Drug Interaction Report

ADJUST DOSING INTERVAL: Concomitant administration of bismuth-containing medications may impair the absorption of oral tetracyclines. The interaction has been studied with tetracycline and doxycycline. The proposed mechanism is chelation of tetracyclines by bismuth.

MANAGEMENT: Administration of a tetracycline and bismuth-containing preparation should either be avoided or separated by two to three hours. However, this precautionary measure is not considered necessary in treatment regimens where bismuth may be given in combination with tetracycline and other medications for the eradication of Helicobacter pylori infection, as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori has not been established.

MONITOR: Tetracyclines may enhance the hypoglycemic effects of insulin and insulin secretagogues (e.g., sulfonylureas, meglitinides). The exact mechanism is unknown; however, proposed mechanisms include increasing the sensitivity of insulin, increasing the half-life of insulin via inhibition of insulin degradation in the liver, interference with epinephrine-induced hyperglycemia via inhibition of glycogenolysis, and tetracycline-induced hepatotoxicity. The authors of one study suggest that tetracycline may also be able to inhibit alpha-amylase and/or alpha-glucosidase, as substrates for these enzymes have similar functional groups to those found in tetracycline. There are case reports available documenting hypoglycemia for patients on doxycycline and one case report demonstrating improved insulin sensitivity in a patient on minocycline. It is possible that other tetracyclines may possess similar abilities to lower glucose levels.

MANAGEMENT: Blood glucose should be monitored more closely during therapy with a tetracycline antibiotic. As the effects of the antibiotic may persist beyond the last dose, it is possible that patients may need to be monitored more closely until the antibiotic is fully eliminated from their body, which will differ depending on the half-life of the antibiotic involved. Insulin and insulin secretagogues may require dosage adjustments if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs unexpectedly. Conversely, patients should be observed for loss of glycemic control following completion of tetracycline therapy.

MONITOR: Coadministration with inhibitors of CYP450 2C9 may increase the plasma concentrations of nateglinide, which is primarily metabolized by the isoenzyme. In 18 healthy volunteers, administration of a single 120 mg oral dose of nateglinide in combination with the CYP450 2C9 inhibitor sulfinpyrazone (200 mg orally twice daily for 7 days) increased mean sulfinpyrazone systemic exposure (AUC) by 28% compared to administration alone. Sulfinpyrazone did not affect the mean peak plasma concentration (Cmax), time to reach peak plasma concentration (Tmax), or the elimination half-life of nateglinide.

MANAGEMENT: Because the antidiabetic effect of nateglinide is dose- and concentration-dependent, close monitoring for the development of hypoglycemia is recommended during coadministration with CYP450 2C9 inhibitors. Patients should regularly monitor their blood sugar and learn how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitation. The dosage of nateglinide may require adjustment if an interaction is suspected. Likewise, patients should be observed for potential loss of glycemic control following discontinuation of the CYP450 2C9 inhibitor, and the nateglinide dosage adjusted as necessary.

MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may be potentiated by certain drugs, including ACE inhibitors, 4-aminoquinolines, amylin analogs, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs, including linezolid), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs, ginseng); decreasing insulin clearance and resistance (4-aminoquinolines); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing postprandial glucagon secretion (amylin analogs). Or, they may increase plasma concentration of insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin secretagogues, particularly in patients with advanced age and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

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 in some foods can form nonabsorbable chelates with tetracycline.

MANAGEMENT: Tetracycline should be administered one hour before or two hours after meals. Because oral tetracycline has caused rare cases of esophagitis and esophageal ulceration, patients should be advised to take tetracycline with a large glass of water while standing or sitting upright and to avoid laying down immediately afterwards.

GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

GENERALLY AVOID: The oral bioavailability of quinolone and tetracycline antibiotics may be reduced by concurrent administration of preparations containing polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc. Therapeutic failure may result. The proposed mechanism is chelation of quinolone and tetracycline antibiotics by di- and trivalent cations, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. Reduced gastrointestinal absorption of the cations should also be considered.

MANAGEMENT: Concomitant administration of oral quinolone and tetracycline antibiotics with preparations containing aluminum, calcium, iron, magnesium, and/or zinc salts should generally be avoided. Otherwise, the times of administration should be staggered by as much as possible to minimize the potential for interaction. Quinolones should typically be dosed either 2 to 4 hours before or 4 to 6 hours after polyvalent cation preparations, depending on the quinolone and formulation. Likewise, tetracyclines and polyvalent cation preparations should typically be administered 2 to 4 hours apart. The prescribing information for the antibiotic should be consulted for more specific dosing recommendations.