Drug Interactions between ganaxolone and Symfi Lo

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 isoenzymes may significantly decrease the plasma concentrations of ganaxolone. According to the prescribing information, ganaxolone is metabolized by CYP450 3A4/5, 2B6, 2C19, and 2D6. In healthy study subjects, coadministration of ganaxolone with rifampin, a potent inducer of CYP450 2C19 and 3A4 and a moderate inducer of CYP450 2B6, decreased ganaxolone peak plasma concentration (Cmax) and systemic exposure (AUC) by 57% and 68%, respectively. Reduced efficacy of ganaxolone may occur. The interaction has not been studied with moderate or weak CYP450 inducers.

MONITOR CLOSELY: Central nervous system depressant or toxic effects may be additively or synergistically increased in patients taking ganaxolone with certain other drugs (such as other CNS-active agents or efavirenz) that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Concomitant use of ganaxolone with potent or moderate CYP450 3A4 inducers should be avoided when possible. If coadministration is necessary, a dosage increase of ganaxolone should be considered; however, the maximum recommended dosage should not be exceeded. In patients on a stable ganaxolone dosage who are initiating or increasing their dosage(s) of enzyme-inducing antiepileptic drug(s) such as carbamazepine, phenytoin, phenobarbital or primidone, an increase in the ganaxolone dosage may be required, not to exceed the maximum daily dosage. Additionally, patients treated with any medication that can cause CNS toxicity symptoms should be advised to seek prompt medical attention if they experience symptoms. Patients should be advised to avoid driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how the medications affect them.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (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; other HIV 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. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (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; other HIV 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. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.