Drug Interactions between bupivacaine / ketamine / ketorolac and idelalisib

MONITOR: The risk of neurotoxicity may be increased when local anesthetics are used together with intraspinal ketamine. Animal and cell studies have shown that the combined neurotoxicity of lidocaine and ketamine are additive.

MANAGEMENT: Caution is advised during concomitant use of local anesthetics with intraspinal ketamine.

GENERALLY AVOID: Coadministration with idelalisib may increase the plasma concentrations of drugs that are substrates of CYP450 3A4. Idelalisib has been shown to be a potent inhibitor of this isoenzyme. In healthy volunteers, administration of a single 5 mg dose of midazolam, a CYP450 3A4 probe substrate, with idelalisib 150 mg for 15 doses increased mean midazolam peak plasma concentration (Cmax) by 2.4-fold and systemic exposure (AUC) by 5.4-fold.

MANAGEMENT: Use of idelalisib should generally be avoided with drugs that are primarily metabolized by CYP450 3A4, particularly those with a narrow therapeutic range (e.g., antiarrhythmics, anticonvulsants, antineoplastics, immunosuppressants) or those that are considered sensitive substrates (e.g., ergot derivatives, statins, oral midazolam, triazolam). Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever idelalisib is added to or withdrawn from therapy, if coadministration is required.

GENERALLY AVOID: Coadministration of idelalisib with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. The use of idelalisib has been associated with elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the upper limit of normal. Serious and fatal hepatotoxicity occurred in 14% of patients treated with idelalisib in premarketing trials. Liver enzyme elevations were generally observed within the first 12 weeks of treatment and were reversible with dose interruption. Following treatment resumption at a lower dose, 26% of patients had recurrence of ALT and AST elevations.

MANAGEMENT: The use of idelalisib with other potentially hepatotoxic agents should be avoided whenever possible (e.g., acetaminophen; alcohol; amiodarone; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; methotrexate; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; tetracyclines; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients treated with idelalisib should have serum ALT, AST, and bilirubin measured prior to initiation of treatment and regularly during treatment in accordance with the product labeling, and the dosing adjusted or interrupted as necessary. Permanent discontinuation of idelalisib is recommended in those who experience recurrent hepatotoxicity following dosage reduction. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.