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%)^†

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.

Gastrointestinal: black stools

Mouth: temporary and harmless darkening of the tongue

The following adverse reactions from the labeling for metronidazole are provided for information.

Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea reported by about 12% of patients, sometimes accompanied by headache, anorexia, and occasionally vomiting, diarrhea, epigastric distress, and abdominal cramping. Constipation has also been reported.

Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy.

Blood: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.

CNS: Convulsive seizures, peripheral neuropathy, dizziness, vertigo, incoordination, ataxia, confusion, irritability, depression, weakness, and insomnia. Two serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur.

Hypersensitivity: urticaria, erythematous rash, flushing, nasal congestion, dryness of mouth (or vagina or vulva), and fever.

Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.

Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” If patients receiving metronidazole drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting, flushing, or headache. A modification of the taste of alcoholic beverages has also been reported. Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Rare cases of pancreatitis, which abated on withdrawal of the drug, have been reported.

The following adverse reactions from the labeling for tetracycline hydrochloride are provided for information.

Gastrointestinal: Anorexia, nausea, epigastric distress, vomiting, diarrhea, glossitis, black hairy tongue, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Rare instances of esophagitis and esophageal ulceration have been reported in patients taking the tetracycline-class antibiotics in capsule and tablet form. Most of the patients who experienced esophageal irritation took the medication immediately before going to bed. (See DOSAGE AND ADMINISTRATION.)

Liver: Hepatotoxicity and liver failure have been observed in patients receiving large doses of tetracycline and in tetracycline-treated patients with renal impairment. Increases in liver enzymes and hepatic toxicity have been reported rarely.

Teeth: Permanent discoloration of teeth may be caused during tooth development. Enamel hypoplasia has also been reported. (See WARNINGS.)

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.

Individual components of the HELIDAC Therapy have a potential interaction with anticoagulants. Tetracycline has been shown to depress plasma pro-thrombin activity. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of pro-thrombin 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 salicy-lates) 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 con-comitantly.

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 phenobarbital, may accelerate the elimination of metron-idazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.

Alcoholic beverages should not be consumed during metronidazole therapy and for at least 1 day afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.

Psychotic reactions have been reported in alcoholic patients who are using metronida-zole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks.

Drug/Laboratory Test Interactions: Bismuth absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract.

Bismuth subsalicylate may cause a temporary and harmless darkening of the stool. However, this does not interfere with standard tests for occult blood.

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide (NAD+ ⇔ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

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