Drug Interaction Report

GENERALLY AVOID: Coadministration with ciprofloxacin may significantly increase the serum concentrations of theophylline and the associated risk of toxicity. The mechanism is ciprofloxacin inhibition of theophylline metabolism via CYP450 1A2. Case reports and pharmacokinetic studies indicate that ciprofloxacin 500 mg to 750 mg twice daily can reduce the clearance of theophylline by approximately 20% to 65%, resulting in toxic theophylline levels and/or clinical toxicity in some patients. Up to fourfold increases in theophylline serum levels have been reported, with onset of clinical toxicity as early as two to three days and typically within a week of initiating ciprofloxacin. However, the interaction is subject to a high degree of interpatient variability and does not consistently produce clinically significant pharmacokinetic changes. Serious and severe reactions have included cardiac arrest, seizure, status epilepticus, respiratory failure, and even death. Seizures may also occur in the absence of toxic theophylline levels due to additive inhibitory effect of ciprofloxacin and theophylline on gamma-aminobutyric acid (GABA) receptor sites. Because elderly patients and patients with chronic obstructive pulmonary disease, congestive heart failure, or cirrhosis generally have lower theophylline clearance rates, they may be particularly vulnerable to theophylline toxicity. Theophylline does not appear to alter the pharmacokinetics of ciprofloxacin and other quinolones.

MANAGEMENT: The use of theophylline or its salts in combination with ciprofloxacin should generally be avoided. If coadministration is required, theophylline dosage may need to be reduced. Pharmacologic response and serum levels should be closely monitored following initiation, discontinuation or change of dosage of ciprofloxacin, and the theophylline dosage adjusted accordingly. Patients should be advised to contact their physician if they experience signs and symptoms suggestive of theophylline toxicity such as nausea, vomiting, diarrhea, anorexia, headache, tremor, irritability, confusion, insomnia, seizure, palpitation, and arrhythmia. Other quinolones including gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin have been reported to cause minor or no changes in theophylline levels at normally recommended dosages and may be safer alternatives in theophylline-treated patients.

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ADJUST DOSING INTERVAL: Concurrent ingestion of dairy products (milk, yogurt) or calcium-fortified foods (i.e., cereal, orange juice) may decrease the activity of certain oral fluoroquinolone antibiotics. The mechanism is chelation of calcium and the quinolone, resulting in decreased bioavailability. In the case of orange juice, inhibition of intestinal transport mechanisms (P-glycoprotein or organic anion-transporting polypeptides) by flavones may also be involved. One study reported an average 41% decrease in maximum plasma concentrations and a 38% decrease in AUC when ciprofloxacin was given with calcium-fortified orange juice instead of water. Administration of ciprofloxacin tablets with enteral nutrition may reduce its bioavailability and maximum serum concentrations. Data have been conflicting and variable by the type of enteral nutrition product, location of the feeding tube, and patient characteristics. Decreased absorption is expected if ciprofloxacin is given by jejunostomy tube.

MANAGEMENT: Oral ciprofloxacin should not be taken with dairy products or calcium-fortified foods alone, but may be taken with meals that contain these products. When taken alone, dairy products or calcium-fortified foods should be ingested at least 2 hours before or after ciprofloxacin administration. When ciprofloxacin tablets are administered to patients receiving continuous enteral nutrition, some experts recommend that the tube feeding should be interrupted for at least 1 hour before and 2 hours after the dose of ciprofloxacin is given. Patients should be monitored for altered antimicrobial efficacy and switched to intravenous ciprofloxacin if necessary. If no enteral route besides a jejunostomy tube is available, it is also recommended to switch to intravenous ciprofloxacin. According to the manufacturer, ciprofloxacin oral suspension should not be administered via nasogastric or feeding tubes due to its physical characteristics.

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GENERALLY AVOID: Coadministration with caffeine may increase the serum concentrations of theophylline. The proposed mechanism involves competitive inhibition of theophylline metabolism via CYP450 1A2, as well as metabolic conversion of caffeine to theophylline in vivo and saturation of theophylline metabolism at higher serum concentrations. In six healthy male volunteers (all smokers), serum concentrations of theophylline (administered as aminophylline 400 mg single oral dose) were significantly higher following consumption of caffeine (2 to 7 cups of instant coffee over 24 hours, equivalent to approximately 120 to 630 mg of caffeine) than after caffeine deprivation for 48 hours. Caffeine consumption also increased the apparent elimination half-life of theophylline by an average of 32% and reduced its total body clearance by 23%. In another study, steady-state concentration and area under the concentration-time curve of theophylline (1200 mg intravenously over 24 hours) increased by 23% and 40%, respectively, in eight healthy volunteers following administration of caffeine (300 mg orally three times a day).

MANAGEMENT: Given the narrow therapeutic index of theophylline, patients should limit or avoid significant fluctuations in their intake of pharmacologic as well as dietary caffeine.

ADJUST DOSING INTERVAL: Administration of theophylline with continuous enteral nutrition may reduce the serum levels or the rate of absorption of theophylline. The mechanism has not been reported. In one case, theophylline levels decreased by 53% in a patient receiving continuous nasogastric tube feedings and occurred with both theophylline tablet and liquid formulations, but not with intravenous aminophylline.

MANAGEMENT: When administered to patients receiving continuous enteral nutrition , some experts recommend that the tube feeding should be interrupted for at least 1 hour before and 1 hour after the dose of theophylline is given; rapid-release formulations are preferable, and theophylline levels should be monitored.

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ADJUST DOSING INTERVAL: Oral preparations that contain magnesium, aluminum, or calcium may significantly decrease the gastrointestinal absorption of quinolone antibiotics. Absorption may also be reduced by sucralfate, which contains aluminum, as well as other polyvalent cations such as iron and zinc. The mechanism is chelation of quinolones by polyvalent cations, forming a complex that is poorly absorbed from the gastrointestinal tract. The bioavailability of ciprofloxacin has been reported to decrease by as much as 90% when administered with antacids containing aluminum or magnesium hydroxide.

MANAGEMENT: When coadministration cannot be avoided, quinolone antibiotics should be dosed either 2 to 4 hours before or 4 to 6 hours after polyvalent cation-containing products to minimize the potential for interaction. When coadministered with Suprep Bowel Prep (magnesium/potassium/sodium sulfates), the manufacturer recommends administering fluoroquinolone antibiotics at least 2 hours before and not less than 6 hours after Suprep Bowel Prep to avoid chelation with magnesium. Please consult individual product labeling for specific recommendations.

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MONITOR: Coadministration with certain quinolones may increase the plasma concentrations and pharmacologic effects of caffeine due to inhibition of the CYP450 1A2 metabolism of caffeine. Quinolones that may inhibit CYP450 1A2 include ciprofloxacin, enoxacin, grepafloxacin, nalidixic acid, norfloxacin, pipemidic acid, and pefloxacin (not all commercially available). In healthy volunteers, enoxacin (100 to 400 mg twice daily) increased systemic exposure (AUC) of caffeine by 2- to 5-fold and reduced its clearance by approximately 80%. Pipemidic acid (400 to 800 mg twice daily) increased AUC of caffeine by 2- to 3-fold and reduced its clearance by approximately 60%. Ciprofloxacin (250 to 750 mg twice daily) increased AUC and elimination half-life of caffeine by 50% to over 100%, and reduced its clearance by 30% to 50%. Norfloxacin 400 mg twice daily increased caffeine AUC by 16%, while 800 mg twice daily increased caffeine AUC by 52% and reduced its clearance by 35%. Pefloxacin (400 mg twice daily) has been shown to reduce caffeine clearance by 47%.

MANAGEMENT: Patients using caffeine-containing products should be advised that increased adverse effects such as headache, tremor, restlessness, nervousness, insomnia, tachycardia, and blood pressure increases may occur during coadministration with quinolones that inhibit CYP450 1A2. Caffeine intake should be limited when taking high dosages of these quinolones. If an interaction is suspected, other quinolones such as gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, and ofloxacin may be considered, since they are generally believed to have little or no effect on CYP450 1A2 or have been shown not to interact with caffeine.

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GENERALLY AVOID: Coadministration with caffeine may increase the serum concentrations of theophylline. The proposed mechanism involves competitive inhibition of theophylline metabolism via CYP450 1A2, as well as metabolic conversion of caffeine to theophylline in vivo and saturation of theophylline metabolism at higher serum concentrations. In six healthy male volunteers (all smokers), serum concentrations of theophylline (administered as aminophylline 400 mg single oral dose) were significantly higher following consumption of caffeine (2 to 7 cups of instant coffee over 24 hours, equivalent to approximately 120 to 630 mg of caffeine) than after caffeine deprivation for 48 hours. Caffeine consumption also increased the apparent elimination half-life of theophylline by an average of 32% and reduced its total body clearance by 23%. In another study, steady-state concentration and area under the concentration-time curve of theophylline (1200 mg intravenously over 24 hours) increased by 23% and 40%, respectively, in eight healthy volunteers following administration of caffeine (300 mg orally three times a day).

MANAGEMENT: Given the narrow therapeutic index of theophylline, patients should limit or avoid significant fluctuations in their intake of pharmacologic as well as dietary caffeine.

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