Criteria for Outpatient Use Guidelines
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Histamine H2-Receptor Antagonists
[Developed, April 2006]
Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].
1.* Dosage
Histamine H2-receptor antagonists (H2RAs) are FDA-approved for use in gastric ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD), esophagitis, and hypersecretory conditions.
Adults
The maximum adult daily doses for H2RAs when prescribed as acute and maintenance therapy for
gastric ulcer, duodenal ulcer, esophagitis, GERD, and hypersecretory conditions are summarized in
Table 1. Dosage regimens exceeding these maximum recommended values will be reviewed.
| DRUG | MAXIMUM DOSE |
|---|---|
| cimetidine (Tagamet®, generics) | acute therapy: duodenal ulcer, GERD: 1600 mg/day gastric ulcer: 1200 mg/day hypersecretory conditions: 2400 mg/day maintenance dose: |
| famotidine (Pepcid®, generics) | acute therapy: duodenal ulcer, gastric ulcer, GERD: 40 mg/day esophagitis: 80 mg/day hypersecretory conditions: 640 mg/day maintenance dose: |
| nizatidine (Axid®, generics) | acute therapy: duodenal ulcer, gastric ulcer, GERD: 300 mg/day maintenance dose: |
| ranitidine (Zantac®, generics) | acute therapy: duodenal ulcer, gastric ulcer, GERD, hypersecretory conditions: 300 mg/day esophagitis: 600 mg/day maintenance dose: |
Current American College of Gastroenterology guidelines state that H2RAs are used infrequently in Helicobacter pylori management. Ranitidine 150 mg twice daily is listed as a treatment option only for those patients who require bismuth quadruple therapy, such as penicillin-allergic patients.
Pediatrics
Maximum recommended pediatric H2RA daily doses for acute and maintenance therapy are summarized in Table 2. Dosages exceeding these recommendations will be reviewed.
| DRUG | MAXIMUM DOSE |
|---|---|
| cimetidine (Tagamet®, generics) | not recommended in children less than 16 years of age unless benefits outweigh risks; doses utilized in limited clinical experience have been 20-40 mg/kg/day |
| famotidine (Pepcid®, generics) | acute therapy: < 3 months of age: GERD: 0.5 mg//kg/day 3 months of age to < 1 year of age: GERD: 1 mg/kg/day 1 year of age to 16 years of age: duodenal ulcer, gastric ulcer: 0.5 mg/kg/day up to 40 mg/day at bedtime GERD: 2 mg/kg/day up to 80 mg/day maintenance dose: |
| nizatidine (Axid®, generics) | acute therapy: > 12 years of age: GERD, esophagitis: 300 mg/day |
| ranitidine (Zantac®, generics) | acute therapy: >1 month of age to 16 years of age: duodenal ulcer, gastric ulcer: 8 mg/kg/day up to 300 mg/day esophagitis, GERD: 10 mg/kg/day maintenance dose: |
2. Duration of Therapy
Adult and Pediatric Patients
Clinical studies document a maximum treatment duration of 56 days (eight weeks) for anti-ulcer therapy in the treatment of acute duodenal ulcer and gastric ulcer. The Texas Vendor Drug Program limits reimbursement for H2RAs and related drugs to 62 days per calendar year at the maximum daily acute dose listed for duodenal ulcer and gastric ulcer in Tables 1 and 2. This treatment duration has been allotted to allow a 31 day supply per prescription. The prescribing physician may continue acute dosage regimens for periods longer than 62 days per calendar year for patients with conditions such as hypersecretory disease states, esophagitis, or GERD. A diagnosis must be written on the prescription for acute treatment regimens exceeding the recommended treatment duration of 62 days per calendar year. In pediatric patients, a maximum GERD acute treatment duration of 8 weeks is recommended. H2RA treatment regimens at acute dosage levels lasting longer than four months will be reviewed.
When used as a component of bismuth quadruple therapy for H. pylori eradication in adults,
ranitidine therapy should be continued for 10 to 14 days.
Maintenance therapy, at recommended daily maintenance doses (Tables 1 and 2), may be continued indefinitely based on patient need.
3.* Duplicative Therapy
The combination of two or more H2RAs is not supported by the current literature. Therefore, concurrent use of this combination will be reviewed as there is no clinical evidence to suggest that these adjunctive therapies improve outcome.
4.* Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.
The following drug-drug interactions are considered clinically relevant for H2RAs. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:
a. Warfarin and Cimetidine [clinical significance level – moderate (DrugReax); 1 (DIF); 2 (Hansten & Horn)]
Interactions with warfarin are clinically significant as this compound possesses a narrow therapeutic index. The combined use of warfarin and cimetidine results in prolongation of prothrombin time and increased bleeding risk. Studies have documented that cimetidine inhibits warfarin hepatic metabolism. The cimetidine-warfarin interaction appears to be dose-related and is associated with considerable interpatient variability.
Even though clinically significant drug interactions have been observed between warfarin and cimetidine, concurrent use is not an absolute contraindication. Adjunctive use could be considered appropriate if proper monitoring and/or dosage adjustments are made. Additionally, the order in which therapy is initiated is important. It is reasonable and clinically safe to add a warfarin prescription to an existing cimetidine drug regimen as the warfarin dosage can be titrated to an acceptable monitoring parameter (e.g., INR). However, if a patient is maintained on warfarin therapy, the addition of cimetidine therapy may enhance the warfarin-induced hypoprothrombinemic response. Other available H2RAs do not significantly interact with warfarin and may be appropriate alternatives for cimetidine. If concurrent warfarin and cimetidine therapy is required, monitor anticoagulant activity and adjust warfarin doses as indicated.
b. Theophyllines and Cimetidine [clinical significance level – major (DrugReax); 2 (DIF); 3 (Hansten & Horn)]
Interactions with theophylline are clinically significant as this compound possesses a narrow therapeutic index. When administered concomitantly, cimetidine impairs theophylline metabolism with resultant increases in theophylline serum levels and/or theophylline toxicity. Studies have shown that cimetidine interferes with the hepatic microsomal enzyme system which subsequently delays theophylline metabolism and elimination.
Concurrent theophylline and cimetidine use could be considered appropriate if proper monitoring and/or dosage adjustments are made. Additionally, the order in which therapy is initiated is important. It is reasonable and clinically safe to add a prescription for theophylline to an existing cimetidine drug regimen since the theophylline dosage can be titrated to an acceptable plasma concentration. However, if a patient is maintained on theophylline therapy, the addition of cimetidine therapy may enhance theophylline pharmacologic and/or adverse effects. Other available H2RAs do not significantly interact with theophylline and may be appropriate alternatives for cimetidine. If theophyllines and cimetidine are administered concomitantly, monitor theophylline serum concentrations and adjust theophylline doses as indicated.
c. Select Azole Antifungal Agents (itraconazole (Sporanox®), ketoconazole (Nizoral®), posaconazole (Noxafil®) [clinical significance level – posaconazole: major, itraconazole, ketoconazole: moderate (DrugReax); 2 (DIF); 3 (Hansten & Horn)]
Concurrent administration of select azole antifungals (i.e., itraconazole, ketoconazole, and posaconazole) with H2RAs may result in reduced azole antifungal bioavailability, a decrease in maximum azole antifungal serum concentrations, and attenuated azole antifungal pharmacologic effects. Azole antifungal oral absorption is dependent on an acidic environment; the addition of an H2RA increases gastric pH and subsequently limits azole antifungal absorption. The manufacturer of posaconazole recommends avoiding the posaconazole-cimetidine drug combination unless benefits outweigh risks. If it is necessary to prescribe itraconazole, ketoconazole, or posaconazole concomitantly with an H2RA, monitor patients carefully for reduced antifungal activity.
d. Cimetidine and Dofetilide (Tikosyn®) [clinical significance level - 1 (DIF); contraindicated (DrugReax); 3 (Hansten & Horn]
Combined administration of cimetidine and dofetilide may result in increased dofetilide serum levels and enhanced pharmacologic effects, including torsades de pointes. Dofetilide is eliminated through renal and hepatic mechanisms. Cimetidine inhibits dofetilide renal and nonrenal clearance through interference with active tubular secretion and moderate inhibition of CYP3A4, one of the enzyme pathways responsible for dofetilide metabolism. These effects have resulted in significant increases in dofetilide plasma concentrations. The manufacturer of dofetilide states that concurrent administration of dofetilide and cimetidine is contraindicated. Alternative medications that have no effect on dofetilide pharmacokinetics, such as omeprazole and ranitidine, should be considered as alternatives to cimetidine. The combined use of cimetidine and dofetilide is not recommended and will be reviewed.
e. Dasatinib (Sprycel®) [clinical significance level – major (DrugReax); 2 (DIF)]
Dasatinib administered concomitantly with an H2RA for an extended duration may result in reduced dasatinib exposure and serum concentrations as dasatinib is dependent on an acidic gastric pH for solubility and absorption. Adjunctive administration of dasatinib with H2RAs is not recommended by the manufacturer. Antacids are an alternative for dasatinib-treated patients requiring acid suppressive therapy, and should be administered 2 hours before or 2 hours after the dasatinib dose for optimal efficacy.
f. Delavirdine (Rescriptor®) [clinical significance level – major (DrugReax); 3 (Hansten & Horn)]
Concurrent administration of H2RAs with delavirdine for an extended treatment duration may result in reduced delavirdine absorption, decreased delavirdine serum concentrations, 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 a prolonged time period. Antacids may be an alternative for delavirdine-treated patients requiring acid suppressive therapy. Antacid and delavirdine doses should be separated by at least one hour, however, as clinical studies have shown impaired delavirdine absorption and reduced delavirdine serum concentrations when administered adjunctively with antacids. Concomitant administration of H2RAs and delavirdine is not recommended.
g. Erlotinib (Tarceva®) [clinical significance level – moderate (DrugReax)]
Erlotinib administered concomitantly with an H2RA for an extended duration may result in reduced erlotinib exposure and serum concentrations as erlotinib is dependent on an acidic gastric pH for solubility and absorption. Antacids are an alternative for erlotinib-treated patients requiring acid suppressive therapy, although studies are not available evaluating the effects of antacids on erlotinib pharmacokinetics. The manufacturer of erlotinib recommends that antacids be administered 2 hours before or 2 hours after the erlotinib dose for optimal efficacy.
References
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- Arakawa T, Higuchi K, Fukada T, et al. H2-receptor antagonist-refractory ulcer: its pathophysiology and treatment. J Clin Gastroenterol. 1991;13 (Suppl 1): S129-S133.
- Hansten PD, Horn JR, eds. Drug interactions analysis and management. St. Louis, MO: Wolters Kluwer Health, Inc.; 2009.
- Drug Interaction Facts. Facts and Comparisons 4.0 [database online]. St. Louis, MO: Wolters Kluwer Health, Inc.; 2009. Available at: http://online.factsandcomparisons.com. Accessed October 26th, 2009.
- Posaconazole (Noxafil®) Package Insert. Schering-Plough, February 2009.
- Dasatinib (Sprycel®) Package Insert. Bristol-Myers Squibb, May 2009.
- Gales MA, Steadman BK. Combination sucralfate and histamine-antagonist therapy. Ann Pharmacother. 1994;28:597-9.
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- Delavirdine (Rescriptor®) Package Insert. Pfizer, Inc., May 2008.
- Erlotinib (Tarceva®) Package Insert. OSI Pharmaceuticals, Inc., April 2009.
- Chey WD, Wong BCY, and the Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.
Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.