Proton Pump Inhibitors: Uses, Misuses, and the Unknown - PowerPoint Presentation

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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

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Disclosure

I have no financial conflicts of interest

Off label uses of these medications will be discussed

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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.

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Proton 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

®)

√

√

√

√

√

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FDA- 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

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Proton Pump Inhibitors Side Effects

Infants

Nausea

Diarrhea

Children

Headache

Nausea

Adolescents/Adults

Headaches

Diarrhea

Nausea

Dry mouthConstipation

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Proton Pump Inhibitors: New Labeling

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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/dyspepsiaUse lowest dose of PPI which is effectiveUse for shortest time period possible

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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

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Adverse 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

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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-

paresthesiasCognitive and behavioral changes

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Adverse Reactions Associated with PPI Use

Iron Deficiency

Iron better absorbed in acidic medium

Risk Factors

Low initial iron stores

Poor nutritional status

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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

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Adverse 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

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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

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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

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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

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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

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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 metabolismTacrolimusAdding PPI to tacrolimus may increase tacrolimus level

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Drug 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

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Evidenced Based or Just a GUT Feeling?

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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

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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

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GER in Infants Less than 1 Year of Age

Symptoms of GER

Regurgitation

Spitting

Crying

Irritability during feeds

Parental distress

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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

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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 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

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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

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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

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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

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Prevention 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

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Prevention 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

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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

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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

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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

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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 hyperresponsivenssNo difference in outcomes for patients with positive pH probe prior to treatment

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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

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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

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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

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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 eventsAdvocate for proton pump inhibitors to be removed for OTC status

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Dwestbro@vidanthealth.com

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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.

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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.

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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/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

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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

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ReferencesCorticosteroid 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.

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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.2013.05.007Kierkus, 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.