environment for absorption/activation
•
•
•
•
Clarithromycin
•
•
Clarithromycin inhibits metabolism of PPI
HIV Medications
•
•
•
Ketoconazole
Mycophenolate Mofetil
Iron salts
Atazanavir and Nelfinavir levels may be decreased with PPI
Saquinavir levels may be increased
Rifampin
• May increase metabolism of PPI decreasing efficacy
Evidenced Based or Just a GUT Feeling?
Common Uses of PPIs in Pediatrics
• GER in infants less than 1 year of age
• Prophylaxis during corticosteroid use
• Prevention of Stress-related Mucosal Disease
• Increase control of
poorly responding asthmatics
GER in Infants Less than 1 Year of Age
•
Rationale for Use
•
Infants are at an increase risk for gastro-esophageal reflux resulting in frequent feeding
difficulties
•
Risks factors for GER
• Decreased lower esophageal sphincter tone
• Shorter esophageal length
• Relatively non-compliant stomach
• Bigger feeding volume in relative to stomach size
• Mostly liquid feedings
• Positioning
GER in Infants Less than 1 Year of Age
•
Symptoms of GER
•
•
•
•
•
Regurgitation
Spitting
Crying
Irritability during feeds
Parental distress
GER in Infants Less than 1 Year of Age
•
Evidence
•
Multi-center randomized trial showed no difference in outcome using lansoprazole
versus placebo in treatment of GER in infants (Orenstein)
•
Multi-center randomized placebo controlled trial showed esomeprazole did not alter
signs an symptoms of GER in infants less than 1- did alter time pH above 4 (Davidson)
•
Esomeprazole is effective in healing erosive esophagitis however symptoms of crying ,
irritability, poor feeding do not always predict which baby has erosive esophagitis
GER in Infants Less than 1 Year of Age
•
Conclusions/Recommendations
No studies have shown that PPI are not effective in treating GER in infants
Parental anxiety should be calmed with reassurances
• Baby is thriving and gaining weight
• Reflux is normal in this age group
• Do not assign a diagnosis of GERD if patient is not failing to thrive or have other symptoms
• Provide education regarding non-pharmacologic management
• Smaller more frequent feeding
• Thickened feeding with cereal
• Changing formula
• Maintain an upright position after feeding
• Elevate the head of baby’s bed
• If patient has symptomatic (GERD) consider a four-eight week trial of PPI/H2-antagonist
• If infant does not respond to PPI treatment further workup needed including an endoscopy
•
•
Prevention of Corticosteroid Induced
Peptic Ulcer Disease
• Rationale
•
Steroids use has been associated with increasing the risk of peptic ulcer
disease
• Risk factors
Concomitant use of non-steroidal anti-inflammatory agents
• Dose of steroids
• Lack of enteral nutrition
•
Prevention of Corticosteroid Induced
Peptic Ulcer Disease
•
Evidence
•
•
•
•
Meta-analysis (Narum et al) showed increase risk for GI bleed only in hospitalized patients on
steroids, no statistical increase in PUD or GI bleed in ambulatory setting
No difference in ulcer risk when patients on oral corticosteroids compared to placebo (RR
1.1)
Increase in GI events when corticosteroids used in combination with NSAIDS (at least 4-fold
increase)
Conclusions/Recommendations
•
•
•
•
•
Consider PPI/H-2 antagonist when patient on high dose steroids
Patient on full feeds does not usually need acid suppression
Consider prophylaxis with H2- antagonist
Consider PPI when patient on steroids and NSAIA
PPI and steroids may have additive adverse effects
• Infection risk ( pneumonia and C. difficile)
• Fracture risk
Prevention of Stress-related Mucosal Disease
(SRMD)
• Rationale
• Acutely ill patients may be at risk of stress related mucosal disease secondary
to an inflammatory or erosive insult to the upper GI tract
Prevention of Stress-related Mucosal
Disease (SRMD)
INDEPENDENT RISK FACTORS
IN PEDIATRICS
INDEPENDENT RISK FACTORS
IN ADULTS
• Coagulopathy
• PRISM Score ≥ 10
• Coagulopathy
• Respiratory Failure
• Respiratory Failure
requiring mechanical
ventilation
• High pressure
ventilation
• Organ Failure
• Shock
• Multiple Trauma
Prevention of SRMD
FACTORS CONTRIBUTING TO CUMULATIVE RISK
Acute hepatic failure
Acute renal failure
Anticoagulation
Burn injury ( greater the 35% body surface area)
High dose corticosteroids (> 250 mg)
History of GI bleed
Hypotension
Major surgery (greater than 4 hours)
Sepsis
Severe head or spinal cord injury
Prevention of SRMD
• Evidence
• Cohort of pediatric ICU patients reported 10% UGI bleed with 1.6% being clinically
significant
• Clinically significant bleeds in adult studies have shown increase in morbidity and
mortality with increased relative risk of 4.1
• Also shown to increase length of ICU stay by 4-8 days
• Meta-analysis in pediatric population suggest prophylaxis may be beneficial in
preventing GI bleed but no change in mortality- Not enough studies to show benefit
of PPI over Histamine 2 antagonist
• Meta-analysis favor PPI to H2 antagonist for reduction of bleeding rates in adults
• Acid suppression therapy has not been shown to decrease mortality in adults
• May increase risk of CDAD and nosocomial infections
• Results in prolonged use of unnecessary agents
Prevention of SRMD
• Conclusions/Recommendations
Assess risk for patient to develop SRMD
• Consider stress ulcer prophylaxis in all ventilated patients or patients that
have at least 1 independent risk factor or 2 cumulative risk factors
• May consider H-2 antagonist or PPI
• Enteral feeds may decrease risk of SRMD
• Reassess continued need for acid suppression once out of intensive care and
eating
• Discontinue acid suppression therapy when discharged from hospital
• Remove stress ulcer prophylaxis from order-sets outside of the intensive
care units
•
PPI: Use in Poorly Controlled Asthmatics
•
Rationale
•
•
•
Asymptomatic GER is common in children with asthma.
Assumption is that poorly controlled asthma may be due to silent reflux
Reflux may lead to aspiration resulting in bronchospasm and increased inflammation
PPIs and Asthma Management
•
Evidence
•
Pediatric Trial (American Lung Association Asthma Clinical Research network and
Holbrook)
• 306 children with poorly controlled asthma who did not have symptoms of GER
treatment
• Randomized to receive lansoprazole or placebo for 6 months
• Half the patients had pH probe suggesting reflux but were asymptomatic
• No difference in outcome between lansoprazole group and placebo
• Asthma Control Questionnaire score
• Asthma related quality of life Score
• Acute episodes of poor asthma control
• Pulmonary function test
• Bronchial hyperresponsivenss
• No difference in outcomes for patients with positive pH probe prior to treatment
PPIs and Asthma Management
• Evidence of Safety
•
Pediatric trial showed more adverse events on patients on PPI that placebo
• Upper respiratory tract infections **
• Sore throats **
• Bronchitis **
• Activity- related bone fracture (p=0.06)
** statistically significant
•
Conclusion/Recommendations
•
•
•
PPI provide no improvement in asthma control in patients who do not have clinical
signs of GERD
Asthmatics with signs and symptoms of GERD should be treated for GERD
PPI use in treatment of asthma symptoms is associated with increase risk of side
effects
Common Uses of PPIs in Pediatrics
• GER in infants less than 1 year of age
• Prophylaxis during corticosteroid use
• Prevention of Stress-related Mucosal Disease
• Increase control of asthmatics
Prevent Therapeutic Creep
Patient Education
•
Not for rapid heart burn relief
•
Takes several days after starting for symptomatic relief to be optimal
•
Needs to be taken regularly not as needed
•
Take in morning 1 hour before breakfast
•
If on twice daily take 1 hour before breakfast and 1 hour before dinner
•
Should not be taken at the same time as H2 antagonist or antacids
•
If on H2- antagonist for nocturnal breakthrough, take H2-antagonist at bedtime to
prevent drug interaction with PPI
•
Talk to your provider before stopping the PPI
CONCLUSIONS
•
PPI is a commonly prescribed class of medications
•
Use in children less than 1 year of age with feeding intolerance (GER) has not been
shown to be beneficial when compared to placebo
•
Use in older infants and adolescents has been extrapolated from adult data
•
Assure patient has appropriate indication for PPI before prescribing
•
Use lowest effective dose for shortest period of time to control symptoms
•
Plan how to monitor and reassess need for continued use
•
Long term use is being associated with more potential adverse events
•
Advocate for proton pump inhibitors to be removed for OTC status
[email protected]
References
•
General References
•
Aronson, Jeffrey K. "Inhibiting the proton pump: mechanisms, benefits, harms,
and questions." BMC Medicine 14.1 (2016): n. pag. Web.
•
Haastrup, P., M. S. Paulsen, L. M. Begtrup, J. M. Hansen, and D. E. Jarbol.
"Strategies for discontinuation of proton pump inhibitors: a systematic review."
Family Practice 31.6 (2014): 625-30. Web.
•
Heidelbaugh, J. J., A. H. Kim, R. Chang, and P. C. Walker. "Overutilization of
proton-pump inhibitors: what the clinician needs to know." Therapeutic Advances
in Gastroenterology 5.4 (2012): 219-32. Web.
•
Ward, Robert M., and Gregory L. Kearns. "Proton Pump Inhibitors in Pediatrics."
Pediatric Drugs 15.2 (2013): 119-31. Web.
References
•
Side Effects and Complications of Proton Pump Inhibitors
•
Abraham, Neena S. "Proton pump inhibitors." Current Opinion in Gastroenterology 28.6 (2012): 615-20. Web.
•
Cohen, Shlomi, Mirjam Bueno De Mesquita, and Francis B. Mimouni. "Adverse effects reported in the use of
gastroesophageal reflux disease treatments in children: a 10 years literature review." British Journal of Clinical
Pharmacology 80.2 (2015): 200-08. Web.
•
Freedberg, Daniel E., Lawrence S. Kim, and Yu-Xiao Yang. "The Risks and Benefits of Long-term Use of Proton Pump
Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association."
Gastroenterology 152.4 (2017): 706-15. Web.
•
Lazarus, MBBS Benjamin. "Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease." JAMA Internal Medicine.
American Medical Association, 01 Feb. 2016. Web. 22 Mar. 2017.
•
Mayor, Susan. "Long term use of proton pump inhibitors may increase risk of impaired kidney function." Bmj (2016):
I2163. Web.
•
Pohl, John F. "Clostridium difficile infection and proton pump inhibitors." Current Opinion in Pediatrics 24.5 (2012): 627-31.
Web.
•
Stark, Christopher M., and Cade M. Nylund. "Side Effects and Complications of Proton Pump Inhibitors:
A Pediatric Perspective." The Journal of Pediatrics 168 (2016): 16-22. Web.
References
•
PPI and Asthma Control
•
Blake, Kathryn, and Hengameh Raissy. "Treatment of Pediatric Asthma with Proton Pump Inhibitors: Three
Strikes, Game Over." Pediatric Allergy, Immunology, and Pulmonology 25.2 (2012): 119-22. Web.
•
Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma. (2009). New England Journal of
Medicine, 360(15), 1487-1499. doi:10.1056/nejmoa0806290
•
Holbrook, J. T., R. A. Wise, B. D. Gold, K. Blake, E. D. Brown, M. Castro, A. J. Dozor, J. J. Lima, J. G.
Mastronarde, M. M. Sockrider, and W. G. Teague. "Lansoprazole for Children With Poorly Controlled
Asthma: A Randomized Controlled Trial." JAMA: The Journal of the American Medical Association 307.4
(2012): 373-80. Web.
•
Goldsobel, A. "Lansoprazole for Children With Poorly Controlled Asthma: A Randomized Controlled Trial."
Pediatrics 130.Supplement (2012): n. pag. Web.
•
Mellis, Craig. "Lansoprazole for poorly controlled asthma: No effect, potential harm and a case of
therapeutic creep?" Journal of Paediatrics and Child Health 49.1 (2013): 79. Web
References
•
Prevention of Stress Related Mucosal Disease
•
Buendgens, Lukas. "Prevention of stress-related ulcer bleeding at the intensive
care unit: Risks and benefits of stress ulcer prophylaxis." World Journal of Critical
Care Medicine 5.1
•
(2016): 57. Web.
•
Desilets, Desilets, Dr. Willett, Cheryl Durand, Dr. Willett, and Desilets. "Proton
Pump Inhibitor use in Hospitalized Patients: Is Overutilization Becoming a
Problem?" Clinical Medicine Insights: Gastroenterology (2012): 65. Web.
•
Reveiz L., Guerrero-Lozano, R., & Camacho, A. (2010). Stress ulcer,gastritis and
gastrointestinal bleeding prophylaxis in critically ill pediatric patients: A systematic
review. Pediatric Critical Care Medicine, 11(1), 124-132.
doi:10.1097/PCC.0b013e3181b80e70
References
•
Corticosteroid Induced GI bleed
•
Narum, Sigrid, Tone Westergren, and Marianne Klemp. "Corticosteroids and risk of
gastrointestinal bleeding: a systematic review and meta-analysis." BMJ Open 4.5
(2014): n. pag. Web.
•
Munson, Jeffrey C., Peter M. Wahl, Gregory Daniel, Stephen E. Kimmel, and Sean
Hennessy. "Factors associated with the initiation of proton pump inhibitors in
corticosteroid users." Pharmacoepidemiology and Drug Safety 21.4 (2012): 366-74.
Web.
References
•
PPI and GER in Infants
•
Davidson, G., Wenzl, T. G., Thomson, M., Omari, T., Barker, P., Lundborg, P., & Illueca, M. (2013). Efficacy and Safety of Once-Daily Esomeprazole for the
Treatment of Gastroesophageal Reflux Disease in Neonatal Patients. The Journal of Pediatrics, 163(3). doi:10.1016/j.jpeds.2013.05.007
•
Kierkus, Jaroslaw, Grzegorz Oracz, Bartosz Korczowski, Edyta Szymanska, Anna Wiernicka, and Marek Woynarowski. "Comparative Safety and Efficacy
of Proton Pump Inhibitors in Paediatric Gastroesophageal Reflux Disease." Drug Safety 37.5 (2014): 309-16. Web.
•
Lightdale, J. R., and D. A. Gremse. "Gastroesophageal Reflux: Management Guidance for the Pediatrician." Pediatrics 131.5 (2013): n. pag. Web.
•
Orenstein, S. R., Hassall, E., Furmaga-Jablonska, W., Atkinson, S., & Raanan, M. (2009). Multicenter, Double-Blind, Randomized, Placebo-Controlled
Trial Assessing the Efficacy and Safety of Proton Pump Inhibitor Lansoprazole in Infants with Symptoms of Gastroesophageal Reflux Disease. The
Journal of Pediatrics, 154(4). doi:10.1016/j.jpeds.2008.09.054
•
Tjon, James A., Michael Pe, Joanna Soscia, and Sanjay Mahant. "Efficacy and Safety of Proton Pump Inhibitors in the Management of Pediatric
Gastroesophageal Reflux Disease." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 33.9 (2013): 956-71. Web.
•
Winter, Harland, Thirumazhisai Gunasekaran, Vasundhara Tolia, Frederic Gottrand, Peter N. Barker, and Marta Illueca. "Esomeprazole for the Treatment
of GERD in Infants Ages 1–11 Months." Journal of Pediatric Gastroenterology and Nutrition 60 (2015): n. pag. Web.
•
Vandenplas, Y., & Rudolph, C. (2009). Pediatric Gastroesophageal Reflux Practice Guidelines: Joint Recommendations for the North American Society
for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology and
Nutrition (ESPGHAN). Journal of Pediatric Gastroenterology and Nutrition, 49, 498-547.