Drug Interaction Report

CONTRAINDICATED: Concomitant use of systemic vitamin A derivatives (e.g., retinoids) with tetracyclines may increase the risk of pseudotumor cerebri, also known as benign intracranial hypertension. These agents have each been individually associated with the development of pseudotumor cerebri and may have additive effects if administered concurrently. This interaction has been suspected in reported cases involving the use of some retinoids (e.g., isotretinoin) in combination with a tetracycline.

MANAGEMENT: Coadministration of most systemic vitamin A derivatives with tetracyclines is considered contraindicated. One publication recommends a drug-free period, or washout, between the two medications. The authors suggest a 7-day washout period if the patient has normal renal and liver function, is using the tetracycline for acne, and is changing from a tetracycline to a vitamin A derivative. All patients should be counseled to contact their healthcare provider immediately if they develop signs or symptoms of pseudotumor cerebri such as papilledema, headache, nausea, vomiting, and/or visual disturbances. The patient should be advised to discontinue the retinoid and tetracycline antibiotic and be referred for immediate neurological evaluation and care if pseudotumor cerebri is suspected as this could result in permanent vision loss.

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CONTRAINDICATED: Ethanol consumption with acitretin leads to the formation of etretinate, which has a much longer half-life than acitretin. Major human fetal abnormalities have been associated with the administration of acitretin, etretinate, and other retinoids. The longer elimination half-life of etretinate relative to acitretin increases the duration of teratogenic potential for female patients. In one case report of a patient with apparent sporadic ethanol intake, etretinate was present in plasma and fat for 52 months after acitretin was discontinued.

MANAGEMENT: Female patients should be warned that ethanol is contraindicated during active treatment with acitretin and for two months after cessation of therapy.

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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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Chronic alcohol consumption may enhance the elimination of doxycycline. The mechanism is induction of hepatic microsomal enzymes by alcohol. In one study, the half-life of doxycycline in six alcoholics was 10.5 hours, compared with 14.7 hours in six control patients. In addition, half the alcoholic patients had serum concentrations below what is generally considered the minimum therapeutic concentration (0.5 mcg/mL) at 12 to 24 hours after the dose. The investigators suggest that twice-a-day dosing may be indicated in these patients, especially if additional inducing drugs are used. The elimination of other tetracyclines probably is not affected by alcohol consumption.

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