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Helidac

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Helidac

CLINICAL PHARMACOLOGY

Pharmacokinetics

Pharmacokinetics for the HELIDAC Therapy components (bismuth subsalicylate chewable tablets, metronidazole tablets, and tetracycline hydrochloride capsules) when coadministered has not been studied. There is no information about the gastric mucosal concentrations of bismuth, metronidazole, and tetracycline after administration of these agents concomitantly or in combination with an acid suppressive agent. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.

Bismuth Subsalicylate

Upon oral administration, bismuth subsalicylate is almost completely hydrolyzed in the gastrointestinal tract to bismuth and salicylic acid. Thus, the pharmacokinetics of bismuth subsalicylate following oral administration can be described by the individual pharmacokinetics of bismuth and salicylic acid.

Bismuth

Less than 1% of bismuth from oral doses of bismuth subsalicylate is absorbed from the gastrointestinal tract into the systemic circulation. Absorbed bismuth is distributed throughout the body. Bismuth is highly bound to plasma proteins ( > 90%). Bismuth has multiple disposition half-lives with an intermediate half-life of 5 to 11 days and a terminal half-life of 21 to 72 days. Elimination of bismuth is primarily through urinary and biliary routes with a renal clearance of 50 ± 18 mL/min. The mean trough blood bismuth concentration after 2 weeks oral administration of 787 mg bismuth subsalicylate (3 chewable tablets) four times daily under fasted condition was 5.1 ± 3.1 ng/mL. In another study, the mean trough blood bismuth concentration after 2 weeks oral administration of 525 mg bismuth subsalicylate (as PEPTO-BISMOL® liquid suspension) four times daily was 5 ng/mL with the highest value being 32 ng/mL.

Salicylic Acid

More than 80% of the salicylic acid is absorbed from oral doses of bismuth subsalicylate chewable tablets. Salicylic acid is about 90% plasma protein bound. The volume of distribution is about 170 mL/kg of body weight. Salicylic acid is extensively metabolized and about 10% is excreted unchanged in the urine. The metabolic clearance of salicylic acid is saturable; accordingly, nonlinear pharmacokinetics is observed at bismuth subsalicylate doses above 525 mg. Salicylic acid metabolic clearance is lower in females than in males. The terminal half-life of salicylic acid upon a single oral dose of 525 mg bismuth subsalicylate is between 2 to 5 hours. After a single oral dose of 525 mg bismuth subsalicylate (2 chewable tablets), the mean peak plasma salicylic acid concentration was 13.1 ± 3.4 μg/mL under fasted condition. The mean steady-state serum total salicylate concentration after 2 weeks oral administration of 525 mg bismuth subsalicylate (as PEPTO-BISMOL liquid suspension) four times daily was 24 μg/mL with the highest value being 70 μg/mL.

Metronidazole

Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between 1 and 2 hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose, with oral administration of 250 mg producing a peak plasma concentration of 6 μg/mL. Studies reveal no significant bioavailability differences between males and females; however because of weight differences, the resulting plasma levels in males are generally lower.

Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole also appears in cerebrospinal fluid, saliva, and human milk in concentrations similar to those found in plasma.

The average elimination half-life in normal volunteers is 8 hours. The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m².

Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. In patients with decreased liver function, plasma clearance of metronidazole is decreased.

Tetracycline Hydrochloride

Tetracycline hydrochloride is absorbed (60%-90%) in the stomach and upper small intestine. The presence of food, milk or cations may significantly decrease the extent of absorption. In the plasma, tetracycline is bound to plasma proteins in varying degrees. It is concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in biologically active form. Tetracycline hydrochloride is distributed into most body tissues and fluids. It is distributed into the bile and undergoes varying degrees of enterohepatic recirculation. Tetracycline hydrochloride tends to localize in tumors, necrotic or ischemic tissue, liver and spleen and form tetracycline-calcium orthophosphate complexes at sites of new bone formation or tooth development. Tetracycline readily crosses the placenta and is excreted in high amounts in breast milk. (See PRECAUTIONS, Nursing Mothers) Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. The relative contribution of systemic versus local antimicrobial activity against H. pylori for agents used in eradication therapy has not been established.

Microbiology

Mechanism of Action

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride are antibacterial agents. Metronidazole is metabolized through reductive pathways into reactive intermediates that have cytotoxic action. Tetracycline hydrochloride interacts with the 30S subunit of the bacterial ribosome and inhibits protein synthesis. The antibacterial action of bismuth salts is not well understood.

Activity In Vitro and In Vivo

Bismuth subsalicylate, metronidazole, and tetracycline administered individually as combination therapy have been shown to be active against most strains of Helicobacter pylori in vitro, and in clinical infections as described in the Clinical Studies and INDICATIONS AND USAGE sections.

Susceptibility Test Methods

In one study, susceptibility testing of Helicobacter pylori isolates was performed for metronidazole using agar dilution methodology1 and minimum inhibitory concentrations (MICs) were determined.

Susceptibility testing of Helicobacter pylori for metronidazole has not been standardized. No interpretive criteria have been established for testing metronidazole against H. pylori. The clinical significance of metronidazole MIC values against H. pylori is unknown.

Clinical Studies

Eradication of H. pylori in Patients with Active Duodenal Ulcer Disease

Three clinical trials in the U.S. (Studies 1, 2 and 3) evaluated the effect of therapy on the eradication of H. pylori using bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. The patient population in these studies consisted predominantly of duodenal ulcer patients with active disease. In addition to bismuth subsalicylate, metronidazole, tetracycline hydrochloride triple therapy, most patients were also prescribed antisecretory therapy at doses recommended for ulcer healing, with the majority receiving ranitidine. The efficacy in these studies was assessed using H. pylori eradication, or cure of infection. Use of cure of infection as a surrogate for reduced ulcer recurrence is based on an extensive review of the literature. Eradication rates are derived from results of Studies 1 (randomized, controlled study) and Study 3 (uncontrolled, nonrandomized) and are shown in Table 2. H. pylori eradication was defined as no positive test (culture, histology, rapid urease, or 13C breath test) at least 4 weeks following the end of treatment. In the analysis performed, dropouts and patients with missing H. pylori tests post-treatment were excluded. HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) was effective in eradicating H. pylori.

Table 2: H. pylori Eradication Rates in Patients with Active Duodenal Ulcer Disease (Studies 1 and 3)

Study Number Eradication Rate in Duodenal Ulcer Patients† 95% Confidence Intervals
Study 1 77% (N = 39) 61% - 89%
Study 3 82% (N = 51) 70% - 92%
† Evaluable patients were defined as having a confirmed duodenal ulcer within 2 years prior to treatment and having taken 14 days of bismuth subsalicylate, metronidazole, and tetracycline (range 11 to 17 days). Eradication was defined as no evidence of H. pylori infection by culture, histology, rapid urease test and/or urea breath test from at least 4 weeks post-treatment up to 1 year posttreatment.

Study 2 evaluated the long-term outcome in patients treated for active duodenal ulcer by frequently monitoring for ulcer recurrence for up to 1 year after therapy. This study compared patients who received bismuth subsalicylate (BSS), metronidazole (MTZ), and tetracycline hydrochloride (TCN) for 2 weeks with ranitidine to those who received ranitidine alone. The ulcer recurrence rates at 6 months (Table 3) and one year (Table 4) regardless of post-treatment eradication status are summarized below for duodenal ulcer patients who were H. pylori positive at baseline.

Table 3: Duodenal Ulcer Recurrence Rates at 6 Months

Therapy All Patients H. pylori Negative Patients Post-Treatment
BSS/MTZ/TCN + Ranitidine 4% (1/25) 6% (1/18)
Ranitidine 85% (17/20) 100% (1/1)

Table 4: Duodenal Ulcer Recurrence Rates at 1 Year

Therapy All Patients H. pylori Negative Patients Post-Treatment
BSS/MTZ/TCN + Ranitidine 9% (2/22) 13% (2/16)
Ranitidine 95% (18/19) 100% (1/1)
† Includes all patients randomized to therapy who were H. pylori positive at baseline (by culture, histology, and/or urea breath test) who had ulcer healing and 24 or 48 weeks of endoscopic follow-up data.

Eradication of H. pylori in Patients with a History of Duodenal Ulcer Disease

A controlled, multicenter trial (Study 4) in the U.S. compared the rates of eradication of H. pylori following 14 days of treatment with HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) or control (bismuth subsalicylate, metronidazole placebo, and tetracycline placebo) in 103 patients infected with H. pylori who had a history of duodenal ulcer disease. No H2-receptor antagonist was used. H. pylori eradication was assessed by rapid urease testing, histology, and culture at least 4 weeks after the last dose. HELIDAC Therapy was effective in eradicating H. pylori. The eradication rates are noted in the table below:

Table 5: H. pylori Eradication Rates in Patients with a History of Duodenal Ulcer Disease (Study 4)

Population Evaluable Population† Intent-To-Treat Population‡
Therapy HELIDAC Therapy Control HELIDAC Therapy Control
Eradication Rate 71% 7% 72% 6%
(Number of Patients) (40/56) (2/30) (41/57) (2/32)
95% confidence interval 60, 83 0a, 16 60, 84 0a, 15
a The lower limit for this calculation was -2.2 but was truncated to 0 for reporting purposes.
† Evaluable patients were defined as having a history of a confirmed duodenal ulcer prior to treatment and having taken ≥ 70% of each component of HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) during the 14-day dosing period. Eradication was defined as no evidence of H. pylori infection by two or three diagnostic tests (culture, histology, and rapid urease test) from at least 4 weeks to 6 weeks post-treatment. Excluded from the evaluable population were patients who were non-compliant with medication, patients who were not infected with H. pylori at baseline, and patients without ulcer documentation. Three patients in the HELIDAC Therapy group and one patient in the Control group were included as eradication failures because they withdrew from the study due to treatment-related adverse events.
‡ Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy. Eradication was defined as no evidence of H. pylori infection by culture, histology, or rapid urease test.

Compliance with the triple therapy regimen was also evaluated in the clinical study. In the intent-to-treat population, 93% of the HELIDAC Therapy group took at least 75% of their medication.

REFERENCES

1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial susceptibility Tests for Bacteria that Grow Aerobically—Approved Standard Seventh Edition. Clinical and Laboratory Standards Institute document M7-A8, Vol. 29, No.2, CLSI, Wayne, PA, January 2009.

Last reviewed on RxList: 6/29/2012
This monograph has been modified to include the generic and brand name in many instances.

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