Comparison of famotidine with cimetidine and ranitidine

The pharmacodynamic, therapeutic, and toxicologic properties of famotidine are evaluated and compared with those of cimetidine and ranitidine. Famotidine, an H2-receptor antagonist with a thiazole nucleus, is approximately 7.5 times more potent than ranitidine and 20 times more potent than cimetidine on an equimolar basis. Therapeutic trials indicate that famotidine 20 mg b.i.d. or 40 mg at bedtime is as effective as standard doses of cimetidine and ranitidine for healing duodenal ulcers. A dose of 40 mg at bedtime appears to heal benign gastric ulcers. A single nocturnal dose of 20 mg is effective in preventing duodenal ulcer relapse. Further studies are required that compare the efficacy of famotidine with cimetidine and ranitidine in the treatment of gastric ulcers and in the prevention of recurrent duodenal ulcers. The overall incidence of adverse effects observed with famotidine appears to be similar to that reported for cimetidine and ranitidine. Like ranitidine, famotidine does not have antiandrogenic effects or substantially inhibit the hepatic metabolism of drugs. Because of its increased antisecretory potency and lack of antiandrogenic effects at higher doses, famotidine may be the H2-receptor antagonist of choice in treating Zollinger-Ellison syndrome. Additional clinical experience, as well as cost and safety factors, will determine the place of famotidine in treating and preventing acid-peptic disorders.     

Ranitidine, cimetidine, famotidine have no effect on post-prandial absorption of ethanol 0.8 g/kg taken after an evening meal

Forty-seven healthy male subjects were studied twice using a randomized, placebo-controlled design. Each subject took an 8-day course of two of the following four regimens; 300 mg ranitidine, 800 mg cimetidine, 40 mg famotidine or placebo (identical either to 300 mg ranitidine or 800 mg cimetidine). The systemic bioavailability of ethanol (integrated 6-h plasma ethanol concentration, peak plasma ethanol concentration, and the time to peak plasma ethanol concentration) was measured after the oral ingestion of 0.8 g of ethanol per kg body weight, given one hour after an evening meal on Day 8 of each regimen. There was no significant difference of integrated 6-h plasma ethanol concentration, peak ethanol concentration, or time to reach peak ethanol concentration after dosing with either ranitidine, cimetidine or famotidine or placebo.     

Short report: the effect of ranitidine on the post-prandial absorption of a low dose of alcohol

Twenty healthy male subjects were studied twice using a double-blind, randomized placebo controlled, cross-over study design. Alcohol absorption (integrated 2-h plasma alcohol concentration, peak plasma alcohol concentration, and time to reach peak concentration) was measured after 8 daily doses of either placebo or 300 mg ranitidine. They were given alcohol, 0.15 g/kg of body weight by month after an evening meal. Compared with placebo, there was a trend towards higher integrated 2-h plasma alcohol concentrations (3.17 and 3.89 mg. h/dL, respectively, P = 0.07), and a statistically significant increase in mean peak plasma alcohol concentration after dosing with ranitidine (4.92 and 6.47 mg/dL, respectively, P = 0.05).     

Impact of food intake on the antisecretory effect of low-dose ranitidine and famotidine

BACKGROUND: Over-the-counter status has recently been approved for low-dose H2-antagonists in several countries. Insufficient information is currently available on the effect of food in low-dose H2-antagonist therapy. AIM: Compare the antisecretory efficacy of low-dose ranitidine and famotidine in fasting and non-fasting volunteers. METHODS: Twenty volunteers were randomized into a double-blind, placebo-controlled, multiple-step crossover study comparing the antisecretory efficacy of 75 mg ranitidine, 10 mg famotidine and placebo over 12 h using intragastric pH-metry. Two standard meals were given after 4 h and 8 h of medication. Fifteen volunteers also participated in a second study comparing the antisecretory effect of both drugs, both with and without meals. RESULTS: In non-fasting subjects, the percentage of time with pH > 4 was similarly elevated for both drugs compared with placebo over the first 8 h: ranitidine 39.3%, famotidine 29.5%, placebo 9.5% (P < 0. 001); but not for the last 4 h after the second meal (P > 0.05). Comparing the first 4-h period with the second, the percentage of pH > 4 was significantly reduced for both drugs in the second period in the subjects given food at the end of the initial 4-h period (ranitidine 56.9% vs. 26.6%, P = 0.005; famotidine 46.6% vs. 13.3%, P < 0.001). It remained more or less constant, however, for the second 4-h period in fasting subjects (ranitidine 41% vs. 28.1%, P = 0.46; famotidine 52.7% vs. 52.2%, P = 0.12). CONCLUSION: In non-fasting volunteers both low-dose H2-antagonists had comparable antisecretory effects and were superior to placebo over the first 8 h of therapy. Both drugs achieved a slightly higher antisecretory effect without food intake compared to with food intake.     

Implementing therapeutic interchange of intravenous famotidine for cimetidine and ranitidine

The steps taken to implement a therapeutic interchange program for i.v. histamine H2-receptor antagonists and to determine the potential cost savings are described. A literature review conducted by pharmacists at a 273-bed nonteaching community hospital showed that i.v. famotidine was as safe and effective as i.v. cimetidine or ranitidine and that it was feasible to add famotidine to total parenteral nutrition (TPN) solutions. Because of famotidine's cost advantage, it was proposed that i.v. famotidine be used in place of specific dosage regimens of i.v. ranitidine or cimetidine and in TPN solutions ordered for patients receiving concurrent H2-antagonist therapy. The approval of the hospital attorney and hospital gastroenterologists was secured, and a formal proposal was submitted. The pharmacy department distributed a memorandum describing the advantages of famotidine, conducted inservice education sessions, and sought the compliance of physicians by placing reminders on order forms and patient charts and by contacting physicians directly. The program was implemented in May 1989. During the first three months, only one physician insisted that patients receive i.v. ranitidine rather than famotidine. It was projected that the interchange of i.v. famotidine for cimetidine or ranitidine would result in a total savings of $37,565 during the first year due to reductions in the cost of drugs, supplies, and nursing labor. The acceptance of a therapeutic interchange program for H2 antagonists was excellent, and the projected savings are substantial.     

The effects of cimetidine, ranitidine and famotidine on rat hepatic microsomal cytochrome P-450 activities

It has been questioned whether the interaction of H2-antagonists with cytochrome P-450 that is observed in vitro is also relevant for the in vivo situation. Until now the possibility that cytochrome P-450 may function with different modes of action has been neglected in this respect. We studied the effect of cimetidine, ranitidine and famotidine on the monoxygenase, the oxidase and the peroxidase action of cytochrome P-450. Biotransformation catalyzed by the monoxygenase and oxidase action of cytochrome P-450 was affected by cimetidine (probably via its ligand interaction with cytochrome P-450), whereas metabolism by the peroxidase mode of action of cytochrome P-450 was hardly influenced. Ranitidine and famotidine (both pharmacodynamically more potent than cimetidine) only slightly affected cytochrome P-450 activities.     

The effect of an antacid and food on the absorption of cimetidine and ranitidine

The effect of varying doses of a liquid antacid preparation containing magnesium hydroxide, aluminum hydroxide and simethicone on the absorption of the H2-receptor antagonists, cimetidine and ranitidine, was determined in 2 groups of 11 volunteers; one group fasted and one group fed a standardized breakfast. The antacid alone caused a significant decrease in the AUC of cimetidine (24%). Similarly, concomitant antacid caused a 59% decrease in the AUC of ranitidine. There were no effects on any of the other pharmacokinetic parameters examined. The absorption of both drugs was similar in fasted and fed volunteers, but in the fed volunteers the antacid did not produce the decrease in AUC seen in the fasted volunteers. These data suggest that H2-receptor antagonists should not be taken at the same time as antacids.     

Early and late effects of low-dose famotidine, ranitidine or placebo on pentagastrin-stimulated gastric acid secretion in man

Background: There are no published comparative studies on the effect of low-dose H₂-antagonists on pentagastrin-stimulated gastric acid secretion. Methods: Twenty-four healthy subjects were dosed with either famotidine 10 mg, ranitidine 75 mg or placebo in a balanced three-period cross-over design. The subjects were studied in groups of 12, simultaneously, under identical controlled environmental conditions. Gastric juice was aspirated in 15-min aliquots during sub-maximal (0.6 μg . h/kg) intravenous pentagastrin stimulation in the third and fourth hours (early period) and the eighth and ninth hours (late period) after oral dosing. The hydrogen ion (H⁺) content of gastric juice was measured ex vivo, by titrating to pH 7 known volumes of gastric aspirate against 0.1 m sodium hydroxide, using a versatile microprocessor-controlled auto-titration unit. Gastric acid output during the period of interest was calculated by adding the hydrogen ion content of 15-min aliquots collected during that period. The geometric mean of the cumulative pentagastrin-stimulated gastric acid output during the early and late periods was determined for the subjects dosed with either famotidine, ranitidine or placebo. Comparisons were performed by ANOVA. Results: During the early period (2–4 h post-dose), when the subjects were given placebo, mean gastric acid output was 46.6 mmol, decreasing by 76% to 11.3 mmol (P<0.001) when treated with famotidine and by 76% to 11.1 mmol (P<0.001) when treated with ranitidine. During the late period (7–9 h post-dose), when the subjects were dosed with placebo, mean gastric acid output was 41.2 mmol, decreasing by 38% to 25.7 mmol (P<0.001) when treated with famotidine and by 27% to 30.0 mmol (P=0.007) when treated with ranitidine. The difference between the inhibitory effects of famotidine and ranitidine on gastric acid output were non-significant during either period. Conclusions: Low-dose famotidine and ranitidine, intended for over-the-counter use, inhibit stimulated gastric acid secretion profoundly in the third and fourth hours after an oral dose. Modest effects are still detectable up to 9 h after dosing.     

The effect of ranitidine and cimetidine on imipramine disposition

Summary The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t_1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 µg·h·ml^–1) or ranitidine (1.14 µg·h·ml^–1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.     

Effect of bupropion on cimetidine and ranitidine absorption in rats

Cimetidine and ranitidine absorption were studied in rats, alone or in combination with concurrent but separate bupropion oral administration. Blood samples were collected before and 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.5, and 6.0 h after dosing. In ranitidine-treated rats, an extra blood sample at 8 h was collected. Assays of cimetidine and ranitidine were carried out using a HPLC method. Mean cimetidine plasma concentrations on concurrent bupropion administration at 0.25 and 0.5 h were approximately 2 and 1.5 times compared to the control. Similarly, mean ranitidine plasma concentrations with bupropion combination at 0.25 and 0.5 h were significantly different and approximately 2 and 3 times higher. Time of maximum concentration for cimetidine and ranitidine on combination were reduced to almost half of the control value. However, only the time of maximum concentration for cimetidine showed statistically significant difference. No significant differences were observed between AUCs, maximum concentrations, and half-lives of cimetidine and ranitidine compared to their respective controls. The results suggest that concurrent bupropion administration may affect the rate but not the extent of absorption of cimetidine and ranitidine.     

The effect of ranitidine and cimetidine on single-dose diltiazem pharmacokinetics

The effects of two histamine 2-receptor antagonists, cimetidine and ranitidine, on the single-dose pharmacokinetics of diltiazem were studied in 6 healthy subjects. A single 60-mg oral dose of diltiazem was administered alone, after ranitidine 150 mg twice daily for 7 days, and after cimetidine 300 mg 4 times a day for 7 days. Plasma samples were obtained over a 10-hour period and analyzed for the parent drug and one of its metabolites, deacetyldiltiazem (DAD). Concurrent cimetidine produced a significant (p less than 0.05) increase in diltiazem levels at most time points, in peak concentration and area under the concentration-time curve. These variables were also increased during concurrent ranitidine administration but did not reach statistical significance. The DAD plasma concentration was below measurable levels during the control phase but increased during concurrent cimetidine and ranitidine administration. Caution should be exercised when diltiazem is administered concurrently with cimetidine and possibly, ranitidine.     

Effect of domperidone on cimetidine and ranitidine absorption in rabbits

Cimetidine and ranitidine absorption were studied after oral administration to rabbits, alone or in combination with oral and intravenous domperidone. Blood samples were collected before and 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.5, and 6.0 h after cimetidine and ranitidine administration. Assays of cimetidine and ranitidine in plasma samples were carried out using HPLC method. Domperidone overall significantly reduced the area under the plasma concentration-time curve (AUC) by approximately 30 per cent for both drugs. However, domperidone had little effect on the maximum plasma concentration (Cmax), the time taken to reach the maximum plasma concentration (Tmax), and the elimination half-life (t1/2) of cimetidine and ranitidine. The results suggest that domperidone affects the extent but not the rate of cimetidine and ranitidine absorption by enhancing gastric emptying.     

Effects of three H2-receptor antagonists (cimetidine,famotidine, ranitidine) on serum gastrin level

We investigated the pattern of changes in serum gastrin level produced by three H2-receptor antagonists (H2RA) in patients with gastric and duodenal ulcers between 1990 and 1999. The subjects were 51 patients (cimetidine: 18 patients; famotidine: 16 patients; ranitidine: 17 patients). The gastrin test (in the fasting and meal-stimulated states) was conducted during drug administration and on the fourth day after drug cessation. After cessation of the drug therapy, the fasting serum gastrin level was significantly lower than that during the drug therapy with the three H2RAs. Gastrin level in the fasting test was significantly higher during famotidine therapy than during cimetidine therapy (p = 0.0123). In the meal-stimulated gastrin test, the AUC of gastrin during treatment with H2RA treatment was significantly higher with famotidine than with cimetidine (p = 0.0024). The results indicate different patterns of change in the serum gastrin level in the fasting and meal-stimulated test according to the H2RA administered. Gastrin level was highest in patients administered famotidine and lowest among those administered cimetidine. The pattern of gastrin change in patients administered ranitidine was intermediate between famotidine and cimetidine.     

Effects of cimetidine or ranitidine on the pharmacokinetics of flurbiprofen

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the nonsteroidal anti-inflammatory agent flurbiprofen was studied. Nine healthy volunteers participated in the study. The subjects were divided into three groups, and each group alternated therapy with each of the following treatments: flurbiprofen 200 mg (two 100-mg tablets), flurbiprofen 200 mg plus ranitidine 150 mg two times daily for seven days before and for two days after receiving flurbiprofen, and flurbiprofen 200 mg plus cimetidine 300 mg four times a day for seven days before and for two days after receiving flurbiprofen. Blood samples were collected at time zero and at various intervals during a 48-hour period. Serum flurbiprofen concentrations were determined by high-performance liquid chromatography. No significant differences in elimination rate constant, peak concentration, time to peak concentration, volume of distribution, or elimination half-life were noted among treatments. The difference in area under the curve (AUC) in subjects treated with flurbiprofen alone and in those treated with flurbiprofen plus cimetidine was significant. Two subjects experienced gastric upset; one case was apparently caused by cimetidine, and the other was likely caused by flurbiprofen. Although a significant increase in AUC was observed in subjects receiving flurbiprofen plus cimetidine, the interaction is probably not clinically important.     

Effects of famotidine at the mouse neuromuscular junction compared with those of cimetidine and ranitidine

The effects of some histamine H2-receptor antagonists on the cholinergic system have been evaluated at the mouse end-plate. Previous data revealed interactions at both pre- and postsynaptic sites for cimetidine and ranitidine. The present work shows the effects of the same two drugs, and of famotidine, on some parameters related to the neuromuscular transmission. Ranitidine potentiates the amplitude of the spontaneously occurring miniature end-plate potentials. Famotidine reduces the same parameter. A common effect achieved with higher concentrations of the three drugs is the reduction of the quantal content. The kinetic parameters of the quantal conductance change is lengthened, in a different manner, by all the assayed drugs too. These results, besides strengthening the hypothesis of an inhibitory action of ranitidine on acetylcholinesterase, indicate a collateral inhibitory effect at presynaptic levels of cimetidine, ranitidine and famotidine.     

Control of intragastric acidity with over-the-counter doses of ranitidine or famotidine

BACKGROUND: Histamine H2-receptor antagonists are available over the counter for the treatment of heartburn. AIM: To compare the effects of low doses of ranitidine and famotidine on intragastric acidity in a three-way crossover study. METHODS: Healthy subjects (12 male, 12 female) were dosed on three occasions with single oral doses of placebo, ranitidine, 75 mg, and famotidine, 10 mg, 1 h after lunch. The pH of gastric aspirates was then measured for 20 h. Subjects ate standard meals and snacks. Analysis of variance was used to determine the statistical significance of differences in acidity (mmol/L) during the day (12.30-22.30 hours) and night (22.30-08.30 hours). RESULTS: Ranitidine and famotidine were superior (P < 0.05) to placebo in decreasing acidity for daytime and night-time intervals. There were no significant differences in mean gastric acidity between ranitidine and famotidine during the daytime (11.37 mmol/L vs. 13.42 mmol/L, respectively) and night-time (23.57 mmol/L vs. 24.74 mmol/L, respectively). Intragastric acidity after ranitidine was significantly lower than that after famotidine in the first 2.5-h period following dosing (4.32 mmol/L vs. 9.28 mmol/L; P < 0.05). CONCLUSIONS: Lunchtime doses of ranitidine and famotidine decreased acidity during day- and night-time periods. The effect of ranitidine was significantly greater for the first 2.5 h after dosing.     

The effect of prophylactic use of famotidine, ranitidine, and sodium citrate in upper abdominal surgery

The effects of famotidine (40 mg), ranitidine (300 mg) and sodium citrate (30 ml) on the gastric pH and volume were tested in 114 patients undergoing upper abdominal surgery. Gastric content was aspirated through a multiorifice tube immediately after intubation, at the end of operation and after a recovery room period of one hour. All three drug regimens significantly increased the mean gastric pH value compared with the control group. Famotidine and ranitidine reduced the volume of gastric content in comparison with sodium citrate and the control group. However, the difference was significant only in the recovery room sample.