Drug Interactions between ciprofloxacin and erlotinib

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.

GENERALLY AVOID: Grapefruit and grapefruit juice may increase the plasma concentrations of erlotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor that increased erlotinib systemic exposure (AUC) by 67%. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

GENERALLY AVOID: Cigarette smoking reduces erlotinib exposure due to induction of hepatic CYP450 1A2, one of the isoenzymes responsible for the metabolic clearance of erlotinib. Induction of CYP450 1A1 in the lungs may also contribute. In one pharmacokinetic study of healthy subjects given a single 150 mg dose of erlotinib, mean erlotinib peak plasma concentration (Cmax), systemic exposure (AUC) and plasma concentration at 24 hours were decreased by 35%, 64% and 88%, respectively, in current smokers compared to former/never smokers. Likewise, in a phase 3 non-small cell lung cancer (NSCLC) trial, the steady-state trough plasma concentrations of erlotinib in current smokers were approximately 2-fold less than in former/never smokers, accompanied by a 24% increase in apparent erlotinib plasma clearance. In a phase 1 dose-escalation study that analyzed the steady-state pharmacokinetics of erlotinib in current smokers with NSCLC, there was a dose-proportional increase in erlotinib exposure when the dose was increased from 150 mg to 300 mg, the maximum tolerated dose in the study population. Median steady-state trough plasma concentration at the 300 mg dose was approximately 3-fold higher than at the 150 mg dose. The clinical impact of smoking on erlotinib efficacy has not been studied.

ADJUST DOSING INTERVAL: Food enhances the oral absorption of erlotinib. According to the product labeling, administration with food increased the oral bioavailability of erlotinib from approximately 60% to almost 100% compared to administration in the fasting state.

MANAGEMENT: Consumption of grapefruit and grapefruit juice should be avoided or limited during treatment with erlotinib. Patients who currently smoke cigarettes are advised to stop smoking as soon as possible. If cigarette smoking is continued while taking erlotinib, the manufacturer recommends increasing the dosage of erlotinib by 50 mg increments at 2-week intervals up to a maximum of 300 mg as tolerated. However, the efficacy and long-term safety of dosages higher than 150 mg daily have not been established. Data from a double-blind, randomized phase 3 study (MO22162, CURRENTS) demonstrated no benefit in progression free survival or overall survival with an erlotinib dosage of 300 mg daily relative to the recommended dosage of 150 mg daily in active smokers (average of 38 pack years) with locally advanced or metastatic NSCLC who have failed chemotherapy, although patients in the study were not selected based on epidermal growth factor receptor (EGFR) mutation status. Safety data were comparable between the two dosages, but a numerical increase in the incidence of rash, interstitial lung disease and diarrhea was observed with the higher dosage. Patients who have received a dosage increase should immediately revert to the recommended dosage of 150 mg or 100 mg once daily (depending on indication) upon cessation of smoking. Erlotinib should be administered on an empty stomach at least one hour before or two hours after the ingestion of food.

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.

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.