Long Term PPI Use and Associated Complications

September 2014

Jessica Farrell, Pharm.D Co-Director Steffens Scleroderma Center Assistant Professor of Pharmacy Practice Albany College of Pharmacy and Health Sciences Do I take a Proton Pump Inhibitor (PPI)? Currently, physicians are pre- irritation, and other ing them increasingly accessible scribing proton pump inhibitors symptoms. PPIs work by inhibiting and commonly misused. For many (PPIs) to treat patients for a variety the proton pump in parietal cells people, the use of a PPI, especially of diseases or symptoms. PPIs are (the cells that create stomach acid). long term use, is not necessary and commonly used to treat heartburn, As a result of this inhibition, the may promote unwanted side effects. ulcers or gastroesophageal reflux amount of stomach acid produced For other patients, such as those disease (GERD). GERD is a condi- is decreased. PPIs are available with Scleroderma, the utility of PPI tion where stomach contents leak in both prescription and over the therapy vastly outweighs the side back into the esophagus causing counter (OTC) formulations, mak- effect associated risks.

Available as Prescription Only Available Over the Counter Brand Name Generic Name Brand Name Generic Name Protonix® Pantoprazole Prilosec® Omeprazole Nexium® Esomeprazole Zegerid® Omeprazole and Vimovo® Esomeprazole and Naproxen Sodium Bicarbonate Dexilant® Dexlansoprazole Prevacid® Lansoprazole Aciphex® Rabeprazole

What is Long-Term Use? – Side effects less commonly seen from using these products, but – PPIs have a variety of Food and include alopecia, upper respira­ to better educate individuals on Drug Administration (FDA) tory tract infection, increased the safety and appropriate use labeled indications, most of liver enzymes, abnormal vision of these medications. which call for a short course and hypomagnesemia of therapy. Self-treatment for (low ­magnesium levels). Gastroesophageal Reflux Disease (GERD) with over the counter What are Potential (OTC) PPI therapy is only recom- Conditions PPIs mended for 2 weeks. Conversely, can Effect? when prescribed by a physician, – Recently, PPIs have PPIs may be utilized for long- gained negative pub- term use if the benefit outweighs licity for the risks the risk. Although there is no associated with their definitive answer as to what long-term use. Through qualifies as long-term therapy, years of clinical experi- multiple sources have identified 1 ence, drug studies and year as the cut off between short increased awareness to and long-term therapy. For cer- tain disease states, such as sclero- the possibility of side derma, long term PPI therapy is effects, PPIs have been recommended in order to avoid associated with effects the complications associated with on: vitamin/mineral gastric reflux. absorption, increased risk of bone fractures, Common Side Effects pneumonia, enteric of PPLs infections, Clostridium – Side effects most commonly difficile ­associated diar- associated with PPI use include rhea and the formation headache, , vomiting, of gastric polyps. The , dizziness, rash, anemia goal of disclosing these and arthralgias; but are generally possible side effects is well tolerated. not to deter patients

2 Decreased Absorption It is very important to of Important Vitamins/ read product labels. Minerals From this Citrical® Supplement Foods label it can be seen Serving Size: 2 tablets – Calcium. PPIs affect the body’s that each serving (2 tablets) is only 500 mg Servings Per Container: (Net Qty Contents/Serving Size [# tablets]) ability to absorb calcium from of elemental calcium. Amount Per Serving % Daily Value Therefore to get the the diet, as well as from calcium Vitamin D 400 IU 100% recommended daily supplements. By lowering the amount of calcium, at Calcium (elemental) 500 mg 50% stomach acid levels, the abil- least 4 tablets should Sodium 5 mg < 1% ity to digest the calcium and be taken every day. adequately absorb it into the body vitamin B12 levels include ane- absence of gastric acid. The terms is decreased. Once your blood cal- mia, fatigue, weakness, constipa- heme and non-heme, describe if cium levels are low, the body will tion, loss of appetite and weight the iron is derived from hemo- attempt to correct this imbalance loss.6 To prevent the development globin (the protein involved in in the only way it can, by taking of these side effects, it is impor- oxygen transport). Heme iron is it from the bones. The longer the tant to have B12 levels monitored found in animal foods that origi- body is low on calcium, the more when on long term PPI therapy. nally contained hemoglobin, while calcium will be removed from the • Low B12 levels may require non-heme iron comes from plant bone. This chain of events can supplementation with oral foods. Patients undergoing long lead to osteoporosis and bone frac- tablets, sublingual tablets or term suppression of gastric acid tures. Studies have found a link fortified foods. If B12 levels do may be at risk for low iron levels between long term PPI use and not normalize with oral supple- so it is important to have your the risk of hip fractures. Studies mentation, vitamin B12 is iron levels monitored.1,3 also show a correlation between available as a monthly injection • According to studies, the higher dosages, and longer that bypasses gastrointestinal absorption of iron bis-glycine is duration of use towards overall absorption. not associated with decreased 1,2,3 increased fracture risk. – Iron is an important part of absorption with changes in • Calcium Citrate is the best many proteins and enzymes that gastric pH.4 Iron-bisglycine is option for calcium supplementa- maintain good health. In addi- available in products known as tion for patients currently on a tion it is an essential component Ferrochels, and Hemagenics. PPI. Calcium citrate does not of oxygen transport in the blood. Also, the possibility of iron require an acidic environment to Iron digestion and absorption can by injection is available for absorb the calcium in the diges- be affected by PPI usage. Like patients not able to tolerate oral tive tract, while calcium carbon- other vitamins and minerals, iron supplementation. Always con- ate does require stomach acid. (specifically non-heme iron, 66% sult with your doctor or phar- – Vitamin B12 is necessary for of iron found in food), has mark- macist before starting a new proper red blood cell formation, edly decreased absorption in the medication. neurological function, and DNA synthesis. It is also an essential factor in metabolism of fats and proteins. In order for the body to absorb vitamin B12, gastric acid is needed to release the B12 from food. There is also an association of decreased absorption in elderly populations. Therefore, patients utilizing long-term PPIs and/ or elderly populations will have decreased absorption of B12 from food sources.1,3,4 To reduce the likelihood of low levels of B12, it is recommended to take B12 sup- plements or ingest B12 fortified foods to counteract malabsorption. Side effects associated with low

3 – Magnesium is an important • To prevent bacteria from enter- stomach acid and thus increase mineral in the body used to main- ing the lungs, prop the bed up the growth of bacteria. By making tain normal muscle and nerve at night or sleep with multiple the stomach less acidic, PPIs may function, and heart rhythm. In pillows to elevate the upper por- leave the door open for infections addition, magnesium supports tion of your body. This will pre- that may not have taken hold the immune system and improves vent both heartburn and gastric if the acid levels had been “nor- bone stability. Although rare, acid from entering the lungs. mal.”2 Recently in February 2012, PPIs have been linked with states Also, there are multiple ways the FDA added a special alert to of hypomagnesemia (low magne- to prevent pneumonia including the drug monographs of PPIs to sium levels), but the mechanism washing your hands before eat- include a possible increased risk is unknown at this time. Theories ing and preparing foods, smok- of C. diff-associated diarrhea. It is suggest that PPI-induced hypo- ing cessation, and being vac- reported that there is an estimat- magnesemia is likely due to cinated. Always consult with ed 1.4 to 2.75 fold increased risk gastrointestinal magnesium loss. your doctor or pharmacist about of developing C.diff-associated Symptoms of hypomagnesemia the need for a vaccination. diarrhea. Risk factors and most include fatigue, unsteadiness, par- reported cases include elderly esthesia, tetany, cardiac arrhyth- Enteric Infections patients, chronic or underlying mias, so it is important to monitor – Enteric infections are defined conditions, simultaneous use of patients’ magnesium level with as an infection of the intestinal broad-spectrum antibiotics (amox- prolonged use of PPIs.3 tract and present with diarrhea, icillin, ciprofloxacin, levofloxacin).7 • If you are experiencing low abdominal discomfort, nausea, • It is recommended to contact magnesium­ levels, your physi- vomiting and anorexia. Patients your physician if patients expe- cian may advise you to take a may be more susceptible to chol- rience persistent watery stools, magnesium supplement in order era and species of Shigella and bloody diarrhea, abdominal to counteract the magnesium Salmonella while under PPI ther- pain/tenderness, nausea, loss of loss in the stomach. Always apy due to small bowel bacterial appetite, or fever while taking consult with your doctor or overgrowth. This increased risk PPIs. It is also advised to use pharmacist before starting a can be attributed to the gastric the lowest dose for the shortest new medication. acid suppression due to PPI ther- duration.7 apy. Normally, gastric acid would PPI Associated Pneumonia destroy the majority of ingested Gastric Polyps – Pneumonia is a breathing condi- bacteria and prevent infection. – Gastric polyps are masses of tion caused by a bacterial infec- Only a few cases of infections in cells that form on the inside tion of the lung. It is an unpleas- patients taking PPIs have been lining of the stomach and are ant condition that affects millions reported and a variety of case considered rare. Gastric polyps of people each year and includes studies argue against this risk.1 are typically asymptomatic and symptoms of cough, fever, shak- • Even with conflicting evidence very rarely progress to cancer- ing chills and shortness of breath. there are still recommendations ous tissue. One risk factor for Patients who use PPIs are at an to avoid such infections. Taking developing gastric polyps is the increased risk for pneumonia extra care in making sure food long term use of PPIs; as there and other upper respiratory tract is not spoiled or contaminated. has been an increased incidence infections.1 PPI use can lead to Practicing not only proper of polyps in recent years due to an increase in bacterial coloniza- hygiene, but proper kitchen increased usage of PPIs. This is tion of the stomach due to a less hygiene (cleaning surfaces and because when parietal cells (acid acidic environment. In addition, utensils after contact with raw producing cells) are suppressed PPI use may be associated with meats). Avoiding sick or infected by PPIs, hyperplasia (increase in pulmonary micro-aspiration and individuals and frequent hand the number of cells) can occur in a lung colonization. In other words, washing are all ways to avoid time dependent manner. In other during ventilation, materials from enteric infections. words, the body will create more the gastrointestinal tract can cells because the previous cells enter the lungs and be deposited. Growth of Gastric Bacteria are not producing acid. Majority Therefore, patients using PPIs – Clostridium difficile (C.diff) can of polyps may not require treat- have more bacterial colonization cause life-threatening cases of ment; treatment is usually indi- leading to an increased risk of diarrhea and conditions like coli- cated only if polyps are cancer- bacteria entering the respiratory tis and inflammation of the lining ous or larger than 1cm. Antral tract. of the colon. PPIs can decrease the polyposis is often attributed to

4 Helicobacter pylori (H. pylori) infection, which has a decreased incidence since the widespread use of PPIs. However, it is not guaranteed that antral polyposis and H. pylori are seen together. PPI usage has been associated with a 4 fold increased risk of developing benign gastric polyps. Typically when PPIs are stopped for a period of months, gastric ­polyps will dissipate.5 Drug Interactions minimize these unwanted effects. – PPIs, like any other drug, can Are Other /Acid Your healthcare professionals interact with other drug therapies Suppressants Safe? are aware of these conditions and you may be taking. Although an – Other over the counter prod- under their supervision, unde- interaction may exist, it may still ucts work to lower the amount sired side effects can be avoided. be safe for you to take the com- of acid produced by the body to If patients are indicated for the bination together. Talk to your fight GERD, heartburn, ulcers, long term use of PPIs, following pharmacist about the risk of com- etc. These products the above advice can help reduce bining these therapies. include Tums, Maalox, Gaviscon, possible adverse effects associated • PPIs may increase the effects Mylanta, Pepto-Bismol and with this class of medication. of: amphetamines (Adderall), Rolaids. Another class of acid aripiprazole (Abilify), benzodiaz- suppressing drugs are Histamine Why am I taking a PPI epines (Xanax, Valium, Ativan), H2-receptor antagonists (H2RA) for the treatment of carvedilol (Coreg), cilostazol which include Pepcid (famotidine), Scleroderma? (Pletal), citalopram (Celexa), Zantac (ranitidine), Tagamet – In Scleroderma, esophageal dys- escitalopram (Lexapro), cyclo- (cimetidine) and Axid (nizatidine). function can lead to severe compli- sporine (Neoral, SandIMMUNE), In contrast to PPIs, antacids only cations if not treated effectively. dexmethylphenidate (Focalin), temporarily neutralize stomach Normally, the lower esophageal fluconazole (Diflucan), phe- acid and similarly H2RAs limit sphincter, or valve, acts as a gate nytoin (Dilantin), methotrexate acid secretion to a lesser degree between the stomach and esopha- (Rheumatrex), pimozide (Orap), than PPIs. Due to their lower gus which opens to allow food raltegravir (Isentress), saqui- degree of acid suppression or neu- to enter the stomach and then navir (Invirase), tacrolimus tralizing, these drugs do not show closes promptly to prevent food (Prograf), vitamin K antagonists the same long term effects as PPIs from coming back up. In systemic (Coumadin, warfarin), voricon- when considering osteoporosis, azole (VFEND). decreased mineral bioavailability scleroderma, the gate does not • PPIs may decrease the effects of: or gastric polyps. close properly and the result is a atazanavir (Reyataz), bisphos- backwash of acid and a burning phonates (Fosamax, Boniva, What should I do? sensation (heartburn) as food and Actonel), cefditoren (Spectracef), – Discuss with your doctor your acid return into the esophagus. clopidogrel (Plavix), clozapine symptoms and overall need for The acid may also injure the lin- (Clozaril), dabigatran (Pradaxa), a PPI instead of alternative ing of the lower portion of the dasatinib (Sprycel), delavir- treatments with over the coun- esophagus, causing scarring and a dine (Rescriptor), erlotinib ter antacids and acid suppres- narrowing (stricture) of the tube. (Tarceva), gefitinib (Iressa), sants. Although there are issues The addition of PPI therapy can indinavir (Crixivan), iron salts with long term use, PPIs are an decrease the risk of scarring and (ferrous sulfate, ferrous gluco- effective and beneficial treat- stricture formation. The benefit nate, ferrous fumarate, Iron), ment for a variety of indications. of using PPIs outweighs the risks itraconazole (Sporanox), mesa- Patients and prescribers must associated with PPI use. In gen- lamine (Asacol), mycophenolate always weigh the risk vs. benefit eral, the side effects associated (CellCept), nelfinavir (Viracept), of medication use, as with all with long-term PPI therapy can posaconazole (Noxafil), rilpi- medications. Increased awareness be prevented with proper monitor- virine (Edurant), tipranavir of the possible side effects and ing by your provider. (Aptivus), vismodegib (Erivedge). precautions is important to help

5 References: 1. Thomson A, Sauve M, Kassam N, Kamitakahara. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol. 2010;16(19):2323-30. 2. Laria A, Zoli A, Gremese E, Ferraccioli GF. Proton pump inhibitors in rheumatic diseases: clinical practice, drug interac- tions, bone fractures and risk of infections. Reumatismo. 2011;63(1):5-10. 3. Ito T, Jenson R. Association of Long-Term Proton Pump Inhibitor Therapy with Bone Fractures and effects on Absorption of Calcium, Vitamin B12, Iron and Magnesium. Curr Gastroenterol Rep. 2010;12(6):448-57. 4. Jameson R Lam, Jennifer L Schneider, Douglas A Corley et al. Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 Deficiency. JAMA. 2013;310(22):2435-2442. 5. Garcia-Casal MN, Layrisse M. The effect of change in pH on the solubility of iron bis-glycinate chelate and other iron com- pounds. Arch Latinoam Nutr. 2001;51(1 Suppl 1):35-6. 6. Alqutub AN, Masoodi I. A case of gastric polyposis in antral area of stomach following prolonged proton-pump therapy. Ger Med Sci. 2010;2(8):pii Doc19. 7. Office of Dietary Supplements. National Institute of Health. Dietary supplement fact sheet: Vitamin B12. Reviewed 2011 June 24. [cited 2012 June 19] Available from: http://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/ 8. U.S. Food and Drug Administration. Proton Pump Inhibitors (PPIs) – Drug Safety Communication: Clostridium Difficile- Associated Diarrhea (CDAD) can be associated with stomach acid drugs. 2012 [cited 2012 June 19] Available from: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm290838.htm

Acknowledgements: I’d like to thank Michael Sautter, PharmD. Candidate 2013 for his hard work on this project.

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