Download Helicobacter pylori Infection & HELIDAC Therapy: Composition, Contraindications, & Pharmac and more Study notes Pharmacokinetics in PDF only on Docsity!
Draft Labeling - Confidential
HELIDAC® Therapy
PHARMACIST INFORMATION & COUNSELING AID
Not intended for distribution to Patient
- This Counseling Aid contains concise information for the Pharmacist and is meant to aid in counseling; please refer to the attached Package Insert for complete prescribing information.
- There is a detailed PATIENT INFORMATION BOOKLET contained in this package which should be read by the patient prior to initiating therapy.
- Instructions for opening the enclosed dosing blister cards can be found on the top of this package.
For Your Information
- Helicobacter pylori ( H. pylori ) infection has been found to play a primary role in the pathogenesis of duodenal ulcers, and is considered the causative organism in 80% to 95% of patients with duodenal ulcers.
- The components of HELIDAC Therapy [bismuth subsalicylate (BSS), metronidazole (MTZ), and tetracycline hydrochloride (TCN)] are indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence. Appropriate doses of an H2 antagonist indicated for the treatment of active duodenal ulcer should be prescribed for ulcer healing.
- HELIDAC Therapy is a combination of three antimicrobial agents: bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. Clinical trials using this combination have demonstrated H. pylori eradication in up to 82% of patients with a duodenal ulcer. Please note: bismuth subsalicylate is used in this combination for its antimicrobial properties and not for symptomatic relief of upset stomach.
- Clinical data show that eradication of H. pylori is directly related to compliance. This therapy has been designed to enhance compliance and contains 14 blister cards, one for each day of the 14-day treatment plan, with each card divided into the 4 daily doses. The therapy also contains a patient-oriented information booklet and patient reminders.
Information To Share With Your Patient
- Scientists have discovered that most ulcers are caused by an infection from a specific germ called H. pylori.
- The medicines in this therapy have been demonstrated to treat the infection in the majority of cases when taken correctly. Treating the infection is important to reduce the risk of the ulcer coming back.
- Each pill of every dose is important. Studies have shown that taking all this medicine is very important to eradicate all the ulcer-causing germs. If doses are skipped or treatment is stopped early, some of these germs may not be eradicated and another ulcer can develop.
Dosing and Administration
It may be useful to open the therapy and explain dosing while showing the patient one of the dosing blister cards.
- Each dose includes 4 pills: 2 pink round chewable tablets (bismuth subsalicylate), 1 white round tablet (metronidazole), and 1 orange & white capsule (tetracycline hydrochloride).
- Take 1 dose (all 4 pills) 4 times a day – at mealtimes and bedtime.
- Chew and swallow the 2 pink tablets.
Then swallow the white tablet and orange and white capsule whole with a full glass of water (8 ounces).
Remember: Chew-Chew-Swallow-Swallow = 1 dose.
- All 4 daily doses are contained on an individual blister card.
- This therapy contains 14 blister cards, one card for each day of the 14-day treatment plan.
- If you miss a dose, do not take a double dose. Instead, make up any missed doses by continuing your normal dosing schedule until the medication is gone. (Please contact prescriber if more than 4 doses are missed.)
- Each dose should be taken with a full glass of water (8 ounces), especially the bedtime dose.*
- Concomitantly prescribed H2 antagonist therapy should be taken as directed.
*To reduce risk of esophageal imitation and ulceration due to tetracycline
OTHER IMPORTANT INFORMATION TO GUIDE YOUR DISCUSSION WITH THE PATIENT
Contraindications: HELIDAC Therapy is contraindicated in the following patient populations:
- Pregnant or nursing women
- Pediatric patients
- Patients with renal or hepatic impairment
- Patients with known hypersensitivity to bismuth subsalicylate, metronidazole or other nitroimidazole derivatives, or any of the tetracyclines; this product does not contain aspirin, but should not be administered to those patients who have a known allergy to aspirin or salicylates.
Warnings and Precautions ( also see Contraindications): The following is a partial list. Please refer to the Package Insert for more complete information.
- Patients should avoid:
- Alcohol during therapy and at least 1 day after completion of all doses due to potential metronidazole effects
- Sun lamps or sun because of possible photosensitivity secondary to tetracycline
- Other medications without first consulting with your pharmacist or prescriber (See Drug Interactions .)
- Administer with caution in patients with central nervous system diseases.
- Administer with caution in elderly patients who may suffer from asymptomatic renal and hepatic dysfunction.
Although there is an anticipated reduction in tetracycline systemic absorption due to an interaction with bismuth and/or bismuth subsalicylate tablet excipients (calcium carbonate), the relative contribution of systemic versus local antimicrobial activity against H. pylori for these agents has not been established.
PACKAGE INSERT
THESE PRODUCTS ARE INTENDED ONLY FOR USE AS DESCRIBED. The individual products contained in this package should not be used alone or in combination for other purposes. The information described in this labeling concerns only the use of these products as indicated in this combination package. For information on use of the individual components when dispensed as individual medications outside this combined use for treating Helicobacter pylori , please see the package inserts for each individual product.
WARNING Metronidazole has been shown to be carcinogenic in mice and rats. (See PRECAUTIONS .) Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the INDICATIONS AND USAGE section below.
DESCRIPTION: HELIDAC Therapy consists of 112 bismuth subsalicylate 262.4-mg chewable tablets, 56 metronidazole 250-mg tablets, USP, and 56 tetracycline hydrochloride 500-mg capsules, USP, for oral administration.
Bismuth subsalicylate chewable tablets: Each pink round tablet contains 262.4 mg bismuth subsalicylate (102 mg salicylate) for oral administration.
Bismuth subsalicylate is a fine, white, odorless, and tasteless powder that is stable and non- hygroscopic. It is a highly insoluble salt of trivalent bismuth and salicylic acid.
Bismuth subsalicylate is 2-Hydroxybenzoic acid bismuth (3+) salt with the following structural formula:
Molecular structure of bismuth subsalicylate goes here
Molecular weight: 362.
Inactive Ingredients: Each bismuth subsalicylate chewable tablet contains calcium carbonate, D&C Red No. 27 aluminum lake, flavor, magnesium stearate, mannitol, povidone, saccharin sodium, and talc.
Metronidazole tablets, USP: Each white round tablet contains 250 mg metronidazole. Metronidazole is 2-Methyl-5-nitroimidazole-1-ethanol, with the following structural formula:
Molecular structure of metronidazole goes here
Molecular weight: 171.
Inactive Ingredients: Each metronidazole tablet contains lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and stearic acid.
Tetracycline hydrochloride capsules, USP: Each pink and white capsule contains 500 mg tetracycline hydrochloride, causing it to appear pale orange and white in color when filled. Tetracycline is a yellow, odorless, crystalline powder. Tetracycline is stable in air but exposure to strong sunlight causes it to darken. Its potency is affected in solutions of pH below 2 and is rapidly destroyed by alkali hydroxide solutions. Tetracycline is very slightly soluble in water, freely soluble in dilute acid and in alkali hydroxide solutions, sparingly soluble in alcohol, and practically insoluble in chloroform and ether.
Tetracycline hydrochloride is (4S,4aS,5aS,6S,12aS)-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, with the following structural formula:
Molecular structure of tetracycline HCL goes here
Molecular weight: 480.
Inactive Ingredients: Each tetracycline hydrochloride capsule contains colloidal silicon dioxide, white ink, FD&C Red No. 40, gelatin, pregelatinized starch, stearic acid, and titanium dioxide.
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 pharmaco- kinetics 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. 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
Pretreatment Resistance: Of the 49 patients enrolled in the P&GP study for whom pretreatment metronidazole susceptibility was determined by agar dilution, 22% (11/49) were classified as non- susceptible.
Metronidazole Susceptibility Test Results and Clinical/Bacteriologic Outcome: In the P&GP clinical study, 42.1% (24/57) of the patients in the intent-to-treat population who received HELIDAC Therapy did not have pretreatment metronidazole susceptibility determined due to non-viability of the isolates or negative cultures.
The pre-treatment Helicobacter pylori metronidazole susceptibility results and the H. pylori eradication results post-treatment are shown in the table below.
Metronidazole Susceptibility Test Results and Clinical/Bacteriological Outcomesa^ for HELIDAC®Therapy (Bismuth subsalicylate 525 mg, metronidazole 250 mg, and tetracycline hydrochloride 500 mg four times daily for 14 days)
Metronidazole Pre-treatment Results
H. pylori negative (Eradicated)
H. pylori positive (Not Eradicated) Post-treatment Metronidazole Results N MIC ≤ (^8) MIC ≥ 16 No MIC MIC ≤ 8 μg/mL 26 23 1 2 0 MIC ≥ 16 μg/mL 7 4 1 1 1 a (^) includes only patients with pre-treatment metronidazole susceptibility test results
It is recommended that all patients not eradicated of H. pylori following bismuth subsalicylate, metronidazole, and tetracycline treatment be retreated with a regimen which does not contain metronidazole.
INDICATIONS AND USAGE: The components of the HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride), in combination with an H 2 antagonist, are indicated for the eradication of H. pylori for treatment of patients with H. pylori infection and duodenal ulcer disease (active or a history of duodenal ulcer). Appropriate doses of H 2 antagonists for the treatment of active duodenal ulcers should be prescribed in all patients. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence in patients with active duodenal ulcer disease. (See CLINICAL STUDIES and DOSAGE AND ADMINISTRATION .)
It is recommended that all patients not eradicated of H. pylori following HELIDAC Therapy plus an H 2 antagonist, should be retreated with a regimen which does not contain metronidazole. (See Microbiology subsection.)
CLINICAL STUDIES: Eradication of H. pylori in Patients with Active Duodenal Ulcer Disease: Investigators in the U.S. (Graham et al., 1991, 1992, and Cutler et al., 1993) and Germany (Labenz et al., 1993) studied 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 primary efficacy variable used in these studies to determine effectiveness of therapy was 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 the randomized, controlled study of Graham et al. and the uncontrolled, nonrandomized study of Cutler et al. 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.
H. pylori Eradication Rates in Patients with Active Duodenal Ulcer Disease
Investigator
Eradication Rate in Duodenal Ulcer Patients †
95% Confidence Intervals
Graham 2,
Cutler 4
(N = 39)
(N = 51%)
† 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 post-treatment.
Graham et al. 1992 3 studied 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 and 1 year regardless of post-treatment eradication status are summarized below for duodenal ulcer patients who were H. pylori positive at baseline.
Duodenal Ulcer Recurrence Rates at 6 Months †
Therapy All Patients H. pylori Negative Patients Post-Treatment BSS/MTZ/TCN + Ranitidine
Ranitidine
Duodenal Ulcer Recurrence Rates at 1 Year †
Therapy All Patients H. pylori Negative Patients Post-Treatment BSS/MTZ/TCN + Ranitidine
Ranitidine
† 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 conducted by P&GP 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. The primary efficacy measurement was H. pylori eradication 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:
H. pylori Eradication Rates in Patients with a History of Duodenal Ulcer Disease
This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE HYDROCHLORIDE IS A COMPONENT OF THE HELIDAC THERAPY, THEREFORE, HELIDAC THERAPY SHOULD NOT BE USED IN THESE PATIENT POPULATIONS. (See CONTRAINDICATIONS .)
Tetracycline hydrochloride, as a component of the HELIDAC Therapy, should not be used during pregnancy. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. Treatment should be discontinued at the first evidence of skin erythema.
The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). While this is not a problem in those with normal renal function, in patients with significantly impaired renal function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis.
PRECAUTIONS: General: Bismuth Subsalicylate
Bismuth subsalicylate may cause a temporary and harmless darkening of the tongue and/or black stool. Stool darkening should not be confused with melena.
Metronidazole
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. (See CONTRAINDICATIONS .) Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of, or history of, blood dyscrasia. A mild leukopenia has been observed; however, no persistent hematologic abnormalities attributable to metronidazole have been observed.
Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candicidal agent.
Tetracycline
As with other antibiotics, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, tetracycline should be discontinued and appropriate therapy should be instituted.
Pseudotumor cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. While this condition and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility for permanent sequelae exists.
Information for Patients: Each dose includes 4 pills: 2 pink round chewable tablets (bismuth subsalicylate), 1 white round tablet (metronidazole), and 1 orange and white capsule (tetracycline hydrochloride). Each dose (all 4 pills) should be taken 4 times a day, at mealtimes and bedtime. Patients should be instructed to chew and swallow the pink round tablets (bismuth subsalicylate tablets) and to swallow the white round tablet (metronidazole tablet) and the pale orange and white capsule (tetracycline hydrochloride capsule) whole with a full glass of water (8 ounces). Concomitantly prescribed H 2 antagonist therapy should be taken as directed.
Administration of adequate amounts of fluid, particularly with the bedtime dose of tetracycline hydrochloride, is recommended to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS .)
Missed doses can be made up by continuing the normal dosing schedule until the medication is gone. Patients should not take double doses. (If more than 4 doses are missed, the prescriber should be contacted.)
This treatment regimen includes salicylates. If taken with aspirin and ringing in the ears occurs, the prescriber should be consulted concerning discontinuation of the aspirin therapy until the HELIDAC Therapy is completed.
Concurrent use of tetracyclines may render oral contraceptives less effective. Patients should be advised to use a different or additional form of contraception. Breakthrough bleeding has been reported. Women who become pregnant while taking components of the HELIDAC Therapy should be advised to notify their prescriber immediately. (See CONTRAINDICATIONS and WARNINGS .)
Alcoholic beverages should be avoided while taking metronidazole and for at least 1 day afterward. (See Drug Interactions .)
Patients taking tetracycline hydrochloride should be cautioned to avoid exposure to sun or sun lamps. (See WARNINGS .)
Bismuth subsalicylate may cause temporary and harmless darkening of the tongue and/or black stool. Stool darkening should not be confused with melena (blood in the stool).
Drug Interactions: Individual components of the HELIDAC Therapy have a potential interaction with anticoagulants. Tetracycline has been shown to depress plasma prothrombin activity. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Salicylates may cause an increased risk of bleeding when administered with anticoagulant therapy. Therefore, monitoring anticoagulant therapy with appropriate adjustment of the anticoagulant dosage may be warranted if - concurrent therapy is instituted.
Caution is advised in the administration of bismuth subsalicylate to patients taking medication for diabetes (possible enhanced hypoglycemic effect when given with salicylates) or patients taking aspirin, probenecid, or sulfinpyrazone.
Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium; preparations containing iron, zinc, or sodium bicarbonate; or milk or dairy products.
There is an anticipated reduction in tetracycline systemic absorption due to an interaction with bismuth and/or calcium carbonate, an excipient of bismuth subsalicylate tablets. The clinical significance of this is unknown as the relative contribution of systemic versus local antimicrobial activity against H. pylori for these agents has not been established.
Since bacteriostatic drugs, such as the tetracycline class of antibiotics, may interfere with the bactericidal action of penicillin, it is not advisable to administer these drugs concomitantly.
The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.
Concurrent use of tetracycline may render oral contraceptives less effective. Patients should be advised to use a different or additional form of contraception. Breakthrough bleeding has been reported. Women who become pregnant while on the HELIDAC Therapy should be advised to notify their prescriber immediately.
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or
Bismuth did not show mutagenic potential in the NTP salmonella plate assay.
No reproductive toxicity studies have been conducted with bismuth subsalicylate.
Tetracycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 25 times the human dose.
Metronidazole, at doses up to 400 mg/kg/day (approximately 3.5 times the recommended maximum human dose based on mg/m^2 ) for 28 days, failed to produce any adverse effects on fertility and testicular function in male rats. Fertility studies have been performed in mice at doses up to six times the maximum recommended human dose based on mg/m^2 and have revealed no evidence of impaired fertility.
Pregnancy: Teratogenic Effects. Pregnancy Category D: Category D is based on the pregnancy category for tetracycline hydrochloride. (See CONTRAINDICATIONS and WARNINGS , Tetracycline and Metronidazole subsections.)
Non-teratogenic Effects: (See WARNINGS .)
Pregnant women with renal disease may be more prone to develop tetracycline-associated liver failure.
Labor and Delivery: The effect of this therapy on labor and delivery is unknown.
Nursing Mothers: Metronidazole and tetracycline are both secreted into human milk. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, and because of the potential for serious adverse reactions in nursing infants from tetracyclines, a decision should be made whether to discontinue nursing or to discontinue therapy, taking into account the importance of the therapy to the mother. Metronidazole is secreted in human milk in concentrations similar to those found in plasma. (See CONTRAINDICATIONS .)
Pediatric Use: Safety and effectiveness in pediatric patients infected with H. pylori have not been established. (See CONTRAINDICATIONS and WARNINGS .)
Geriatric Use: Clinical studies of HELIDAC Therapy did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing HELIDAC Therapy. As stated in the CONTRAINDICATIONS section, this therapy is contraindicated in patients with renal or hepatic impairment.
ADVERSE REACTIONS: The most common adverse reactions (≥ 1%) reported in clinical trials when all three components of this therapy were given concomitantly are listed in the table below. The majority of the adverse reactions were related to the gastrointestinal tract, were reversible, and infrequently led to discontinuation of therapy.
Incidence of Adverse Reactions Reported in Clinical Trials (≥ 1%) †
BSS/MTZ/TCN ‡ (N = 266) Adverse Reactions % Patients Nausea 12. Diarrhea 6. Abdominal Pain 6. Melena 3. Upper Respiratory Infection 2. Constipation 1. Anorexia 1. Asthenia 1. Vomiting 1. Discolored Tongue 1. Headache 1. Dyspepsia 1. Dizziness 1. Stool Abnormality 1. Duodenal Ulcer 1. Sinusitis 1. Taste Perversion 1. Flatulence 1. GI Hemorrhage 1. Pain 1. Insomnia 1. Anal Discomfort 1. Paresthesia 1.
† Includes reactions reported at ≥ 1% in patients taking BSS/MTZ/TCN in Graham, Cutler, and P&GP studies.
‡ In the Graham and Cutler studies (N = 197), most patients were on concomitant acid suppression therapy.
The additional adverse reactions (< 1%) reported in clinical trials when all three components of this therapy were given concomitantly are listed below and divided by body system:
Gastrointestinal: dry mouth, dysphagia, eructation, GI monilia, glossitis, intestinal obstruction, rectal hemorrhage, stomatitis
Skin: acne, ecchymosis, photosensitivity reaction (see WARNINGS ), pruritus, rash
Cardiovascular: cerebral ischemia, chest pain, hypertension, myocardial infarction
CNS: nervousness, somnolence
Musculoskeletal: arthritis, rheumatoid arthritis, tendonitis
Metabolic: SGOT increase, SGPT increase
Urogenital: urinary tract infection
Other: conjunctivitis, flu syndrome, infection, malaise, neoplasm, rhinitis, syncope, tooth disorder
The following adverse reactions from the labeling for bismuth subsalicylate are provided for information.
Blood: hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia, and eosinophilia
CNS: Pseudotumor cerebri (benign intracranial hypertension) in adults and bulging fontanels in infants. (See PRECAUTIONS: Tetracycline.) Dizziness, tinnitus, and visual disturbances have been reported. Myasthenic syndrome has been reported rarely.
Hypersensitivity: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus and serum sickness-like reactions, as fever, rash, and arthralgia
Renal: Rise in BUN has been reported and is apparently dose related. (See WARNINGS ).
Skin: Maculopapular and erythematous rashes have been reported. Exfoliative dermatitis has been rarely reported. Photosensitivity (see WARNINGS ), onycholysis, and discoloration of the nails have been reported rarely.
Other: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur.
OVERDOSAGE: In case of an overdose, patients should contact a physician, poison control center, or emergency room. If all three components of this therapy are involved in an overdose, acute treatment should focus on the salicylate intoxication. There is neither a pharmacologic basis nor data suggesting an increased toxicity of the combination compared to individual components.
Bismuth Subsalicylate: The main concern of an acute bismuth subsalicylate (BSS) overdose focuses on the salicylate burden and not on bismuth, since less than 1% of the bismuth is normally absorbed. Each 262.4-mg tablet of BSS contains an amount of salicylate comparable to approximately 130 mg aspirin. Acute ingestion of less than 150 mg/kg of aspirin (i.e., less than one tablet of bismuth subsalicylate per kilogram of body weight) is not expected to lead to toxicity. Mild to moderate toxicity may result from the ingestion of 150 to 300 mg/kg, while severe toxicity may occur from ingestions over 300 mg/kg. Salicylate intoxication is well described in the literature and presents a complex clinical picture. Multiple respiratory and metabolic effects result in fluid, electrolyte, glucose, and acid-base disturbances. Initial symptoms of salicylate toxicity include hyperpnea, nausea, vomiting, tinnitus, hyperpyrexia, lethargy, tachycardia, and confusion. In severe cases, these symptoms may progress to severe hyperpnea, convulsions, pulmonary or cerebral edema, respiratory failure, cardiovascular collapse, coma, and death.
Treatment: There is no specific antidote for salicylate poisoning. If there are no contraindications, vomiting should be induced as soon as possible with syrup of ipecac, or gastric lavage should be instituted, provided that no more than one hour has elapsed since ingestion. Activated charcoal and a cathartic may be administered as primary decontamination therapy in those cases where greater than one hour has elapsed since ingestion, or to further decontaminate the gastrointestinal tract in those who have already received ipecac or gastric lavage. Plasma salicylate levels may be useful; a common nomogram can be used to help predict the severity of intoxication. Supportive and symptomatic treatment should be provided, with emphasis on correcting fluid, electrolyte, blood glucose, and acid-base disturbances. (Note: An acidotic blood pH increases the un-ionized salicylate form, allowing more to reach the central nervous system.) Elimination may be enhanced by urinary alkalinization, hemodialysis, or hemoperfusion. Since hemodialysis aids in correcting acid-base disturbances, this method may be preferred over hemoperfusion.
Metronidazole: Single oral doses of metronidazole, up to 19.5 g in adults, have been reported without resultant serious toxicity in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia.
Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.
Treatment: There is no specific antidote for metronidazole overdose. Management of the patient should consist of symptomatic and supportive therapy. Metronidazole is dialyzable. Tetracycline: The acute toxicity of tetracycline in overdose is not well established in the literature. Therapeutic and overdose quantities of tetracycline can cause gastrointestinal symptoms such as nausea, vomiting, and diarrhea.
Treatment: There is no specific antidote for tetracycline overdose. Management of the patient should consist of symptomatic and supportive therapy. Tetracycline is not dialyzable.
DOSAGE AND ADMINISTRATION: Adults: The recommended dosages are: bismuth subsalicylate, 525 mg (two 262.4 mg-chewable tablets), metronidazole, 250 mg (one 250-mg tablet), and tetracycline hydrochloride, 500 mg (one 500-mg capsule) taken four times daily (q.i.d.) for 14 days plus an H 2 antagonist approved for the treatment of acute duodenal ulcer. Patients should be instructed to take the medicines at mealtimes and at bedtime. The bismuth subsalicylate tablets should be chewed and swallowed. The metronidazole tablet and tetracycline hydrochloride capsule should be swallowed whole with a full glass of water (8 ounces). Concomitantly prescribed H (^2) antagonist therapy should be taken as directed.
Ingestion of adequate amounts of fluid, particularly with the bedtime dose of tetracycline hydrochloride, is recommended to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS .)
Missed doses can be made up by continuing the normal dosing schedule until the medication is gone. Patients should not take double doses. If more than 4 doses are missed, the prescriber should be contacted.
HOW SUPPLIED: The HELIDAC Therapy is supplied in a carton containing patient instructions, patient reminders, and 14 blister cards, each card containing the following daily dosage:
8 bismuth subsalicylate 262.4-mg chewable tablets, each pink round tablet engraved “PG 11”
4 metronidazole 250-mg tablets, each white round tablet engraved “PG” on the upper half and “10” on the lower half of the tablet
4 tetracycline hydrochloride 500-mg capsules, each pale orange and white capsule printed “PG 12” in white ink
NDC 65483-0495 carton containing 14 days of therapy
Store at controlled room temperature 20°-25°C (68°-77°F) [See USP].
REFERENCES:
- National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.
- Graham DY, Lew GM, Evans DG, Evans DJ Jr, Klein PD. Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. Ann Intern Med 1991; 115:266-69.
- Graham DY, Lew GM, Klein PD, Evans DG, Evans DJ Jr, Saeed ZA, Malaty HM. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. Ann Int Med 1992; 116:705-08.
- Cutler AF, Schubert TT. Long-term Helicobacter pylori recurrence after successful eradication with triple therapy. Am J Gastroenterol 1993; 88:1359-61.
Sold under U.S. Patents 5,256,684; 5,403,830; 5,407,688; and 5,601,
PEPTO-BISMOL is the registered trademark of The Procter & Gamble Company.
