Drug Interactions between bismuth subcitrate potassium / metronidazole / tetracycline and ozanimod

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.

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.

GENERALLY AVOID: Foods that contain large amounts of tyramine may precipitate a hypertensive crisis in patients treated with ozanimod. The proposed mechanism involves potentiation of the tyramine pressor effect due to inhibition of monoamine oxidase (MAO) by the major active metabolites of ozanimod, CC112273 and CC1084037. Monoamine oxidase in the gastrointestinal tract and liver, primarily type A (MAO-A), is the enzyme responsible for metabolizing exogenous amines such as tyramine and preventing them from being absorbed intact. Once absorbed, tyramine is metabolized to octopamine, a substance that is believed to displace norepinephrine from storage granules causing a rise in blood pressure. In vitro, CC112273 and CC1084037 inhibited MAO-B (IC50 values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over MAO-A (IC50 values >10000 nM). Because of this selectivity, as well as the fact that free plasma concentrations of CC112273 and CC1084037 are less than 8% of the in vitro IC50 values for MAO-B inhibition, ozanimod is expected to have a much lower propensity to cause hypertensive crises than nonselective MAO inhibitors. However, rare cases of hypertensive crisis have occurred during clinical trials for the treatment of multiple sclerosis (MS) and ulcerative colitis (UC) and in postmarketing use. In controlled clinical trials, hypertension and blood pressure increases were reported more frequently in patients treated with ozanimod (up to 4.6% in MS patients receiving ozanimod 0.92 mg/day) than in patients treated with interferon beta-1a (MS) or placebo (UC).

Administration of ozanimod with either a high-fat, high-calorie meal (1000 calories; 50% fat) or a low-fat, low-calorie meal (300 calories; 10% fat) had no effects on ozanimod peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration under fasted conditions.

MANAGEMENT: Dietary restriction is not ordinarily required during ozanimod treatment with respect to most foods and beverages that contain tyramine, which usually include aged, fermented, cured, smoked, or pickled foods (e.g., air-dried and fermented meats or fish, aged cheeses, most soybean products, yeast extracts, red wine, beer, sauerkraut). However, certain foods like some of the aged cheeses (e.g., Boursault, Liederkrantz, Mycella, Stilton) and pickled herring may contain very high amounts of tyramine and could potentially cause a hypertensive reaction in patients taking ozanimod, even at recommended dosages, due to increased sensitivity to tyramine. Patients should be advised to avoid the intake of very high levels of tyramine (e.g., greater than 150 mg) and to promptly seek medical attention if they experience potential signs and symptoms of a hypertensive crisis such as severe headache, visual disturbances, confusion, stupor, seizures, chest pain, unexplained nausea or vomiting, and stroke-like symptoms. Blood pressure should be regularly monitored and managed accordingly. Because of the long elimination half-lives of the major active metabolites, these precautions may need to be observed for up to 3 months following the last ozanimod dose. Ozanimod can be administered with or without food.

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.