Drug Interactions between mitotane and morphine / naltrexone

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.

MONITOR: Coadministration with alcohol or other central nervous system (CNS) depressants may enhance the sedative effects of mitotane and increase the likelihood and/or severity of central nervous system (CNS) side effects. In clinical studies and post marketing reports, CNS side effects occurred in 40% of patients, primarily consisting of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%). Mitotane plasma concentrations exceeding 20 mcg/mL are associated with a greater incidence of severe neurologic toxicity. Clinical data are not available for the concomitant use of mitotane with other CNS depressants.

MANAGEMENT: Caution and clinical monitoring for increased CNS adverse effects is advised if mitotane is coadministered with alcohol, other CNS depressants, or agents that cause dizziness or vertigo. Patients should not drive, operate machinery, or engage in hazardous activities requiring mental alertness and motor coordination until they know how the medications affect them. In addition, more frequent monitoring of serum mitotane levels may be considered.

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.