View Table: Mechanisms of Drug Interactions

Itraconazole (Sporanox - Janssen), an antifungal triazole, has been approved by the US Food and Drug Administration (FDA) for oral treatment of histoplasmosis and blastomycosis. These two endemic mycoses occur both in normal hosts and in immunocompromised patients, such as those with AIDS (RW Bradsher, Clin Infect Dis, 14:S82, 1992; LJ Wheat, Clin Infect Dis, 14:S91, 1992).

Serious adverse interactions between drugs continue to be reported. Many of these are due to inhibition or induction of cytochrome P450 (CYP) enzymes, particularly CYP3A4. CYP3A is thought to be involved in the metabolism of more than 50 percent of currently prescribed drugs.2 CYP3A4, which is more abundantly expressed than CYP3A5, accounts for most CYP3A activity in vivo.

The FDA has approved the marketing of tolvaptan (Samsca - Otsuka), an oral vasopressin receptor antagonist, for treatment of hypervolemic or euvolemic hyponatremia due to congestive heart failure (CHF), cirrhosis or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). A similar drug, conivaptan (Vaprisol) is already available for intravenous (IV) treatment of euvolemic hyponatremia in hospitalized patients. Tolvaptan was approved by the FDA for both inpatient and outpatient use, but it should be started in a hospital.

Four new drugs have become available in the USA for HIV infection or its complications. Nevirapine (Viramune - Roxane), intravenous cidofovir (Vistide - Gilead), and amphotericin B oral suspension (Fungizone Oral Suspension - Bristol-Myers Squibb) have been approved by the US Food and Drug Administration; nelfinavir (Viracept - Agouron) is currently available only through an "Expanded Access Program."

The FDA has approved a fixed-dose combination of omeprazole, amoxicillin, and rifabutin (Talicia – RedHill) for treatment of Helicobacter pylori infection in adults. Talicia is the first rifabutin-based product to be approved for this indication.

Warfarin sodium (Coumadin, and others) and other coumarin anticoagulants prevent thrombosis, but patient response is highly variable and overanticoagulation can lead to hemorrhage. Genotyping patients for single nucleotide polymorphisms (SNPs) that affect coumarin metabolism and sensitivity may help clinicians estimate the therapeutic warfarin dose. The FDA has added a note to warfarin labeling recommending lowrange doses for patients with such genetic variations. Commercial tests for these variants are now available and cost about $500 per test.

A recent letter to the editor of the Annals of Internal Medicine documented a single case of myopathy apparently due to an interaction between simvastatin (Zocor, and others) and green tea. Since it became available generically, simvastatin has surpassed atorvastatin (Lipitor) as the best selling statin. As such, it is probably the most common cause of statin-induced myopathy, which is often a result of drug interactions.

Probiotics are live, nonpathogenic microorganisms (usually bacteria or yeasts) marketed as dietary supplements. They have not been approved by the FDA for any indication. Since our last article on this subject, some new data have become available.

Clobazam (Onfi – Lundbeck), an oral benzodiazepine, has been approved by the FDA for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients ≥2 years old. It has been available in Canada (Frisium) and other countries for years for treatment of anxiety and many types of epilepsy.