Drug Interaction Report

ADJUST DOSE: Coadministration with tenofovir disoproxil fumarate may increase the plasma concentrations and toxicity of didanosine (ddI). The mechanism of interaction has not been established but may involve competitive inhibition of didanosine renal tubular secretion into the urine via human organic anion transporter 1 (hOAT1). In 14 healthy volunteers, tenofovir DF (300 mg/day) increased the steady-state peak plasma concentration (Cmax) and systemic exposure (AUC) of ddI (buffered tablets 250 or 400 mg/day, depending on weight) by an average of 28% and 44%, respectively, while ddI had no effect on the pharmacokinetics of tenofovir. Similar findings have been reported in pharmacokinetic studies using enteric-coated ddI, and the interaction occurred whether the drugs were administered simultaneously or 1 to 2 hours apart and with or without a light meal. Clinically, the interaction has been suspected in several cases of pancreatitis and lactic acidosis, some resulting in death, in patients who have previously tolerated ddI without tenofovir DF. Likewise, a retrospective analysis of 575 patients from an HIV clinic within a 2-year period found a higher incidence of pancreatitis in patients receiving ddI plus tenofovir DF than in those receiving ddI without tenofovir DF or tenofovir DF without ddI (2.7% vs. 0.5% and 0%, respectively). The interaction has also been associated with several cases of acute tubular necrosis and Fanconi's syndrome. In addition, compromised immunologic response and even deleterious effects on CD4 and CD8 cell counts have been reported with the combination. In one study, more than half of the 302 patients receiving regimens containing standard-dose ddI and tenofovir DF experienced a decline of more than 100 CD4 cells/mm3 (up to 30% had a decrease of more than 200 cells/mm3) at 48 weeks follow-up despite the maintenance of viral suppression, whereas patients receiving tenofovir DF without ddI or vice versa did not. Subsequent dose reduction of ddI led to a decrease in ddI plasma levels and a recovery of CD4, CD8, and total lymphocyte counts in a subgroup of the patients. A high rate of early virological failure has also been reported in patients receiving tenofovir DF and ddI with a nucleoside or nonnucleoside reverse transcriptase inhibitor.

MANAGEMENT: Due to reports of poor immunologic response and high rate of early virological failure, some experts do not recommend the coadministration of tenofovir DF and ddI within any antiretroviral regimen, particularly in patients with high viral load and low CD4 cell count. If the combination is prescribed, patients should be monitored closely for long-term ddI adverse effects such as pancreatitis, peripheral neuropathy, lactic acidosis, and nephropathy. In adults with normal renal function weighing more than 60 kg, the ddI dosage should be reduced from 400 to 250 mg/day when prescribed with tenofovir DF. For patients under 60 kg, the ddI dosage should be reduced from 250 mg to 200 mg once daily. During coadministration, the drugs may be taken on an empty stomach or with a light meal (less than 400 kcal, less than 20% fat) if the enteric-coated formulation of ddI is used. The drugs should be taken on an empty stomach if ddI is administered as one of the buffered formulations. Patients should be advised to seek medical attention promptly if they experience potential symptoms of ddI toxicity such as nausea, vomiting, abdominal pain/distention, fatigue, anorexia, unexplained weight loss, tachypnea, dyspnea, motor weakness, numbness, tingling, and pain in hands and feet.

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ADJUST DOSING INTERVAL: Didanosine bioavailability is decreased when administered with food. Loss of efficacy may result.

MANAGEMENT: Didanosine should be administered in the fasting state, at least 30 minutes before or more than 2 hours after eating.

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Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.

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