Drug Interactions between AccessPak for HIV PEP Expanded with Viracept and Xylon 10

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of hydrocodone, which is substantially metabolized by the isoenzyme. Increased hydrocodone concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Because hydrocodone is also partially metabolized by CYP450 2D6, the magnitude of interaction may be even greater with concomitant use of a CYP450 3A4 and a CYP450 2D6 inhibitor, or concomitant use of a drug that is a dual inhibitor of both isoenzymes.

MANAGEMENT: Extreme caution is advised if hydrocodone is prescribed with CYP450 3A4 inhibitors, particularly potent and moderate inhibitors (e.g., azole antifungal agents, protease inhibitors, aprepitant, ceritinib, ciprofloxacin, chloramphenicol, clarithromycin, cobicistat, conivaptan, crizotinib, delavirdine, diltiazem, dronedarone, erythromycin, fusidic acid, idelalisib, imatinib, letermovir, mibefradil, mifepristone, nefazodone, netupitant, quinupristin-dalfopristin, telithromycin, verapamil) or weak inhibitors that also inhibit CYP450 2D6 (e.g., abiraterone, amiodarone, cimetidine, pazopanib, ranolazine). A fatal overdose may occur following the initiation of a CYP450 3A4 inhibitor in patients already receiving hydrocodone. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. Following discontinuation of the CYP450 3A4 inhibitor, patients should be monitored for reduced efficacy of hydrocodone or development of withdrawal symptoms due to reduced plasma hydrocodone levels.

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GENERALLY AVOID: Coadministration of tenofovir with other nephrotoxic agents may increase the risk of renal impairment due to additive effects on the kidney. Additionally, renal impairment secondary to the use of these agents may reduce the clearance of tenofovir, which is primarily eliminated by a combination of glomerular filtration and active tubular secretion. The use of tenofovir has been associated with dose-related nephrotoxicity including acute renal failure and Fanconi syndrome characterized by renal tubular injury with severe hypophosphatemia, possibly as a result of mitochondrial toxicity. Cases of acute renal failure after initiation of high-dose or multiple nonsteroidal anti-inflammatory agents have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir therapy. Some patients required hospitalization and renal replacement therapy. Available clinical data seem to suggest a lower risk of nephrotoxicity with tenofovir alafenamide fumarate (TAF) than with tenofovir disoproxil fumarate (TDF), presumably due to lower tenofovir systemic exposure following administration of TAF relative to TDF. Whereas TDF is metabolized in plasma to tenofovir and phosphorylated intracellularly to the active moiety tenofovir diphosphate, TAF is largely metabolized and phosphorylated intracellularly, resulting in substantially higher intracellular concentrations of tenofovir diphosphate and lower plasma levels of tenofovir at the therapeutic dose of 25 mg compared to TDF 300 mg. It has been further reported that tenofovir is actively transported into the proximal renal tubular cell by organic anion transporters (OAT) 1 and 3, but that TAF is not a substrate for these transporters and thus less likely to cause tubular injury. There have been no cases of Fanconi syndrome or proximal renal tubulopathy in clinical trials of various TAF-containing products according to the manufacturers.

MANAGEMENT: The use of tenofovir in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; aminosalicylates; antiviral agents such as acyclovir, adefovir, cidofovir, foscarnet, and ganciclovir; 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) should be avoided if possible. Renal function tests including serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein should be performed prior to and during therapy with tenofovir. Patients with renal insufficiency at baseline or during treatment may require dosage adjustment in accordance with the manufacturer's product labeling. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

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