Drug Interactions between E.E.S.-400 and naltrexone / oxycodone

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of oxycodone, which is substantially metabolized by the isoenzyme. Increased oxycodone concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. According to some manufacturers, oxycodone systemic exposure (AUC) was, on average, approximately 2.4-times higher (range 1.5 to 3.4) during coadministration with itraconazole (200 mg orally for 5 days); 1.8 times higher (range 1.3 to 2.3) during coadministration with telithromycin (800 mg orally for 4 days); 3.6 times higher (range 2.7 to 5.6) during coadministration with voriconazole (200 mg twice daily for 4 days); and 1.7 times higher (range 1.1 - 2.1) during coadministration with grapefruit juice (200 mL three times daily for 5 days). Because oxycodone 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 oxycodone is prescribed with CYP450 3A4 inhibitors, particularly potent and moderate inhibitors (e.g., azole antifungal agents, protease inhibitors, aprepitant, ciprofloxacin, chloramphenicol, clarithromycin, cobicistat, conivaptan, crizotinib, delavirdine, diltiazem, dronedarone, erythromycin, fusidic acid, idelalisib, imatinib, mibefradil, mifepristone, nefazodone, netupitant, quinupristin-dalfopristin, telithromycin, verapamil) or weak inhibitors that also inhibit CYP450 2D6 (e.g., abiraterone, amiodarone, cimetidine, pazopanib, ranolazine). Some authorities advise that the oxycodone dose may need to be adjusted. A fatal overdose may occur following the initiation of a CYP450 3A4 inhibitor in patients already receiving oxycodone. 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 oxycodone or development of withdrawal symptoms due to reduced plasma oxycodone levels.

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CONTRAINDICATED: Naltrexone can antagonize the effects of opioids via competitive inhibition of opioid receptors. Patients receiving naltrexone may not benefit from opioid-containing medications such as cough and cold products, antidiarrheal preparations, and narcotic analgesics. Likewise, patients dependent on opioids may experience withdrawal symptoms when given naltrexone. Following use of naltrexone, patients may have increased sensitivity to opioids.

**Note: This warning does not apply to opioid products that are specifically formulated with naltrexone to deter abuse via snorting or intravenous injection when crushed.**

MANAGEMENT: The use of naltrexone is considered contraindicated in patients receiving opioids or dependent on opioids, including those maintained on opiate agonists (e.g., methadone) or partial agonists (e.g., buprenorphine). Naltrexone should also not be given to patients in acute opioid withdrawal. In an urgent situation when analgesia may be required in a patient who has received full blocking doses of naltrexone, consideration should be given to regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid analgesics, or general anesthesia. If opioid analgesia is required, the amount of opioid needed may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged. A rapidly-acting opioid analgesic that minimizes the duration of respiratory depression is preferred. Clinicians should be aware that reversal of full naltrexone blockade by administration of large doses of opiates can cause histamine release. Therefore, patients may experience non-opioid receptor-mediated effects such as facial swelling, itching, generalized erythema, and bronchoconstriction. Irrespective of the drug chosen to reverse naltrexone blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.

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GENERALLY AVOID: Coadministration of naltrexone with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Naltrexone, especially in larger than recommended doses (more than 50 mg/day), has been associated with hepatocellular injury, hepatitis, and elevations in liver transaminases and bilirubin. Other potential causative or contributory etiologies identified include preexisting alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other hepatotoxic drugs.

MANAGEMENT: The use of naltrexone with other potentially hepatotoxic agents should be avoided whenever possible (e.g., acetaminophen; alcohol; 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; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; 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 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. Periodic monitoring of hepatic function is advisable.

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