About The Drug Ranitidine Bismuth Citrate aka Tritec
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Find Ranitidine Bismuth Citrate side effects, uses, warnings, interactions and indications. Ranitidine Bismuth Citrate is also known as Tritec.
Ranitidine Bismuth Citrate
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About Ranitidine Bismuth Citrate aka Tritec |
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What's The Definition Of The Medical Condition Ranitidine Bismuth Citrate?Clinical Pharmacology 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.
Drug Description DESCRIPTION TRITEC (ranitidine bismuth citrate) Tablets contain a complex of ranitidine, trivalent bismuth, and citrate.
Chemically, ranitidine bismuth citrate is N-2-[5-Dimethylaminomethyl-2-furanylmethylthio]ethyl-N'- methyl-2-nitroethenediamine 2-hydroxy-1,2,3- propanetricarboxylate, bismuth (III).
Analysis shows that ranitidine bismuth citrate is substoichiometric in ranitidine and citrate.
Ranitidine bismuth citrate is a white to off-white amorphous powder.
The approximate molecular formula is [C13H22N4O3S] 0.84 Bi[ C6H5O7] 0.94, and the approximate molecular weight is 651.
It is readily soluble in water.
Each TRITEC (ranitidine bismuth citrate) Tablet for oral administration contains 400 mg of ranitidine bismuth citrate, equivalent to approximately 162 mg of ranitidine (base), 128 mg of trivalent bismuth, and 110 mg of citrate.
Each aqueous film-coated tablet also contains the inactive ingredients FD&C Blue No.
2 Aluminum Lake, magnesium stearate, methylhydroxypropylcellulose, microcrystalline cellulose, Povidone K30, sodium carbonate (anhydrous), titanium dioxide, and triacetin.
Indications & Dosage INDICATIONS TRITEC (ranitidine bismuth citrate) in combination with clarithromycin is indicated for the treatment of patients with an active duodenal ulcer associated with H.
pylori infection.
Most patients not eradicated of H.
pylori following TRITEC (ranitidine bismuth citrate) plus clarithromycin treatment will have clarithromycin resistant H.
pylori isolates.
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 TRITEC (ranitidine bismuth citrate) plus clarithromycin or with regimens which include clarithromycin as the sole antimicrobial agent.
The eradication of H.
pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence.
(See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY, CLINICAL STUDIES.) NOTE: TRITEC (ranitidine bismuth citrate) should not be prescribed alone for the treatment of active duodenal ulcer.
DOSAGE AND ADMINISTRATION Eradication of H.
pylori Infection in Patients With an Active Duodenal Ulcer: The recommended dosage of TRITEC (ranitidine bismuth citrate) is 400 mg b.i.d.
for 4 weeks (28 days) in conjunction with clarithromycin 500 mg b.i.d.
t.i.d.
for the first 2 weeks (14 days).
TRITEC (ranitidine bismuth citrate) and clarithromycin can be taken with or without food.
Days 1-14 Days 15-28 TRITEC (ranitidine bismuth citrate) 400 mg b.i.d plus clarithromycin 500 mg b.i.d.
TRITEC (ranitidine bismuth citrate) 400 mg b.i.d.
An alternative dosage regimen of TRITEC (ranitidine bismuth citrate) 400 mg b.i.d.
for 4 weeks (28 days) in conjunction with clarithromycin 500 mg t.i.d.
for the first 2 weeks (14 days) has been shown to be equally effective.
Dosage Adjustment in Elderly Patients: No dosage adjustment is necessary in elderly patients.
(See PRECAUTIONS: Geriatric Use and clarithromycin package insert.) Dosage Adjustment in Renally Impaired Patients: Because the principal route of excretion is renal, care should be exercised when administering this combination therapy to renally impaired patients.
This combination therapy is not recommended in patients with creatinine clearance less than 25 mL/min.
HOW SUPPLIED TRITEC (ranitidine bismuth citrate) Tablets 400 mg are blue, aqueous film-coated tablets in an elongated octagonal shape engraved with "TRITEC (ranitidine bismuth citrate) " on one side and a stomach-shaped logo on the other.
They are available in bottles of 100 (NDC 0173-0488-01) tablets and unit dose packs of 100 tablets (NDC 0173-0488-02).
Store between 2° and 30° C (36° and 86° F) in a dry place.
Protect from light.
Replace cap securely after each opening.
For information on clarithromycin, refer to package insert.
CAUTION: Federal US law prohibits dispensing without prescription.
REFERENCE 1.
National Committee for Clinical Laboratory Standards, Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL, January 11-13, 1998.
Medication Guide PATIENT INFORMATION See WARNINGS, CONTRAINDICATIONS, and PRECAUTIONS.
Overdosage & Contraindications 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.
Side Effects & Drug Interactions SIDE EFFECTS Placebo-controlled trials in patients with active duodenal ulcer in the United States included 1,428 patients given TRITEC (ranitidine bismuth citrate) alone or in combination with clarithromycin, 120 patients given clarithromycin alone, and 469 patients given placebo.
Incidence of Drug-Related Adverse Reactions in Placebo-Controlled Clinical Trials: The following table lists drug- related adverse reactions that occurred at a frequency of ³1% among patients treated with TRITEC (ranitidine bismuth citrate) who participated in US placebo-controlled trials.
Table 3: Drug- Related Adverse Reactions During Treatment* Adverse Reaction Placebo (n=469) TRITEC (ranitidine bismuth citrate) Tablets 800 mg (n=903) Clarithromycin 1500 mg (n=120) TRITEC (ranitidine bismuth citrate) Tablets 800 mg + Clarithromycin 1,000 mg (n=196) TRITEC (ranitidine bismuth citrate) Tablets 800 mg + .Clarithromycin 1,500 mg (n=329) Gastrointestinal Diarrhea 1% 2% 5% 4% 58% Nausea & Vomiting 1%
Warnings & Precautions WARNINGS The physician should consult the package insert for clarithromycin for information concerning warnings and precautions associated with this drug.
PRECAUTIONS General The bismuth derived from TRITEC (ranitidine bismuth citrate) may cause a temporary and harmless darkening of the tongue and/or stool.
Stool darkening should not be confused with melena (blood in the stool).
TRITEC (ranitidine bismuth citrate) in combination with clarithromycin should not be used in patients with a history of acute porphyria.
This combination therapy is not recommended in patients with creatinine clearance less than 25 mL/min.
(See DOSAGE AND ADMINISTRATION.) Laboratory Tests No specific clinical laboratory tests are recommended for monitoring patients prior to and/or after treatment with TRITEC (ranitidine bismuth citrate) plus clarithromycin.
False-positive tests for urine protein with MULTISTIX® may occur during ranitidine therapy, and therefore, testing with sulfosalicylic acid is recommended.
Drug Interactions Coadministration of TRITEC (ranitidine bismuth citrate) with clarithromycin resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%).
Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant.
Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC (ranitidine bismuth citrate) .
These effects are clinically insignificant.
For information on drug interactions associated with ranitidine, refer to the ZANTAC ® package insert.
Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month oral carcinogenicity study in B6C3F1 mice, ranitidine bismuth citrate at daily doses up to 1,000 mg/kg was not carcinogenic.
For a 50-kg person of average height (1.46 m2 body surface area), this dose represents five times the recommended clinical dose of 400 mg b.i.d.
(592 mg/m2 ).
In a 24-month oral carcinogenicity study in Sprague-Dawley rats, ranitidine bismuth citrate at daily doses up to 500 mg/kg, five times the recommended human dose based on body surface area, was not carcinogenic.
Ranitidine bismuth citrate was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/ TK+/-) forward mutation test, the ex vivorat gastric mucosal unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test.
It was positive in vitro human lymphocyte chromosomal aberration assay.
Ranitidine bismuth citrate at oral doses up to 1,800 mg/ kg per day (18 times the recommended human dose based on an average body surface area of 1.46 m2 ) was found to have no effect on impairment of fertility and reproductive performance of male and female rats.
Pregnancy Teratogenic Effects: Pregnancy Category C: TRITEC (ranitidine bismuth citrate) used in combination with clarithromycin carries a Pregnancy Category C because clarithromycin carries Pregnancy Category C.
(See clarithromycin package insert Pregnancy subsection and WARNINGS section.) Nonteratogenic Effects of Ranitidine Bismuth Citrate: Teratology studies have been performed in pregnant rats at oral doses up to 1,800 mg/kg per day (18 times the recommended human dose based body surface area) and pregnant rabbits at oral doses up to 300 mg/kg per day (6 times the recommended human dose based on body surface area) and have revealed no evidence of harm to the fetus due to ranitidine bismuth citrate.
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Five patients became pregnant while they were receiving ranitidine bismuth citrate alone at varied doses.
Three of these patients had normal pregnancies and newborns,; one had a voluntary abortion, and one delivered a baby with postaxial polydactyly.
This Caucasian woman had a history of unexplained spontaneous abortions.
She had received ranitidine bismuth citrate for 7 days prior to conception and for 20 days after conception.
The investigator considered the event unrelated to TRITEC (ranitidine bismuth citrate) .
Postaxial polydactyly is about 10 times more frequent in blacks than in Caucasians.
In American whites, incidence figures vary from 1:3,300 to 1:630 live births, and in American blacks figures vary from 1:300 to 1:100 live births.
(March of Dimes 1996.) Nursing Mothers It is not known whether ranitidine bismuth citrate is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when ranitidine bismuth citrate is administered to a nursing woman.
It is known that both ranitidine and bismuth are excreted in rat milk.
Pediatric Use Safety and effectiveness of ranitidine bismuth citrate plus clarithromycin in pediatric patients have not been established.
Geriatric Use Ulcer healing and relapse rates in elderly patients (³65 years of age) were no different from those in younger age-groups.
The incidence rates for adverse events and laboratory abnormalities also were not different from those seen in other age-groups.
In a pharmacokinetic study, serum levels of ranitidine were increased in elderly patients, but serum bismuth levels were equivalent to those seen in the overall population.
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