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The safety of PYLERA™ plus omeprazole for 10 days to eradicate Helicobacter pylori was evaluated in 324 patients (aged 18 to 75 years) in two clinical trials world-wide. One trial was conducted in the US and Canada (North American Trial). The other trial was conducted in Europe, Australia, Canada and the US (International Trial).

In the North American trial, patients with a duodenal ulcer or history of an ulcer were randomized to PYLERA™ plus omeprazole (OBMT) or omeprazole, amoxicillin, and clarithromycin (OAC). The International trial differed from the North American trial in that there was no comparator group and all patients received OBMT. Also, patients enrolled in the International trial all had gastrointestinal symptoms (i.e., non-ulcer dyspepsia). It was not necessary for these patients to have a history or current duodenal ulcer.

Two hundred and ninety-nine (299) patients (147 OBMT and 152 OAC) were exposed to at least one dose of the study drugs in the North American trial. Of these patients, 86/147 (58.5%) in the OBMT group and 90/152 (59.2%) in the OAC group reported adverse events. In the OBMT group there were 212 events reported and 236 events reported in the OAC group. An adverse event was defined as any event not present prior to exposure to study medication or any event present at study entry that worsens in either intensity or frequency following exposure to study medication.

The most frequent adverse events incidence >1%) by treatment group from the North American trial in order of decreasing incidence for the OBMT group are shown below in Table 5. For both treatments, gastrointestinal adverse events (e.g., diarrhea, dyspepsia, abdominal pain, and nausea) are the most commonly reported.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials or another drug and may not reflect the rates observed in practice.

Table 5. Adverse Events of Incidence > 1% in Controlled Clinical Trial By Treatment Group, By Decreasing Frequency [n (%)]

The following selected adverse reactions from the labeling for bismuth subsalicylate, a similar bismuth-containing product to bismuth subcitrate potassium, are provided for information.

Gastrointestinal: black stools

Mouth: temporary and harmless darkening of the tongue

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

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: 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 (vagina or vulva), and fever.

Other: 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. Rare cases of pancreatitis, which abated on withdrawal of the drug, have been reported.

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

Gastrointestinal: 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.

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 has been reported rarely. (See WARNINGS)

Interactions with Metronidazole

Lithium

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.

Alcohol

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. Since some pharmaceutical products may contain alcohol, caution should be exercised in patients taking these medications. Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks.

Anticoagulants

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Therefore, frequent monitoring therapy with appropriate adjustment of the anticoagulant dosage is warranted with initiation of PYLERA™.

Cimetidine, Phenytoin, or Phenobarbital

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 metronidazole, resulting in reduced plasma levels. Impaired clearance of phenytoin has also been reported in this situation.

Interactions with Tetracycline

Methoxyflurane and Tetracycline

The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.

Oral Contraceptives and Tetracycline

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 PYLERA™ should be advised to notify their prescriber immediately.

Anticoagulants

Tetracycline has been shown to depress plasma prothrombin activity. Therefore, frequent monitoring of anticoagulant therapy with appropriate adjustment of the anticoagulant dosage is warranted with initiation of PYLERA™.

Penicillin

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.

Antacids, Multivitamins, or Dairy Products

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium; preparations containing iron, zinc, or sodium bicarbonate; or milk or dairy products. The clinical significance of reduced tetracycline systemic exposure is unknown as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori has not been established. PYLERA™ should be given after meals and at bedtime, in combination with omeprazole twice a day. (See DOSAGE AND ADMINISTRATION)

Bismuth

There is an anticipated reduction in tetracycline systemic absorption due to an interaction with bismuth. The clinical significance of reduced tetracycline systemic exposure is unknown as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori has not been established.

Drug/Laboratory Test Interactions

Bismuth absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract.

Bismuth subcitrate potassium 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.

Last reviewed on RxList: 6/13/2007
This monograph has been modified to include the generic and brand name in many instances.