Drug Interaction Report

GENERALLY AVOID: Concomitant use of black cohosh (Cimicifuga racemosa rhizome) with other agents that are known to induce hepatotoxicity may theoretically increase the risk of liver injury. Black cohosh has been suspected in rare cases of liver toxicity ranging from abnormal liver function tests and jaundice to various forms of hepatitis and hepatic failure requiring transplantation. The onset has typically been within the first 3 months after initiation of black cohosh. Although approximately half of the cases resulted in hospitalization, most improved or resolved following discontinuation of the product. Many of the cases were not well documented with respect to the specific herbal formulation and dose used or timeframe of treatment in relation to onset of reaction, or they were complicated by multiple confounding factors. Some of the cases also involved products containing multiple herbal or other medicinal substances. Nevertheless, the European Medicines Agency (EMEA) and the Committee on Herbal Medicinal Products (HMPC) reviewed 42 such cases and released an assessment statement in 2006 indicating a potential connection between products containing Cimicifuga racemosa rhizome and human hepatotoxicity. The Medicines and Healthcare products Regulatory Agency (MHRA) in the U.K. also issued an assessment report supporting a causal association after reviewing data from over 40 cases received through their reporting system and similar systems in other countries, as well as in the published literature. Hepatotoxicity warnings are currently required on products containing black cohosh marketed in many European countries and Australia.

MANAGEMENT: Until more information is available, patients should consider avoiding the use of black cohosh if they are receiving other potentially hepatotoxic agents (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; other herbals and nutritional supplements such as 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.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.