Deborah E Westbrook BSMS 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 ID: 930856
Download Presentation The PPT/PDF document "Proton Pump Inhibitors: Uses, Misuses, a..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
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
Slide2Disclosure
I have no financial conflicts of interest
Off label uses of these medications will be discussed
Slide3Objectives
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.
Slide4Slide5Slide6Proton Pump Inhibitors: FDA-Approved Indications
Erosive Esophagitis
GERD
H pylori
Active
Gastric Ulcer
Active Duodenal Ulcer
NSAID-Associated
Gastric Ulcer
Upper
GI
Bleed
Pantoprazole
(
Protonix
®)
√
√
Omeprazole
(Prilosec®)
√
√
√
√
√
√
Esomeprazole
(Nexium®)
√
√
√
√
Lansoprazole
(
Prevacid
®)
√
√
√
√
√
√
Dexlansoprazole
(
Dexilant
®)
√
√
Rabeprazole
(
Aciphex
®)
√
√
√
√
√
Slide7FDA- Approved Indications for PPIs in Pediatric Patients
Age
Range (Years)
0
1
2
3
4
5
6
7
89101112131415161718esomeprazolelansoprazoleomeprazolepantoprazolerabeprazole
Symptomatic GERD
Healing of Erosive Esophagitis
https://www.accessdata.fda.gov/drugsatfda_docs
Slide8Proton Pump Inhibitors Side Effects
Infants
Nausea
Diarrhea
Children
Headache
Nausea
Adolescents/Adults
Headaches
Diarrhea
Nausea
Dry mouthConstipation
Slide9Proton Pump Inhibitors: New Labeling
Slide10Adverse 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/dyspepsiaUse lowest dose of PPI which is effectiveUse for shortest time period possible
Slide11Adverse 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
Slide12Adverse Effects Associated with PPI Use
Hypomagnesemia
Decreased oral absorption of magnesium
Consequences
Life-threatening arrhythmias
Seizures
Risk
F
actors
Concomitant diuretic therapyPPI use greater than 3 monthsMonitoringBaseline magnesium prior to starting PPI in patients at riskTreatmentOften unresponsive to magnesium supplementationDiscontinuation of PPI
Slide13Adverse 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-
paresthesiasCognitive and behavioral changes
Slide14Adverse 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 antibioticsHospitalized patients on PPI alonePatients on immunosuppressive therapiesComorbidities such as cancer, cystic fibrosisPatients in ambulatory care settingEvidenceObservational studies have shown a 1.4-2.75 times higher risk for patients on PPI to develop CDAD than those patients not on PPIObservational study in children showed 4.5 times more likely to develop CDAD on PPI compared to children not on PPI
Slide16Adverse Effects Associated with PPI Use
Clostridium
difficile
Infections
Clinical Consequences
Life threatening complications
Dehydration
Toxic
Megacolon
Necrotic Bowel
Colonic Perforation
Asymptomatic carriersIncreased risk of recurrent disease after treatmentDecreased response to antibiotic therapyDeathConsequencesPoor patient outcomesIncrease length of hospital stayAdditional health care cost
Slide17Adverse 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
Slide18Adverse 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
Slide19Adverse 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
Slide20Adverse 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
Slide21Drug 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 metabolismTacrolimusAdding PPI to tacrolimus may increase tacrolimus level
Slide22Drug Interactions and Proton Pump Inhibitors
Drugs dependent on acidic environment for absorption/activation
Ketoconazole
Mycophenolate
Mofetil
Iron salts
ClarithromycinClarithromycin inhibits metabolism of PPI HIV MedicationsAtazanavir and Nelfinavir levels may be decreased with PPI Saquinavir levels may be increased RifampinMay increase metabolism of PPI decreasing efficacy
Slide23Evidenced Based or Just a GUT Feeling?
Slide24Common 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
Slide25GER 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
Slide26GER in Infants Less than 1 Year of Age
Symptoms of GER
Regurgitation
Spitting
Crying
Irritability during feeds
Parental distress
Slide27GER 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
Slide28GER 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 feedingElevate the head of baby’s bedIf patient has symptomatic (GERD) consider a four-eight week trial of PPI/H2-antagonistIf infant does not respond to PPI treatment further workup needed including an endoscopy
Slide29Prevention 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 NSAIAPPI and steroids may have additive adverse effectsInfection risk ( pneumonia and C. difficile)Fracture risk
Slide31Prevention 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
Slide32Prevention of Stress-related Mucosal Disease (SRMD)
INDEPENDENT RISK FACTORS
IN
PEDIATRICS
Coagulopathy
PRISM Score
≥ 10
Respiratory
Failure requiring mechanical ventilation
High pressure ventilation
Organ Failure
INDEPENDENT RISK FACTORS IN ADULTSCoagulopathyRespiratory FailureShockMultiple Trauma
Slide33Prevention of SRMD
FACTORS CONTRIBUTING TO CUMULATIVE RISK
Acute hepatic
f
ailure
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)SepsisSevere head or spinal cord injury
Slide34Prevention 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
Slide35Prevention 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
Slide36PPI: 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
Slide37PPIs 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 hyperresponsivenssNo difference in outcomes for patients with positive pH probe prior to treatment
Slide38PPIs 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
Slide39Common 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
Slide40Patient 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
Slide41CONCLUSIONS
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 eventsAdvocate for proton pump inhibitors to be removed for OTC status
Slide42Dwestbro@vidanthealth.com
Slide43References
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.
Slide44References
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.
Slide45References
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/nejmoa0806290Holbrook, 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
Slide46References
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
Slide47ReferencesCorticosteroid 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.
Slide48References
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.2013.05.007Kierkus, 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.2008.09.054Tjon, 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.