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OVERDOSE

There has been limited experience with overdosage. Adverse events related to overdosage with ranitidine are usually reversible, nonspecific, and non- life threatening and result in no adverse sequelae. Although not seen in clinical trials with TRITEC (ranitidine bismuth citrate) , bismuth intoxication from prolonged overdosage or deliberate self- poisoning can result in neurotoxicity and nephrotoxicity and possibly other symptoms seen with the use of soluble bismuth compounds. In the event of an overdose or suspected bismuth toxicity, measures should be employed to remove unabsorbed material from the gastrointestinal tract, and symptom monitoring and other supportive therapy should be employed, if indicated.

Single oral doses of ranitidine bismuth citrate at 3,000 and 4,000 mg/ kg in male and female mice, respectively (approximately 15 to 20 times the recommended human dose based on body surface area), and at 2,000 and 3,000 mg/ kg in male and female rats, respectively, (approximately 20 to 30 times the recommended human dose based on body surface area) were lethal. Symptoms of acute toxicity were piloerection, tremors, hunched posture, rapid respiration, and decreased activity.

CONTRAINDICATIONS

TRITEC (ranitidine bismuth citrate) is contraindicated in patients known to have hypersensitivity to ranitidine bismuth citrate or any of its ingredients.

For information on clarithromycin contraindications, see clarithromycin package insert.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Following ingestion, ranitidine bismuth citrate dissociates in intragastric fluid, giving rise to ranitidine and soluble and insoluble forms of bismuth.

Absorption: Following a single oral 400-mg dose of TRITEC (ranitidine bismuth citrate) to healthy volunteers, mean (± SD) peak ranitidine plasma concentration of 455 (± 145.3) ng/mL occurred at 0.5 to 5 hours. The rate and extent of absorption of ranitidine derived from TRITEC (ranitidine bismuth citrate) increased proportionally with increasing doses up to 1,600 mg. Ranitidine plasma concentrations showed no evidence of accumulation during a 28-day dosing period.

Oral absorption of bismuth is variable. A mean (± SD) peak bismuth plasma concentration of 3.3 (± 2.0) ng/mL occurs at 15 to 60 minutes after a 400-mg dose. The rate and extent of absorption of bismuth from TRITEC (ranitidine bismuth citrate) do not increase with increasing doses up to 800 mg, but increase more than proportionally with increasing doses above 800 mg. The rate of absorption of bismuth derived from an 800-mg dose of TRITEC (ranitidine bismuth citrate) is decreased by 50%, and the extent of absorption is decreased by 25% when taken 30 minutes after a meal as compared to 30 minutes before a meal. The absorption of bismuth from an 800-mg dose of TRITEC (ranitidine bismuth citrate) increased when gastric pH exceeded 6. The increased pH resulted from the administration of an 800-mg dose of TRITEC (ranitidine bismuth citrate) given 3 hours previously. Mucosal penetration and absorption of bismuth from TRITEC (ranitidine bismuth citrate) are not affected by the degree of gastritis, the presence of Helicobacter pylori, or an active ulcer. Small amounts of bismuth accumulate in plasma during twice-daily dosing with TRITEC (ranitidine bismuth citrate) . In a 28-day study at 800 mg b.i.d. (twice the recommended daily dose), peak bismuth concentrations did not exceed 20 ng/mL at any time in any patient, with a median peak concentration of 6.3 ng/mL on day 28. Median peak and trough concentrations on day 28 were 105% and 68% of predicted steady-state peak and trough concentrations. In a study at 400 mg b.i.d. for 12 weeks (three times the recommended duration), trough bismuth concentrations did not exceed predicted accumulation in any patient, with a median trough concentration of 2.8 ng/mL at week 12.

Distribution: The volume of distribution for ranitidine is 1.7 L/kg. Serum protein binding of ranitidine averages 15%. Bismuth is 98% bound to human plasma proteins, primarily albumin.

Metabolism: Ranitidine is metabolized to the N-oxide, S-oxide, and N-desmethyl metabolites, accounting for approximately 4%, 1%, and 1% of the dose, respectively. It is not known whether bismuth undergoes any biotransformation.

Excretion: The elimination half-life of ranitidine derived from TRITEC (ranitidine bismuth citrate) is 2.8 to 3.1 hours. The principal route of elimination for ranitidine is renal, accounting for 30% of the dose. Renal clearance averages 530 mL/min, indicating active tubular secretion. Total clearance is 760 mL/min. Elimination of bismuth is polyexponential, with a terminal elimination half-life of 11 to 28 days. Bismuth has an average renal clearance of 30 to 60 mL/min, indicating net tubular secretion. Less than 1% of bismuth derived from TRITEC (ranitidine bismuth citrate) is recovered in urine after oral administration. Up to 28% of bismuth was recovered in the feces during a 6-day postdose period. Bismuth also undergoes minor excretion in the bile.

Special Populations

Geriatric: Clinically insignificant increases in plasma concentrations of ranitidine were observed in elderly patients. Bismuth concentrations may be elevated in elderly patients as a result of decreased renal elimination.

Pediatric: No information on the pharmacokinetics of ranitidine or bismuth derived from TRITEC (ranitidine bismuth citrate) was obtained in this population.

Gender: There is no evidence of a difference in the pharmacokinetics of ranitidine between males and females when adjusted for body weight. There is no difference in the extent of absorption of bismuth when adjusted for body weight; significant differences are observed for peak bismuth plasma concentrations in healthy females.

Race: There is no evidence of any racial differences in the pharmacokinetics of bismuth based on trough concentrations observed in clinical studies.

Renal Insufficiency: The renal clearances of ranitidine and bismuth are correlated with renal function (i. e., creatinine clearance), while nonrenal elimination of ranitidine is unaltered by renal impairment. Thus, ranitidine and bismuth concentrations may be elevated in renally impaired patients as a result of decreased renal elimination.

Hepatic Insufficiency: Elimination of either ranitidine or bismuth by the hepatic route is relatively unimportant. Therefore, the pharmacokinetics of ranitidine or bismuth derived from TRITEC (ranitidine bismuth citrate) were not studied in patients with hepatic insufficiency owing to the minimal impact of this condition.

Pharmacodynamics

Antisecretory Activity

1. Effects on Acid Secretion:

Ranitidine, derived from TRITEC (ranitidine bismuth citrate) , inhibits both daytime and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food, betazole, and pentagastrin.

2. Effects on Other Gastrointestinal Secretions:

Plasma Pepsinogen I and II: Ranitidine derived from TRITEC (ranitidine bismuth citrate) does not alter plasma pepsinogen I and II concentrations or pepsin activity.

Serum Gastrin: Ranitidine derived from TRITEC (ranitidine bismuth citrate) has little or no effect on fasting or postprandial serum gastrin.

There is no information about the gastric mucosal concentrations of ranitidine, bismuth, clarithromycin, or hydroxy-clarithromycin after administration of TRITEC (ranitidine bismuth citrate) and clarithromycin.

For information on the clinical pharmacology of clarithromycin, refer to the

CLINICAL PHARMACOLOGY

section of the clarithromycin package insert.

Microbiology

Some H. pylori isolates obtained from patients treated with clarithromycin plus acid- suppressive regimens demonstrate an increase in clarithromycin MICs over time, indicating decreasing susceptibility and increasing resistance Ranitidine bismuth citrate plus clarithromycin has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Helicobacter Helicobacter pylori

Pre-treatment Resistance Clarithromycin pre-treatment resistance was 12.6% (44/348) in the ranitidine bismuth citrate plus clarithromycin b.i.d. versus t.i.d. clinical study (H2BA3001) conducted in 1996.

Table 1: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes*

Clarithromycin Pre-treatment Results	Clarithromycin Post-treatment Results
	H. pylori negative-eradicated	H. pylori positive-not eradicated Post-treatment susceptibility results
		S †	I†	R†	No MIC
Ranitidine Bismuth Citrate 400 mg B.I.D plus Clarithromycin 500 mg T.I.D. (H2BA3001)
Susceptible† 124	98	4		14	8
Intermediate† 3	2				1
Resistant† 17	1			15	1
Ranitidine Bismuth Citrate 400 mg B.I.D plus Clarithromycin 500 mg T.I.D. (H2BA3001)
Susceptible† 125	106	1	1	12	5
Intermediate† 2	2
Resistant† 20	1			19

* Includes only patients with pre-treatment clarithromycin susceptibility test results

† Susceptible (S) MIC£0.25 ìg/ mL, Intermediate (l) MIC 0.5-1.0 ìg/mL, Resistant (R) MIC³2 ìg/mL

Most patients not eradicated of H. pylori following ranitidine bismuth citrate plus clarithromycin treatment will have clarithromycin resistant H. pylori. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should not be treated with ranitidine bismuth citrate plus clarithromycin or with regimens which include clarithromycin as the sole antimicrobial agent.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. 1 One to three microliters of an inoculum equivalent to a No.2 McFarland standard (1x107-1x108 CFU/mL for H. pylori are inoculated directly onto freshly prepared antimicrobial containing Mueller- Hinton agar plates with 5% aged defibrinated sheep blood (³2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for campylobacters. After 3 days of incubation, the MIC's are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin MIC values should be interpreted according to the following criteria:

Clarithromycin MIC (g/mL) *	Interpretation
£0.25	Susceptible (S)
0.5-1.0	Intermediate (I)
³2.0	Resistant (R)

* These are tentative breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin powder should provide the following MIC values:

Microorganism	Antimicrobial Agent	MIC (g/mL)*
H.pylori A.C. 43504	Clarithromycin	0.015-0.12

 

* These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.

CLINICAL STUDIES

Eradication of H. pylori Associated With Active Duodenal Ulcer: In a US double-blind, randomized, multicenter, dose comparison trial TRITEC (ranitidine bismuth citrate) 400 mg b.i.d. for 4 weeks plus clarithromycin 500 mg b. i. d. for the first 2 weeks was found to have an equivalent H pylori eradication rate (based on culture and histology) when compared to TRITEC (ranitidine bismuth citrate) 400 mg b. i. d. for 4 weeks plus clarithromycin 500 mg t.i.d. for the first 2 weeks. The intent-to-treat and per protocol H. pylori eradication rates are shown in Table 2.

Table 2: H. pylori Eradication Rates in Study H2BA-3001

Analysis	TRITEC (ranitidine bismuth citrate) 400 mg + Clarithromycin 500 mg B.I.D..	TRITEC (ranitidine bismuth citrate) 400 mg + Clarithromycin 500 mg T.I.D.	95% CI Rate Difference
ITT	65%(122/188) [58%-72%]	63% (122/195) [55%-69%]	(-8%-12%)
Per Protocol	72% (117/162) [65%- 79%]	71% (120/170) [63%- 77%]	(-9%-12%)

H. pylori was defined as no positive test at 4 weeks following the end of treatment. Patients must have had two tests performed and these must have been negative to be considered eradicated of H.pylori. The following patients were excluded from the proof protocol analysis: patients not infected with H. pylori prestudy, dropouts, patients with major protocol violations, patients with missing H. pylori tests. Patients excluded from the intent-to-treat analysis included those not infected with H. pylori prestudy and those with missing H. pylori tests prestudy. Patients were assessed for

H. pylori eradication (4 weeks following treatment) regardless of their healing status (at the end of treatment).

The relationship between H. pylori eradication and duodenal ulcer recurrence was assessed in a combined analysis of six US randomized, double-blind, multicenter, placebo-controlled trials using TRITEC (ranitidine bismuth citrate) with or without antibiotics. The results from approximately 650 US patients showed that the risk of ulcer recurrence within 6 months of completing treatment was two times less likely in patients whose H. pylori infection was eradicated compared to patients in whom H. pylori infection was not eradicated.

PATIENT INFORMATION

See WARNINGS, CONTRAINDICATIONS, and PRECAUTIONS.