P&T News: June 1994, Volume 14, Number 12

Histamine2 Receptor Antagonists- Revisited

Julie A. Peroutka, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Robert W. Summers, M.D., Professor, Gastroenterology Division, Department of Internal Medicine

There are currently four H2RAs available in the United States: cimetidine (Tagamet® and generic tablets), ranitidine (Zantac®), famotidine (Pepcid®), and nizatidine (Axid®).

The H2RAs have been compared to each other in relation to their efficacy, side effect profile, and potential to cause significant drug interactions since their introduction to the market p lace. Because of the huge profits associated with the H2RAs, each pharmaceutical manufacturer has attempted to influence pr4scribing by informing prescribers of the benefits of its product over the others. However, as often occurs when similar products are compared, the smaller the differences, the larger the volume of published information.(3) The plethora of published information has emphasized the subtle differences between the H2RAs beyond their clinical importance.(1) Further clouding the picture is the lack of comparative trials among the agents. After careful review of the literature, it becomes apparent that there are no clinically significant differences among the H2RAs, and in all respects the similarities of these agents far outweigh any differences.

The Pharmacy and Therapeutics Subcommittee has concluded that cimetidine and ranitidine are equivalent for general use and cimetidine has been designated for primary use. Ranitidine is available for use in select patients in the following situations:

1. Potential for a significant drug interaction exists (e.g., concomitant drug therapy involving warfarin, theophylline, phenytoin, lidocaine, or procainamide). 2. Known or suspected adverse reactions to cimetidine. These include significant central nervous system toxicity, endocrine-related side effects, and hematologic adverse effects. 3. Documented cases of therapeutic failures with cimetidine.

Prescribers who write for ranitidine when none of the above conditions are met will be asked to consider ordering cimetidine. If the prescriber still desires that the patient receive ranitidine, it will be dispensed and the reason for use will be documented as part of the Drug Use Evaluation process.

In addition, at times the manufacturers attempt to influence prescribing by touting the advantages of their product over another; this can unfortunately cause the promotion of a product to become misleading. In January 1993, the Food and Drug Administration (FDA) charged Glaxo with having undertaken a repetitive course of conduct to disseminate misleading information about ranitidine (Zantac®) in advertising and promotions. The FDA letter cites that Glaxo used drug interaction data to suggest superiority over other H2RAs in order to falsely suggest that Zantac has fewer interactions, and grossly exaggerated the clinical significance of drug interactions with Tagamet. In addition, the FDA charged Glaxo with utilizing promotional materials which suggest the use of Zantac in critically ill patients in a manner which would imply an indication for treatment and/or prevention of stress ulceration. The FDA also objected to the assertion that Zantac® is unsurpassed as a treatment for endoscopically diagnosed erosive esophagitis, citing that there is no evidence that Glaxo has conducted comparative trials with other anti-ulcer therapies.(4)

The remainder of this review will focus on the two agents stocked at UIHC, cimetidine and ranitidine.

Pharmacokinetics/Pharmacodynamic Properties
Both cimetidine and ranitidine suppress the secretion of basal and nocturnal gastric acid, as well as acid secretion stimulated by insulin or meals. Although ranitidine is a more potent inhibitor on gastric acid secretion, all H2RAs are equal in their ability to suppress acid secretion when appropriate doses are administered.(3,5) Because the oral formulations of inhibit gastric acid secretion to the same extent as parenteral therapy, parenteral therapy should be reserved for only those instances in which oral therapy is not tolerated.(5) When parenteral therapy is indicated, continuous H2RA infusion therapy has been shown to be more effective in maintaining gastric pH greater than/equal to 4 than standard intermittent bolus dosing.(3,6) The pharmacokinetic and pharmacodynamic properties are outlined in Table 1(3,7,8) and Table 2(3,7-10) respectively.

Table 1. Pharmacokinetic Properties of H2Rasa
	Cimetidine	Ranitidine
Absorption Oral bioavailability (%) Antacids reduce the bioavailability; however, this is clinically insignificant Food does not reduce the bioavailability Onset of action is within 1 to 3 hours	60 to 70	41 to 57
Distribution (L/kg) Both agents cross into the cerebrospinal fluid in equipotent amounts	0.8 to 1.2	1.2 to 1.9
Protein Binding (%)	13 to 25	15
Elimination Total Clearance (L/hr) Elimination half-life (hr) Urinary recovery of unchanged drug at 24 hours after dose Oral (%) Parenteral (5) In patients with compromised renal function, the H2RAs exhibit a prolonged half-life and decreased total body clearance; therefore, dosage reductions for both agents are necessary.	33 to 39 2.0     50 80	34 to 43 2.5     30 70
____________ a Derived from references 3, 7, 8.

Indications for Use
Cimetidine and ranitidine are equally effective in the treatment of duodenal ulcer, gastric ulcer, hypersecretory diseases and gastroesophageal reflux disease when equipotent doses are used.3,9,10 FDA-labeled indications, dosages, regimens, and costs for cimetidine and ranitidine are outlined in Table 3.(7,8) There is a lack of direct comparative trials of cimetidine versus ranitidine; however, several individual studies have concluded that cimetidine and ranitidine are both effective in the treatment of duodenal ulcers at appropriate doses.10-12 Both drugs have comparable healing rates of 84% to 97% at 8 weeks.(12-14) Clinical studies have indicated that suppression of nocturnal acid is the most important factor in duodenal healing; therefore, each manufacturer has concluded that a once-daily at bedtime dosage regimen may be the most appropriate.(9) For the prevention of duodenal ulcer relapse, a review of the comparative studies cimetidine and ranitidine reveals no statistically significant differences for up to 12 months.(3,15,16) Rates of recurrence were 16% to 23%.(15) Factors shown to have adverse effects on the relapse rate are smoking, duration and severity of illness, genetic traits, and presence of H. pylori .(15-17) Healing rates for gastric ulcers range from 78% to 90%.(18-20) No clinically important differences in efficacy have been seen between cimetidine and ranitidine.

The symptoms of gastroesophageal reflux disease are improved in 75% to 80% of patients receiving either cimetidine or ranitidine. Endoscopic improvement is seen in up to 67%; however, complete recovery is only reported in 33% of patients.(3,21,22) Treatment of reflux esophagitis typically requires higher doses and a longer duration (approximately 12 weeks).(7,8)

Hypersecretory conditions are more resistant to treatment. Higher success rates may be achieved at very high dosages (e.g., 10 grams of cimetidine per day); however, the administration of these large doses increases the incidence of side effects and makes patient compliance less than optimal.(3,23-25)

Both cimetidine and ranitidine are effective in raising gastric pH above 4 to 5 and may prove useful in protecting against stress ulceration; however, the data are conflicting in this regard. Continuous infusions have been superior to intermittent bolus administration.(3,6,26,27) Three important concerns have been raised with regard to stress ulcer prophylaxis:

1) how is effectiveness measured (i.e., if a patient does not develop an ulceration, what is the likelihood he/she would have without the prophylaxis?)

2) have improvements in intensive-care therapy negated the need for prophylaxis; and

3) dose an increase in the pH to a level of 4 to 5 place the patient at an increased risk for gram-negative respiratory infections by allowing increased colonization of gut flora in the upper respiratory tract.(3)

Currently, only cimetidine has an FDA-labeled indication for prevention of upper gastrointestinal bleeding in critically ill patients.(7)

Other common indications for H2RAs, which are not FDA-labeled, include prophylaxis for anesthesia-associated pneumonitis and gastritis induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Both cimetidine and ranitidine reduce gastric acid secretion and increase gastric pH when administered on the evening prior to elective surgery.(3,28,29) In emergent situations, both agents are less effective.(3) The healing or prevention of ulcers induced by NSAIDs has had mixed results. In one double-blind, placebo-controlled trial, cimetidine healed mucosal injury in 65% of patients; however, there also was a rather large placebo effect at 27%.(3,30) A second study found no difference in healing or in prevention of NSAID-induced ulcers versus placebo.(3,31)

Adverse Reactions
More than 60 million patients have received H2RA therapy with minimal side effects. When reviewing the number and frequency of side effects associated with cimetidine and ranitidine, care must be taken. Because of FDA's adverse-reaction reporting system is voluntary, commonly expected adverse reactions tend to be underreported for newer agents in the same therapeutic class.(3) Likewise, in published case reports, the number of reactions reported for each drug is affected by previously published reports of similar reactions, the duration of drug availability, the relative market shares of the drugs, and the unintentional biases of clinicians.(32) These factors, combined with frequent lack of data on the demographics of the patient populations exposed to an H2RA,often render case report data useless in determining the relative incidence of adverse reactions.(32)

One of the most commonly reported side effects associated with all H2RAs has been central nervous system (CNS)-related effects. These include headache, lethargy, confusion, hallucination, depression, and insomnia.(1) The assumption has emerged that cimetidine is more likely to cause these reactions than are other H2RAs. Critical review of the literature, however, reveals a lack of data to support this assumption. A comprehensive literature review for incidence of CNS-related side effects was undertaken in 1991 to determine the propensity of each H2RA to cause CNS reactions.(32) In this review, the authors conclude that in case reports cimetidine has been associated with CNS reactions more often than the other H2RAs; however, they believe that inherent biases have resulted in underreporting of CNS related reactions of the other H2RAs. The authors also conclude that comparative trials of H2RAs have failed to detect differences in the incidence of CNS reactions. In fact, all H2RAs may cause CNS-related side effects. Recently, there have been several case reports published in the literature associating ranitidine with similar CNS side effects,(33,34) and at the UIHC there have recently been several reports of ranitidine-associated mental status changes. Many of these case reports appear to be dose related.

Table 2. Pharmacodynamic Properties of H2RAsa
	Inhibition of Gastric Acid Secretion
	Percent (%)	Duration (Hours)
Cimetidine
300 mg oral 800 mg oral 300 mg parenteral	80 85 to 94 80	4 to 5 4 to 5 4 to 5
Ranitidine
150 mg oral 300 mg oral 50 mg parenteral	50 85 to 94 50	12 12 6 to 8
Continuous intravenous infusion of either agent may produce consistent and sustained control of gastric acidity as measured by a pH greater than or equal to 4.
__________ a Derived from references 3, 7-10.

Proposed risk factors for H2RA-associated CNS reactions include advanced age, use of concomitant psychotropic medications, high-dose H2RA therapy, pre-existing psychiatric disorder, and the presence of liver or kidney disease.(1,7,8,32,35) The incidence of CNS reactions tends to be higher in hospitalized patients, and intensive care unit patients have yielded even higher rates of reactions.(32) It is difficult to perform a causality assessment for incidence of H2RA-induced CNS effects. For example, elderly patients are know to exhibit CNS disturbances more commonly during stress or illness; concomitant liver or renal dysfunction may predispose patients to mental status changes; CNS reactions appear to be idiosyncratic and not only dose related; there may be an increased incidence of mental status changes in hospitalized patients or they may be more closely monitored for adverse reactions; and studies have shown that 15% to 50% of control patients in the intensive care units shown CNS manifestations.(32) Because of the H2RAs are renally eliminated, dosage reductions are necessary for patients exhibiting renal dysfunction. This alone may prevent the occurrence of CNS adverse effects. If an adverse reaction is suspected, it typically resolves within 3 to 4 days of discontinuation of the drug. In general, adverse CNS effects in patients receiving H2RAs are rare and reversible, and in the outpatient setting CNS reactions do not differ from patients not receiving H2RAs.(1,32) Post marketing surveillance studies have demonstrated an incidence of adverse effects of less than 2%.(1) There is no real evidence that the incidence of CNS effects is more frequent with any one of the H2RAs.(32,35,36)

Gastrointestinal reactions are the most commonly reported adverse effect associated with H2RA therapy, occurring in 1% to 1.5% of patients. Constipation or diarrhea, dry mouth, nausea, and abdominal discomfort have been noted. Pancreatitis has been associated with cimetidine therapy, but is most likely a hypersensitivity reactions.(1,3,7,8) Gynecomastia has been a well documented endocrinologic side effect associated with cimetidine therapy; however, this has been after very high doses (greater than 2400 mg/day) and long-term therapy.(3,35,36) Cimetidine has also been associated with male impotence; however, this has been following high dose therapy as well.(3,35,36) Use of all H2RAs has been associated in rare cases with hematologic abnormalities. Most of the case reports have been associated with cimetidine; however, they cannot be conclusively linked to cimetidine use.(3,35) The reported incidence of cimetidine-induced neutropenia is approximately 1 per 100,000 patients.(7) In most of these instances, the patients had serious concomitant illnesses making it difficult to establish a direct cause-and effect relationship. Hepatic enzyme elevations up to twice the normal limit have been reportedly associated with H2RA therapy. In the majority of patients, these levels return to normal with continued therapy. It is more commonly reported in patients receiving high doses of an H2RA for more than five days of therapy, but has also been reported following normal daily dosages of oral ranitidine.(1,3,7,8,36) Cardiovascular reactions, including bradycardia, hypotension, and cardiac arrhythmias, have been occasionally reported following rapid intravenous infusion of H2RAs, probably due to histamine receptors which are present within the myocardium and peripheral blood vessels.(3,7,8,35,36) Intermittent infusions should be administered over a period of at least 20 minutes.

Drug Interactions
It has been long established that all H2RAs inhibit cytochrome P-450 hepatic metabolism - although ranitidine usually causes this effect to a lesser extent than cimetidine. Because of this inhibition, drugs dependent upon the P-450 systems for elimination may attain toxic levels. Most of the reported drug interactions can be prevented by proper drug serum monitoring and reducing the dosage of the potentially interacting drug.

Cimetidine reduces theophylline clearance; however, theophylline toxicity has been reported rarely.(1,35,37) Although it was originally believed that ranitidine, which binds much less strongly to the cytochrome P-450 enzyme system, would not interact with theophylline, subsequent case reports and clinical evaluations have lined ranitidine to theophylline toxicity.(1,35,37,38) Both cimetidine and ranitidine may interact with warfarin. Cimetidine, however, interacts with the less active stereoisomer of warfarin, leaving the more active stereoisomer unaffected.(1,35,38) It has been recommended that prothrombin time be monitored for seven to ten days or until stabilization occurs in patients receiving either cimetidine or ranitidine and warfarin concomitantly.(35) There have been conflicting case reports on the pharmacokinetic interaction between phenytoin and cimetidine or ranitidine. Due to the complex pharmacokinetics of phenytoin, any change in metabolism may lead to dramatic changes in serum concentrations(35,38) Benzodiazepines which extensively undergo hepatic metabolism may be more slowly inactivated during H2RA therapy.(38) These reactions have been more common with concomitant higher dose cimetidine therapy.

There have been many published reports regarding the pharmacokinetic interactions of cimetidine; however, these reports often do not provide data on the pharmacodynamic and clinical consequences of the alterations in drug disposition. Also, many of the published reports have utilized the previously recommended dosage for cimetidine of 1200 mg per day, while currently 800 mg per day is the recommended dosage.(35,37,38) As with adverse effects, lower daily dosages of cimetidine have been associated with fewer drug interactions. For drugs with narrow therapeutic-to-toxic rations, such as theophylline, warfarin, phenytoin, procainamide, and lidocaine, serum drug concentrations should be routinely monitored(37,38) The clinicians should be aware of the potential for a drug interaction with all H2RAs and monitor serum drug concentrations accordingly.

Cost
Cimetidine and ranitidine are available as oral tablets, oral suspensions, and in a parenteral dosage from. In May 1994, cimetidine tablets became available as a generic product and are now available from multiple vendors. The price for cimetidine has dropped 50% since its conversion to generic availability and this decline is expected to continue. Based on current UIHC acquisition costs, the cost differential between ranitidine and cimetidine is every greater for patients who must pay for their prescriptions out-of-pocket. For a patient on duodenal ulcer maintenance therapy, the difference in drug acquisition cost is approximately $16 per month or $195 per year.

Additionally, a significant cost savings could be realized by switching a patient from parenteral to oral therapy if the patient is receiving other oral medications or is receiving oral feedings (Table 3). Indications for parenteral therapy include persistent nausea, critical illness preventing reliable absorption of oral dosage forms, orders for the patient to receive nothing by mouth, and the prevention of acid aspiration pneumonitis.(5)

Summary
The Pharmacy and Therapeutics Subcommittee at the UIHC has declared cimetidine and ranitidine as therapeutically equivalent and designated cimetidine as the preferred H2RA. Ranitidine therapy may be an alternative for those cases in which cimetidine is clearly contraindicated or for those instances in which an adverse effect has occurred with cimetidine. It is also recommended that patients receiving parenteral H2RA therapy be converted to oral therapy whenever possible.

Table 3: FDA-labled Indications, Dosage, and Regimens
Indication	Cimetidine Dose/Regimen[a]	Rantidine Dose/Regimen[a]
Active Duodenal Ulcer (Most patients heal within 4 weeks)	800 mg po hs 400 mg po BID 300 mg po QID	300 mg po hs 150 mg po BID
Maintenance Therapy for Duodenal Ulcer	400 mg po hs	150 mg po hs
Active Benign Gastric Ulcer (Most patients heal within 6 weeks)	800 mg po hs 300 mg po QID	150 mg po BID
Erosive Gastroesophageal Reflux Disease	800 mg po BID 400 mg po QID	150 mg po BID
Pathologic Hypersecretory Conditions	300 mg po QID	150 mg po BID
Prevention of Upper Gastrointestinal Bleeding	50 mg IV per hr	----b
Dosage Guidelines for Parenteral Therapy[c] Continuous Therapy Intermittent Therapy	37.5 mg/hr 300 mg q8hr 300 mg q6hr	6.25 mg/hr 50 mg q8hr 50 mg q6hr
Dosage Guidelines for Oral Suspension	300 mg po QID 400 mg po BID	150 mg po BID
Dosage Guidelines for Oral Suspension	300 mg po QID 400 mg po BID	150 mg po BID
Dosage Adjustments for Renal Impairment CrCld 10 to 50 ml/min oral parenteral CrCld less than 10 ml/min oral parenteral	300 mg q12hr 300 mg q12hr 300 mg q24hr 300 mg q24hr	150 mg q24hr 50 mg q12 to 24hr 150 mg q24h4 50 mg 124hr
[a] Dose for adults with normal renal function [b] Not FDA-labled for this indication [c] For inpatients unable to tolerate oral therapy [d] Creatinine clearance

References

1. J Clin Gastroenterol 1990;12(Suppl 2):S48-53.

2. Business Week 1994; May 9:30-1.

3. Arch Intern Med 1990;150:745-51.

4. F-D-C Reports 1993;February 8:21-3.

5. Ann Pharmacother 1993;27:232-7.

6. Gastroenterology 1985;89-532-7.

7. SmithKline Beecham Pharmaceuticals. Tagamet package insert. Philadelphia, PA: 1993 February.

8. Glaxo Pharmaceuticals, Inc. Zantac package insert. Research Triangle Park, NC: 1993 March.

9. Gut 1988;29:81-8.

10. Clin Pharmacol Ther 1986;40:665-72.

11. Gut 1987:28:294-9.

12. Gut 1986;27:1091-5.

13. Scand J Gastroenterol 1982;22(Supple 134):21-8.

14. Br Med J 1984;298:1418-20.

15. J Clin Gastroenterol 1987;9:644-50.

16. Gut 1986;27:1213-8.

17. Postgrad Med J 1986;62:347-51.

18. Scand J Gastroenterol 1984;19:119-21.

19. Ann Intern Med 1985;102:573-6.

20. S Afr Med J 1982;61:115-8.

21. Gastroenterology 1978;74:821-4.

22. Digestion 1984;29:119-23.

23. Am J Surg 1983;146:116-23.

24. Scand J Gastroenterol 1981;16(Suppl 69):119-21.

25. Ann Intern Med 1983;98:59-75.

26. Gastroenterology 1985;88(5 pt2):1359. Abstract.

27.Dig Dis Scie 1986;31(Suppl):4S. Abstract.

28. J Trauma 1981;21:49-51.

29. Anaesthesia 1982;37:22-5.

30. Gastroenterology 1988;95:289-94.

31. Arch Intern Med 1987;147:1778-801.

32. Ann Intern Med 1991;114:1027-34.

33. Arch Intern Med 1992;152:2325-9.

34. Psychosomatics 1990;31:98-100.

35. Am J Med 1987;83(Suppl 6A):58-67.

36. Gastroenterology 1990;11:3-14.

37. J Clin Gastroenterol 1990;12(Suppl 2):S64-8.

38. Drug Safety 1992;7:245-67.

As of July 1, 1994, oral vancomycin may be used only in patients with C. difficile colitis who meet the following criteria:

1. The patient has repeatedly relapsed following metronidazole therapy;
2. There is potential for an alcohol-disulfiram like drug interaction with the use of metronidazole;
3. The patient has severe hepatic dysfunction; or
4. The patient has an allergy to metronidazole.

As with other protocol drugs, a Protocol Drug Order Form must be completed by the physician in order for the patient to receive the drug. The automatic 24-hour expiration will apply to oral vancomycin as it does to other protocol drugs if a completed Protocol Drug Order Form is not submitted to Pharmacy. The Oral Vancomycin Protocol Order Form number is 640.

---

Pharmacy and Therapeutics Subcommittee Actions

Drugs Added to Stock

ALTRETAMINE Capsules:50 mg. Altretamine (hexamethylmelamine, Hexalen® - U.S. Bioscience) is an antineoplastic agent indicated for the palliative treatment of persistent or recurrent ovarian cancer.

CEFPODOXIME Tablets: 100 mg and 200 mg. Oral Suspension: 100 mg per 5 ml. Cefpodoxime (Vantin® - Upjohn) is an oral third-generation cephalosporin indicated for the treatment of infections such as community-acquired pneumonia, skin and skin structure, otitis media, and gonorrhea, caused by susceptible organisms. The usual adult dose of cefpodoxime is 200 mg every 12 hours; the usual pediatric dose is 5 mg per kg every 12 hours. NOTE: Due to cefpodoxime's broader spectrum of activity, it will replace cefixine.

CISAPRIDE Tablets: 20 mg. Cisapride (Propulsid® - Janssen) is indicated for the management of gastroesphogeal reflux disease.

CYCLOSPORINE Capsules: 50 mg. Cyclosporine (Sandimmune® - Sandoz) is indicated for the prevention or organ rejection.

MISOPROSTOL Tablets: 100 mcg. Misoprostol (Cytotec® - Searle) is indicated for the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcers.

NIFEDIPINE Extended-Release Tablets: 30 mg, 60 mg, 90 mg. Nifedipine extended-release tablets (Adalat® CC - Miles) are indicated for the treatment of hypertension. They are much less costly than the other sustained-release nifedipine product (Procardia®XL).

ROCURONIUM Injection: 10 mg per ml, 5 ml via. Rocuronium (Zemuron® - Organon) is a nondepolarizing skeletal muscle relaxant indicated as an adjunct to anesthesia to facilitate intubation or mechanical ventilation.

Drugs Deleted from Stock

CEFIXIME TABLETS AND ORAL SUSPENSION Cefpodoxime (Vantin® - Upjohn) will replace cefixime as the formulary oral, third-generation cephalosporin.

DILTIAZEM SUSTAINED - RELEASE (Cardizem SR®, dosed twice daily) CAPSULES Diltiazem controlled-dissolution (Cardizem CD®, dosed once daily) capsules are available.

ERGOTAMINE TARTRATE (Ergomar®) SUBLINGUAL TABLETS Discontinued by the manufacturer. Cafergot® tablets and suppositories are available.

GALLAMINE (Flaxedil®) INJECTION Succinylcholine, pancuronium, rocuronium, atracurium, and vecuronium injections are available.

HYDROMORPHONE 3 mg TABLETS Discontinued by the manufacturer. Hydromorphone 2 mg and 4 mg tablets are available.

IOTHALAMATE MEGLUMINE 9(Cysto-Conray® II) 17.2% INJECTION Other radiocontrast agents are available.

METOCURINE (Metubine®) INJECTION Succinylcholine, pancuronium, rocuronium, atracurium, and vecuronium injections are available.

METYRAPONE (Metopirone®) TABLETS Discontinued by the manufacturer.

SALICYLIC ACID 6% (Keralyt®) TOPICAL GEL Discontinued by the manufacturer.

Next Page | Previous Page | Title Page