Drug Interaction Report

ADJUST DOSING INTERVAL: Administration of a bismuth-containing preparation within two to three hours of a tetracycline may significantly decrease serum tetracycline concentrations. Data are available for tetracycline and doxycycline. The proposed mechanism is chelation of tetracycline by bismuth.

MANAGEMENT: Administration of a tetracycline and bismuth-containing preparation should be separated by two to three hours. Patients should be monitored for diminished tetracycline efficacy.

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MONITOR: Clopidogrel has been shown to potentiate the inhibition of platelet aggregation due to aspirin. Single-dose studies have not shown a prolongation of bleeding time when aspirin was added to clopidogrel; however, the risk of gastrointestinal (GI) bleeding may be increased. A large clinical trial reported that clopidogrel 75 mg/day plus aspirin 75 to 325 mg/day for up to 1 year was associated with a higher incidence of major GI bleeding (1.3% vs 0.7% with aspirin alone). These two medications are routinely used together for their additive antiplatelet, antistroke effect. The safety of chronic administration of aspirin or other salicylates with clopidogrel has not been established.

MANAGEMENT: Until further data are available, caution is recommended, especially in patients at risk of bleeding (i.e., GI ulceration), if clopidogrel is coadministered on a long-term basis with drugs that may cause GI lesions. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, red or black stools, or bloody or coffee-ground emesis. Patients should also be counseled to avoid any other over-the-counter salicylate products.

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CONTRAINDICATED: Use of alcohol or products containing alcohol during nitroimidazole therapy may result in a disulfiram-like reaction in some patients. There have been a few case reports involving metronidazole, although data overall are not convincing. The presumed mechanism is inhibition of aldehyde dehydrogenase (ALDH) by metronidazole in a manner similar to disulfiram. Following ingestion of alcohol, inhibition of ALDH results in increased concentrations of acetaldehyde, the accumulation of which can produce an unpleasant physiologic response referred to as the 'disulfiram reaction'. Symptoms include flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, weakness, vertigo, blurred vision, and confusion. Severe reactions may result in respiratory depression, cardiovascular collapse, arrhythmia, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. However, some investigators have questioned the disulfiram-like properties of metronidazole. One study found neither elevations in blood acetaldehyde nor objective or subjective signs of a disulfiram-like reaction to ethanol in six subjects treated with metronidazole (200 mg three times a day for 5 days) compared to six subjects who received placebo.

MANAGEMENT: Because clear evidence is lacking concerning the safety of ethanol use during nitroimidazole therapy, patients should be apprised of the potential for interaction. Consumption of alcoholic beverages and products containing propylene glycol is specifically contraindicated during and for at least 3 days after completion of metronidazole and benznidazole therapy according to their product labeling.

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ADJUST DOSING INTERVAL: Administration with food, particularly dairy products, significantly reduces tetracycline absorption. The calcium content of these foods forms nonabsorbable chelates with tetracycline.

MANAGEMENT: Tetracycline should be administered one hour before or two hours after meals.

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GENERALLY AVOID: The bioavailability of oral tetracyclines and iron salts may be significantly decreased during concurrent administration. Therapeutic failure may result. The proposed mechanism is chelation of tetracyclines by the iron cation, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. In ten healthy volunteers, simultaneous oral administration of ferrous sulfate 200 mg and single doses of various tetracyclines (200 mg to 500 mg) resulted in reductions in the serum levels of methacycline and doxycycline by 80% to 90%, oxytetracycline by 50% to 60%, and tetracycline by 40% to 50%. In another study, 300 mg of ferrous sulfate reduced the absorption of tetracycline by 81% and that of minocycline by 77%. Conversely, the absorption of iron has been shown to be decreased by up to 78% in healthy subjects and up to 65% in patients with iron depletion when ferrous sulfate 250 mg was administered with tetracycline 500 mg. Available data suggest that administration of iron 3 hours before or 2 hours after a tetracycline largely prevents the interaction with most tetracyclines except doxycycline. Due to extensive enterohepatic cycling, iron binding may occur with doxycycline even when it is given parenterally. It has also been shown that when iron is administered up to 11 hours after doxycycline, serum concentrations of doxycycline may still be reduced by 20% to 45%.

MANAGEMENT: Coadministration of a tetracycline with any iron-containing product should be avoided if possible. Otherwise, patients should be advised to stagger the times of administration by at least three to four hours, although separating the doses may not prevent the interaction with doxycycline.

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