Drug Interaction Report

GENERALLY AVOID: Concomitant use of intravascular radiocontrast media with other nephrotoxic agents may potentiate the risk of contrast-induced nephropathy and renal impairment. Contrast-induced nephropathy is most commonly defined as an increase in serum creatinine >=0.5 mg/dL or 25% from baseline within 24 to 72 hours of intravascular contrast administration in the absence of alternative etiologies, although nephropathy may occur up to a week after contrast exposure. Pathogenesis has not been fully elucidated, but may involve renal hypoperfusion and ischemia, direct cytotoxicity on tubular epithelial cells, and generation of reactive oxygen species. While the condition is usually transient and asymptomatic, it can be associated with increased risk of renal failure, dialysis, prolonged hospitalization, significant long-term morbidity, and mortality. Patients at increased risk of developing contrast-induced nephropathy include those with diabetes (especially diabetic nephropathy), preexisting renal insufficiency (serum creatinine >1.5 mg/dL or GFR <60 mL/min/1.73 m2), volume depletion (e.g., diuretic use), advanced age (>70 years), congestive heart failure, multiple myeloma, hypoalbuminemia, and concomitant use of nephrotoxic agents (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; aminosalicylates; antiviral/antiretroviral agents such as acyclovir, adefovir, cidofovir, foscarnet, and tenofovir; antineoplastics such as aldesleukin, cisplatin, clofarabine, ifosfamide, streptozocin, and high intravenous dosages of methotrexate; chelating agents such as deferasirox, deferoxamine, edetate disodium, and edetate calcium disodium; immunosuppressants such as cyclosporine, everolimus, sirolimus, and tacrolimus; intravenous bisphosphonates; intravenous pentamidine; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents; gallium nitrate; lithium; penicillamine). The incidence has been reported to be approximately 10% to 30% in patients with risk factors, and as high as 90% in diabetics with chronic kidney disease. Intraarterial administration of contrast media is also associated with increased risk of nephropathy relative to intravenous administration.

MANAGEMENT: Alternative imaging techniques that do not require contrast should be considered in patients who are at increased risk for contrast-induced nephropathy. Otherwise, experts recommend discontinuing other nephrotoxic drugs 1 to 2 days before administration of contrast media, depending on the clinical feasibility of doing so. The smallest effective dose (100 mL or less) of a nonionic, low-osmolar (e.g., iohexol, iomeprol, iopamidol, iopental, iopromide, ioversol) or iso-osmolar (e.g., iodixanol, iotrolan) contrast medium should be used whenever possible, since the risk of nephrotoxicity may be increased with increasing contrast dose, osmolarity, and ionicity. Some studies suggest a lower risk for iso-osmolar contrasts compared to low-osmolar contrasts, although data are limited. Serum creatinine levels should be measured before contrast administration (if procedure is not urgent) and continued for 24 to 48 hours after. In addition, patients should be adequately hydrated with either intravenous normal saline or sodium bicarbonate starting 3 (outpatient) to 6 (inpatient) hours before and continued for 6 to 24 hours after procedure. Oral fluids are also beneficial, but not as effective as intravenous hydration. N-acetylcysteine the day before and day of contrast administration, or theophylline up to 30 minutes before contrast administration, have also been used in high-risk or critically ill patients. Preferably, a nephrologist should be consulted to optimize prophylactic measures for preventing contrast-induced nephropathy in high-risk patients and to guide treatment if the condition occurs. Any repeat procedures with contrast media, if necessary, should not occur until at least 48 to 72 hours after the previous contrast exposure and renal function has fully recovered.

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ADJUST DOSING INTERVAL: Food may interfere with the gastrointestinal absorption of penicillamine. In a study of six healthy volunteers, administration of penicillamine (500 mg) following a standard breakfast reduced the mean peak plasma concentrations of penicillamine by 48% compared to administration in the fasting state.

MANAGEMENT: Penicillamine should be administered on an empty stomach, at least one hour before or two hours after meals, and at least one hour apart from any other drug, food, or milk. This permits maximum absorption and reduces the likelihood of inactivation by metal binding in the gastrointestinal tract.

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ADJUST DOSING INTERVAL: Oral administration of aluminum, copper, iron, zinc, magnesium, and possibly other minerals such as calcium may decrease the gastrointestinal absorption of penicillamine, and vice versa. The proposed mechanism involves chelation of penicillamine to polyvalent cations, which leads to formation of a nonabsorbable complex. In a study of six healthy volunteers, administration of penicillamine (500 mg) following a single dose of ferrous sulfate (300 mg) or antacid (Maalox Plus 30 mL) reduced the mean peak plasma concentration of penicillamine by 65% and 34%, respectively, compared to administration in the fasting state. In addition to chelation, some investigators suggest that antacids may also reduce penicillamine bioavailability by increasing gastric pH, which favors the oxidation of penicillamine to its poorly absorbed disulfide form. These changes could result in diminished therapeutic effects of penicillamine.

MANAGEMENT: Mineral supplements or other products containing polyvalent cations (e.g., antacids or preparations containing antacids such as didanosine buffered tablets or pediatric oral solution) should be administered at least two hours before or two hours after the penicillamine dose. In addition, pharmacologic response to penicillamine should be monitored more closely whenever these products are added to or withdrawn from therapy, and the penicillamine dosage adjusted as necessary. When penicillamine is coadministered with Suprep Bowel Prep (magnesium/potassium/sodium sulfates), the manufacturer recommends administering penicillamine at least 2 hours before and not less than 6 hours after Suprep Bowel Prep to avoid chelation with magnesium.

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