Histamine H2 - Receptor Antagonists - Index

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • July 23, 2021
    • May 2019
    • Dec. 2016
    • March 2015
    • June 2013
    • Nov. 2011
    • Sept. 2011
    • Sept. 2009
    • June 2009
    • Dec. 2005
    • Nov. 2003
    • Oct. 2002.
  • Initially developed
    • Dec. 2001

1. Dosage

Histamine H2-receptor antagonists (H2RAs) are FDA-approved for use in gastric ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD), esophagitis, hypersecretory conditions, and non-ulcer indigestion/heartburn.

In April 2020, the Food and Drug Administration requested that manufacturers remove all prescription and over-the-counter (OTC) formulations of ranitidine from the market. The request for removal was precipitated by the discovery of N-nitrosodimethylamine (NDMA), a probable human carcinogen, in various ranitidine products. Zantac® is one of several trade names for ranitidine, and in June 2021, Sanofi Pharmaceuticals released Zantac 360°® as an OTC product. However, this new formulation contains famotidine rather than ranitidine.

1.1. Adults

The maximum adult H2RA daily doses when prescribed for acute and maintenance FDA-approved conditions are summarized in Table 1 and Table 2. Dosage regimens exceeding these maximum recommended values will be reviewed.

Table 1. Adult Maximum Daily Acute Doses for Histamine H2-Receptor Antagonists: Monotherapy1-10
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage 
cimetidine (generics) 200 mg, 300 mg, 400 mg, 800 mg tablets; 300 mg/5 mL oral solution duodenal ulcer 1200 mg/day ^
    gastric ulcer 1200 mg/day
    gastroesophageal reflux disease (GERD) - nonerosive 1600 mg/day
    heartburn 400 mg/day
    hypersecretory conditions 2400 mg/day
famotidine (Pepcid, Zantac 360°, generics) 10 mg, 20 mg, 40 mg tablets; 40 mg/5 mL oral suspension duodenal ulcer 40 mg/day
    erosive esophagitis (EE) 80 mg/day
    gastric ulcer 40 mg/day
    GERD - nonerosive 40 mg/day
    heartburn 40 mg/day
    hypersecretory conditions 640 mg/day
nizatidine (generics) 150 mg, 300 mg capsules; 15 mg/mL oral solution  duodenal ulcer 300 mg/day in single or divided doses
    gastric ulcer 300 mg/day in single or divided doses
    GERD - nonerosive 300 mg/day in single or divided doses

Legend:

  • ^ Patients who are heavy smokers with duodenal ulcers greater than 1 cm may benefit from cimetidine 1600 mg at bedtime.
Table 2. Adult Maximum Daily Maintenance Dose for Histamine H2-Receptor Antagonists: Monotherapy1-10
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage 
cimetidine (generics) 200 mg, 300 mg, 400 mg, 800 mg tablets; 300 mg/5 mL oral solution duodenal ulcer 400 mg/day
    hypersecretory conditions 2400 mg/day
famotidine (Pepcid®, generics) 10 mg, 20 mg, 40 mg tablets; 40 mg/5 mL oral suspension duodenal ulcer 20 mg/day
    hypersecretory conditions 640 mg/day
nizatidine (generics) 150 mg, 300 mg capsules; 15 mg/mL oral solution  duodenal ulcer 150 mg/day at bedtime

Current American College of Gastroenterology guidelines recommend the use of a proton pump inhibitor over H2RAs for Helicobacter pylori treatment regimens13.

Currently, famotidine is available as a combination product with ibuprofen, and it is marketed under the trade name Duexis®. Duexis® is FDA approved for the prophylaxis against upper gastrointestinal ulcers in adult patients with osteoarthritis or rheumatoid arthritis.14 Dosing for this agent is provided in Table 3.

Table 3. Adult Maximum Daily Dose for Histamine H2-Receptor Antagonists: Combination Therapy1,2,14
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
famotidine/ ibuprofen (Duexis®, generics) 26.6 mg/ 800 mg oral tablets gastric ulcer prophylaxis in osteoarthritis or rheumatoid arthritis 79.8 mg / 2400 mg/day in three divided doses

1.2. Pediatrics

Maximum recommended pediatric H2RA daily doses for acute and maintenance therapy are summarized in Table 4. Dosages exceeding these recommendations will be reviewed.

Table 4. Pediatric Maximum Daily Acute Doses for Histamine H2-Receptor Antagonists: Monotherapy1-10
Drug Name Patient Characteristics Treatment Indication Maximum Recommended Dosage
cimetidine (generics) Greater than or equal to 16 years of age duodenal ulcer 1200 mg/day ^
  Greater than or equal to 16 years of age gastric ulcer 1200 mg/day
  Greater than or equal to 16 years of age gastroesophageal reflux disease (GERD) - nonerosive 1600 mg/day
  Greater than or equal to 12 years of age heartburn 400 mg/day
  Greater than or equal to 16 years of age hypersecretory conditions 2400 mg/day
famotidine (Pepcid®, generics) 1 to 17 years of age duodenal ulcer tablet: 40 mg/day*
suspension: 40 mg/day
  1 to 17 years of age erosive esophagitis (EE) tablet: 80 mg/day*
suspension: 80 mg/day
  1 to 17 years of age gastric ulcer tablet: 40 mg/ day*
suspension: 40 mg/day
  1 to 16 years of age GERD - nonerosive tablet: 40 mg/day*
suspension: 80 mg/day 
  3 months to 1 year of age GERD - nonerosive suspension: 1 mg/kg twice daily (maximum of 40 mg daily)
  Less than 3 months of age GERD - nonerosive suspension: 1 mg/kg once daily
famotidine (Pepcid®, Zantac 360°,  generics) Greater than or equal to 12 years of age heartburn 40 mg/day
nizatidine (generics) Greater than or equal to 12 years of age EE 300 mg/day in single or divided doses
  Greater than or equal to 12 years of age GERD - nonerosive 300 mg/day in single or divided doses

Legend:

  • ^ Patients who are heavy smokers with duodenal ulcers greater than 1 cm may benefit from cimetidine 1600 mg at bedtime
  • * dosing for pediatric patients weighing greater than or equal to 40 kg
Table 5. Pediatric Maximum Daily Maintenance Doses for Histamine H2-Receptor Antagonists1-4
Drug Name Patient Characteristics Treatment Indication Maximum Recommended Dosage
cimetidine (generics) Greater than or equal to 16 years of age duodenal ulcer 400 mg at bedtime
  Greater than or equal to 16 years of age hypersecretory conditions 2400 mg/day

1.3. Dosage in Renal Impairment

H2RAs are primarily renally excreted. Dosage modifications for H2RA use in renal impairment are summarized in Table 6.

Table 6. H2RA Dosage Modifications in Renal Impairment1-10
Drug Name Dosage Adjustments in Renal Impairment
cimetidine
  • CrCl greater than or equal to 30 mL/min: No dose adjustment recommendations
  • CrCl less than 30 ml/min: 300 mg orally every 12 hours; may increase to every 8 hours cautiously based on patient response
famotidine
  • CrCl 30-60 mL/min
    • active duodenal ulcer, active gastric ulcer, and erosive esophagitis diagnosed by endoscopy: 20 mg orally daily; or 40 mg orally every other day 
    • symptomatic non-erosive GERD: 20 mg orally daily
    • risk reduction of duodenal ulcer recurrence: 20 mg orally every other day
    • pathological hypersecretory conditions: avoid use
  • CrCl less than 30 mL/min
    • active duodenal ulcer, active gastric ulcer, erosive esophagitis diagnosed by endoscopy, and symptomatic non-erosive GERD: 10 mg orally daily; or 20 mg orally every other day 
    • risk reduction of duodenal ulcer recurrence: 10 mg orally every other day
    • pathological hypersecretory conditions: avoid usenizatidine
nizatidine

active treatment:

  • CrCl 20-50 ml/min: 150 mg/day orally 
  • CrCl less than 20 ml/min: 150 mg orally every other day

maintenance therapy:

  • CrCl 20-50 ml/min: 150 mg every other day orally
  • CrCl less than 20 ml/min: 150 mg every 3 days orally

2. Duration of Therapy

Adult and Pediatric Patients

Clinical trials document a maximum treatment duration of 56 days (eight weeks) for anti-ulcer therapy in treating acute duodenal and gastric ulcers. In pediatric patients, an 8-week maximum GERD acute treatment duration is recommended.  H2RA treatment regimens at acute dosage levels lasting longer than four months will be reviewed.

When used for nonulcer indigestion/heartburn, H2RA treatment duration should not exceed 14 days at the maximum dose, unless directed by a physician.

Maintenance therapy, at recommended daily maintenance doses (Tables 2, 3, and 5), may be continued indefinitely based on patient need.

H2RAs may be used in conjunction with PPIs in GERD patients experiencing nocturnal breakthrough symptoms.

3. Duplicative Therapy

The current literature does not support the combination of two or more H2RAs. Therefore, concurrent use of this combination will be reviewed as there is no clinical evidence to suggest that adjunctive administration improves outcomes.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Table 7 summarizes major drug-drug interactions considered clinically relevant for H2RAs. Only those drug-drug interactions identified as severe or those considered life-threatening which have not yet been classified will be reviewed.

Table 7. Major H2RA Drug-Drug Interactions1-10,14
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
cimetidine clopidogrel (Plavix®) co-administration may result in decreased clopidogrel active metabolite levels, platelet inhibition, and clopidogrel efficacy; clopidogrel requires metabolism through CYP2C19 to active metabolite and cimetidine is CYP2C19 inhibitor
 		 cimetidine-clopidogrel combination should be avoided; H2RA alternatives (e.g., famotidine, ranitidine) that are not CYP2C19 inhibitors can be substituted for cimetidine
 		 major (CP)
cimetidine dofetilide (Tikosyn®) concurrent use may potentially increase dofetilide serum levels/ enhance pharmacologic effects (e.g., torsades de pointes) as dofetilide metabolized by CYP3A4, eliminated through renal and hepatic mechanisms; cimetidine inhibits dofetilide clearance through interference with active tubular secretion and moderate CYP3A4 inhibition dofetilide manufacturer states that concurrent administration of dofetilide and cimetidine is contraindicated; medications without effect on dofetilide pharmacokinetics (e.g., omeprazole, ranitidine, antacids) are potential alternatives to cimetidine severe (CP)
cimetidine theophylline adjunctive use may cause theophylline toxicity as cimetidine inhibits theophylline hepatic metabolism adjunctive use possible if proper monitoring and/or dosage adjustments are made; order in which therapy initiated important - adding theophylline to existing cimetidine drug regimen can be safe as theophylline dosage titrated to acceptable serum concentrations, but adding cimetidine to existing theophylline regimen may enhance theophylline pharmacologic/ adverse effects; other available H2RAs do not significantly interact with theophylline and may be appropriate alternatives for cimetidine major (CP)
cimetidine warfarin combined use may result in increased INR and moderate to severe bleeding in some patients as cimetidine stereoselectively inhibits hepatic metabolism of warfarin R-isomer adjunctive use possible if proper monitoring and/or dosage adjustments are made;  order in which therapy is initiated is important - adding warfarin to existing cimetidine drug regimen can be safe as warfarin dosage titrated to acceptable monitoring parameter (e.g., INR), but adding cimetidine to existing warfarin regimen may enhance warfarin-induced hypoprothrombinemic response;  other H2RAs do not significantly interact with warfarin - may be appropriate alternatives for cimetidine major (CP)
H2RAs atazanavir (Reyataz®) concurrent use may cause reduced atazanavir efficacy and increased resistance, as increased gastric pH with H2RAs causes decreased atazanavir solubility/ absorption/plasma levels administer atazanavir either with and/or at least 10 hours after H2RA dose and monitor for decreased efficacy/increased resistance major (CP)
H2RAs select azole antifungals (itraconazole (Sporanox®), ketoconazole, posaconazole (Noxafil®) combined use may result in reduced azole antifungal  bioavailability,  decreased maximum azole antifungal serum levels, and attenuated azole antifungal pharmacologic effects, as H2RAs increase gastric pH and azole antifungal oral absorption is dependent on acidic environment posaconazole manufacturer recommends avoiding the posaconazole-cimetidine drug combination unless benefits outweigh risks; if H2RA-azole antifungal combination necessary, monitor patients carefully for reduced antifungal activity major (CP)
H2RAs drugs pH- dependent for solubility (e.g., dasatinib- Sprycel®; erlotinib – Tarceva®) adjunctive administration for extended duration may result in reduced exposure and serum levels in select medications dependent on acidic gastric pH for solubility and absorption combined use not recommended; alternative acid suppressives (e.g., antacids) should be administered 2 hours before or 2 hours after pH-dependent medication for optimal efficacy major (CP)
H2RAs delavirdine (Rescriptor®) combined use for extended treatment duration may result in reduced delavirdine absorption, decreased delavirdine serum levels, and attenuated delavirdine efficacy as delavirdine is dependent on an acidic gastric pH for absorption; separating drug doses may not improve delavirdine absorption as H2RAs affect gastric pH for prolonged time concomitant use not recommended; antacids may be alternative acid suppressive therapy, with  antacid and delavirdine doses separated by at least one hour major (CP)

Legend:

  • *CP = Clinical Pharmacology
  • H2RAs = histamine (H2) receptor antagonists
  • INR = International Normalized Ratio

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: June 20, 2023).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2023. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed June 20, 2023.
  3. Cimetidine film coated oral tablets package insert. Mylan Pharmaceuticals, Inc., July 2019.
  4. Cimetidine hydrochloride oral solution package insert. Pharmaceutical Associates, Inc., June 2022.
  5. Famotidine film coated oral tablets package insert. Camber Pharmaceuticals, Inc., November 2021.
  6. Famotidine powder for oral suspension package insert. Northstar Rx, LLC., June 2021.
  7. Zantac 360°® (famotidine) film coated oral tablets package insert. Chattem, Inc., May 2022.
  8. Pepcid AC® Maximum Strength (famotidine) film coated oral tablets package insert. Johnson & Johnson Consumer, Inc., April 2023.
  9. Nizatidine oral capsule package insert. Glenmark Pharmaceuticals, Inc., December 2018.
  10. Nizatidine oral solution package isnert. Amneal Pharmaceuticals, LLC., December 2022.
  11. United States Food and Drug Administration. FDA News Release: FDA requests removal of all ranitidine products (Zantac) from the market. (April 1, 2021). Available at: https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market. Accessed June 20, 2023.
  12. Famotidine (Zantac 360°®) oral tablets. Sanofi Pharmaceuticals. Available at: https://www.zantacotc.com/en-us/heartburn-medicine/maximum-strength/. Accessed June 20, 2023.
  13. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol. 2017;112:212-38.  
  14. Duexis® (ibuprofen/ famotidine) oral tablet package insert. Horizon Therapeutics USA, Inc., June 2021.