Antacid and h2 blocker combination

Risk associated with PPI

1. Hyperacidity The Main Problem in GI Disorders By Aadil Sayyed Medical Affairs M- Pharm (Pharmacology)

2. What Are GI Disorders

3. Other Causes Of Acidity

4. Common Symptoms in GI Problems

5. Management Of GI Disorders

6. Antacid? H2 Blocker? PPI?

7. Selection is dependent on Safety & Efficacy The Efficacy of these agents is well established. Efficacy of PPI>H2 blocker>Antacids but safety of H2 blocker>Antacid>PPI

8. How H2 blockers are more safe than PPIs? PPI Achlorhydria malabsorption and deficiencies of Ca & Vit B12 bone loss Malabsorption of Mg Hypomagnesemia Increased Fracture Risk In March 2011, the FDA released a warning regarding low serum magnesium levels associated with long-term use of PPIs . Health Canada issued an alert in April 2013 stating that patients with existing risk factors for osteoporosis should be monitored closely and should also receive short-term PPI therapy at the lowest effective dose Increase in gastrin levels PPIs are better inhibitors of gastric acid secretion than H2 receptor blockers and are therefore associated with higher gastrin levels Hypergastrinemia

9. PPIs are associated with increased risk of fracture PPIs (but not H2RAs ) are associated with an increased risk of fracture 1 . 35% increased risk of fracture, 31% increased risk of hip fracture 54% increased risk of vertebral fracture Moreover Indians already have high prevalence (Up to 62% 2 ) of Osteoporosis ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 9, NO. 3 ✦ MAY/JUNE 2011 Int J Womens Health . 2015; 7: 841–850.

10. PPIs are associated with Hypomagnesemia More common in older patients (mean age 64.4 years) FDA Suggests, patients who present with clinically significant hypomagnesemia may require discontinuation of PPI therapy , magnesium replacement via oral or IV methods, and treatment with an alternative class of drugs for GI conditions such as an H2RAs US Pharm. 2013;38(12):38-42 In 60% of adults the Magnesium intakes from food do not meet the estimated average requirement J Med Nutr Nutraceut [serial online] 2014 [cited 2017 Jul 26];3:66-72

11. PPIs are associated with CKD Kidney disease is a newer concern associated with PPI use. PPI therapy causes interstitial nephritis, which is a cause of acute kidney damage. This acute kidney damage, coupled with the potential for hypomagnesemia, can lead to an increased risk of chronic kidney damage with PPI use. A 2016 study by Lazarus et al. shows that, use of PPIs is independently associated with a 20% – 50% higher risk of incident chronic kidney disease Same study showed that the risk for CKD was lacking in patients prescribed histamine-2 receptor antagonists , suggesting that the increased risk for chronic kidney disease is specifically associated with PPI use and not all acid-suppressive therapy June 2016 Long-Term Care Updates

12. PPIs & B12 & Iron Deficiency Vitamin B12 & Iron deficiency is another side effect sometimes seen with acid-suppressive therapy. Gastric acid is needed for the dissociation of vitamin B12 & Iron from food. Prevalence of Vitamin B12 is 25% & Folate 51% in India Indian J Med Res. 2011 Oct; 134(4): 432–439. June 2016 Long-Term Care Updates

13. PPIs & Risk of Dementia Another new concern with long-term PPI use is the development of dementia. Potential mechanisms for dementia development include vitamin B12 deficiency , which has been associated with cognitive decline, and the possible enhancement of amyloid beta peptide levels in the brain. A recent study by Gomm et al. suggests that long-term PPI use is associated with a 44% increased risk of dementia in patients 75 years of age and older. JAMA Neurol 2016;73(4):410-6.

14. PPIs associated with Increased risk of Infection PPI Acid suppression Raising PH Prevents gastric Acid from killing of ingested  C. difficile CDI (C. Difficile Infection) Gastric acid provides a host defense by killing ingested pathogens Antimicrob. Agents Chemother. October 2009  vol. 53 no. 10 4133-4137 Clostridium difficile   (C. difficile  or  C. diff ) is a gram-positive, spore-forming, anaerobic bacterium transmitted through spores or bacteria in stools or through spores in the environment

15. PPIs Delayed gastric emptying Increased gastric contents Increased bacterial load Increased pressure on the lower esophageal sphincter Retrograde movement of gastric contents up the esophagus Increase the risk of subsequent aspiration of both the gastric contents and the bacteria CAP World J Gastrointest Pharmacol Ther 2011 June 6; 2(3):17-26

16. PPIs associated with Increased risk of Infection The 2013 American College of Gastroenterology (ACG) guidelines warned about the risk of increased infections of C difficile & CAP 74% higher risk of developing C difficile infection. 75% of the patients with reported cases were over the age of 65 years . Not only does long-term use of PPIs cause an increased incidence of C difficile, but patients who received a PPI during treatment of C difficile were also 42% more likely to have a recurrent infection after finishing therapy. US Pharm. 2013;38(12):38-42 The 2013 ACG guidelines state that short-term PPI use may increase the risk of CAP. *BMJ  2016;355:i6041

17. CONTD In 2012, Health Canada issued an advisory about the possible association of PPI use and CDI. 2  PPI prescribing information must now include the precaution that a decrease in stomach acid may increase the risk of gastrointestinal infections such as  Salmonella, Campylobacter,  and  C. diff. This warning reminds health professionals that PPIs should be used at the lowest possible dose for the shortest possible duration.

18. PPIs & Gastric Motility PPIs can inhibit gastric motility and delay emptying rate and, as a consequence, dyspeptic symptoms may actually be worsened by PPI therapy or, alternatively, new symptoms (especially postprandial fullness) may arise during treatment. In this is the case, patients could be switched to the H 2 RAs, which, in addition to their antisecretory activity, display a cholinergic-like activity & have been shown to accelerate gastric emptying . On the other hand, a Cochrane meta-analysis showed that H 2 RAs are better than placebo in achieving symptom relief in patients with Functional Dyspepsia.

19. Summary Limitation of PPI PPI Goes into Stomach Causes reduction in acid levels Reduces absorption of Nutrition Increases Gastrin Reduces B12 Absorption Reduces Ca Absorption Reduces Mg Absorption Increases chn This Leads to….…..

20. Summary: A potent Acid inhibitor may lead to potent adverse effect PPI are associated with number of serious adverse effects PPI No more choice of drug Increased risk of fracture Increased risk of Hypergastrinemia Increased risk Dementia Hypomagnesemia Vitamin B12 & Iron Deficiency Increased risk of Infection Need of Safer option

21. H2 Blockers H2-receptor antagonists are considered by many gastroenterologists to be the 'gold standard’. Comparable efficacy to PPIs. Safer option than PPIs. Not associated with fracture risk. Less effect on nutrition malabsorption than PPIs. 1994, the American Academy of Pediatrics classified H2 blocker as compatible with breast feeding & PPIs are contraindicated . Aliment Pharmacol Ther.  1993;7 Suppl 2:35-40. Aliment Pharmacol Ther. 2005;22(9):749-757. 

22. Limitation of H2 Blocker Slow Onset of Action. Rapid acid suppression is highly desirable in hyperacidity. Hence onset of action should be fast. Combining with Antacid can overcome this problem

23. Famotidine with Calcium Carbonate/Magnesium Hydroxide Chewable Tablet For Immediate & Sustained control of Acidity A Safe & Effective combination

24. Famotidine + Calcium Carbonate/Mg Histamine H₂ receptor antagonist that inhibits stomach acid production Onset of action is 90 min & duration is up to 12 hours Suppress 24-hour acid secretion by 70%. Neutralizes Acid Rapid onset of action, neutralizes 6.7 mmol of acid in the first 30 minutes. Duration of action is short up to 2 hours. Aliment Pharmacol Ther.  2002 Jul;16(7):1317-26. JAMA . 1996;275:1428-1431 Clinical Pharmacology And Rational Therapeutics (2Nd Edition)

25. Rationale of Combination Famotidine reduces the acid and pepsin production, as well as the volume of basal, nocturnal and stimulated gastric secretion. Calcium carbonate is antacids and neutralize intraluminal acid on contact. Combination Combines the prolonged duration of effect of famotidine with the rapid onset of action of antacids . Parameters Famotidine 1 Calcium carbonate 1 Magnesium Hydroxide Onset of action 90 minutes 30 minutes Duration of action 10-12 Hours 60-120 minutes

26. Benefits of Adding Antacid Calcium carbonate & Magnesium can neutralize the pH in the range of 3.5 to 5 in just 15 minutes which is ideal. Quick onset of action than PPI Less chances of acid rebound as it is combined with H2 blocker. Journal of institute of medicine Volume 20 Number 1 & 2 Jan-Mar/Apr-Jun 1998

27. Benefits of Chewable Tablet Better bioavailability through bypassing disintegration (that increase dissolution) Improved patient acceptance (especially pediatric) through pleasant taste Patient convenience; need no water for swallowing Possible to use as a substitute for liquid dosage forms where rapid onset of action is needed Absorption of drug is faster The large size of the dosage form is difficult to swallow. In such cases chewable tablet offers advantages over it Effectiveness of therapeutic agent is improved by the reduction in size that occurs during mastication of tablet before swallowing. The Pharma Innovation Journal 2015; 4(5): 100-105

28. Composition Each Chewable Tablet Contains Famotidine 10 mg Magnesium hydroxide 165 mg Calcium carbonate 800 mg Dose One tablet to be chewed for the relief of symptoms. No more than two tablets to be taken in 24 hours

29. Clinical Efficacy

30. Effect of Combination on Gastric & Esophageal Ph Conducted on 23 patients Results Administration of Combination of Famotidine with Antacid with 60ml of water one hour after a high-fat evening meal produced an increase of esophageal pH within 2 minutes . The increase of the gastric pH, above the increase observed with placebo and antacid alone, remained for 12 hours . Pepcidtwo tablet PI 1

31. Comparison of the Effects of Over-the-counter Famotidine & Calcium Carbonate Antacid on Postprandial Gastric Acid Participants.   —Eighteen healthy volunteers (10 men and 8 women) aged 25 to 62 years with normal gastric acid secretion rates. Interventions.   —The subjects received the histamine2-receptor antagonist famotidine 10mg, calcium carbonate antacid tablets 1000 mg, or placebo medications 1 hour after a test meal. Two identical meals were taken 2.5 and 6.0 hours after the medication was given. (JAMA. 1996;275:1428-1431) 2

32. Main Outcome Measures Intragastric pH was maintained at 4.0 by in vivo intragastric titration with 0.3N sodium bicarbonate for 10 hours (1 hour before and 9 hours after medication). Reduction in sodium bicarbonate titrant use in the 2 treatment groups compared with titrant use with placebo was reflective of acid secretion inhibited by famotidine or acid neutralized by calcium carbonate tablets. (JAMA. 1996;275:1428-1431)

33. Results When evaluated in increments of 30 minutes, calcium carbonate had a rapid onset of action , neutralizing 6.7 mmol of acid in the first 30 minutes . However, its duration of effect was only 60 minutes. Famotidine had a delayed onset of action compared with antacid, beginning after 90 minutes. However, famotidine had a duration of effect of at least 540 minutes . At its peak effect, 210 minutes after administration, famotidine reduced acid secretion by 7.3 mmol per 30 minutes . (JAMA. 1996;275:1428-1431)

34. Conclusions Recommended over-the-counter doses of famotidine and calcium carbonate tablets have different pharmacokinetic profiles when taken in the postprandial period. The antacid has a rapid onset and short duration of action, while the histamine 2 -receptor antagonist has a delayed onset and a prolonged duration . (JAMA. 1996;275:1428-1431)

35. Clinical study on the influence of a fixed-dose combination of famotidine with calcium carbonate and magnesium hydroxide on the bioavailability of famotidine. A randomized, open-label, two-period, crossover study was carried out on 12 healthy Chinese volunteers. Plasma concentration-time profiles of famotidine were similar with the FDC formulation and common formulation. Confidence interval (90% CI) for maximal concentration (C(max)) and area under the curve (AUC(o-t)) of famotidine were 94.8-112.2% and 94.2-112.3%, respectively. These findings suggest that calcium carbonate/magnesium hydroxide antacids have no significant effects on famotidine pharmacokinetics when they are administered together with famotidine as an FDC formulation. 3 Arzneimittelforschung .  2008;58(11):581-4

36. Summary PPIs are associated malabsorption of Ca, Mg, Vitamin B12 & Iron. We Indians are already highly deficient of these nutrients. PPIs (But not H2 blockers) are associated with increased risk of fracture, infection & CKD. PPIs are also associated with hypergastrinemia. PPIs may worsened dyspeptic symptoms as they inhibit gastric motility. Unlike of PPIs, H2 blockers increases gastric motility. H2 blockers are appeared as safer yet efficacious option than PPI. H2 blockers are the gold standard in gastric disorders Combination of H2 blockers+Antacid can offer very rapid (2 mins) & prolonged duration of action. Chewable tablet can offer extra advantage over normal tablet with better compliance. PPIs are contraindicated in lactation whereas H2 blockers & Antacids are not.

37. GI Problem? Don’t Worry Have Famotidine with Antacid & Ensure Rapid & prolonged Relief