Genetics is asserting its importance in drug therapy and transforming how we understand and manage risks and effectiveness of treatment.

The Food and Drug Administration's (FDA's) recent requirement to add a genetic-testing recommendation to the label of carbamazepine and warfarin is just one indication of the changes leading to a future of more individualized patient care.

In December 2007, the prescribing information for the anticonvulsant carbamazepine—approved for neuropathic pain and seizure disorders such as epilepsy and with a long-acting version approved for episodes of mania and bipolar disorder I—was revised to include the recommendation for a genetic test for a particular human leukocyte antigen (HLA) gene variation, known as HLA-B^*1502 allele, in patients of Asian ancestry.

The allele is associated with greatly increased risk of the potentially fatal skin reactions of Stevens Johnson syndrome and toxic epidermis necrolysis.

One study conducted in Taiwan cited by the FDA in its announcements found that this allele was present in 59 of 60 patients with the severe skin reactions associated with carbamazepine and only 4 percent of those who tolerated the drug. HLA-B^*1502 is carried "almost exclusively in patients with ancestry across broad areas of Asia, including South-Asian Indians," according to the agency's announcement. "If they test positive, carbamazepine should not be started unless the expected benefit clearly outweighs the increased risk of serious skin reactions."

The recommendation calls for with-holding carbamazepine based on the presence of the allele, not on a patient's racial identity. Rather, one's apparent racial classification is a factor in deciding whether he or she should receive the genetic test.

The FDA recommended that the test be performed for most patients of Asian ancestry because the broad categories of Asians carry wide variations of the relevant gene, and this particular mutation may be present in as many as 15 percent or more of the people in certain parts of China and southeast Asia, but as low as 1 percent or less in Japan and Korea. Scientists have pointed out that racial and ethnic classifications are not precise reflection of genetic make-up of a person, and the FDA recommendations specifically pointed out the "difficulty in ascertaining ethnic ancestry and the likelihood of mixed ancestry."

The agency's recommendations also note that not all patients positive for HLA-B^*1502 will develop Stevens Johnson syndrome or toxic epidermis necrolysis, and those who have tolerated carbamazepine for several months should be considered relatively safe from the reactions even if they carry the genetic marker and regardless of ethnicity.

As scientists identify more genetic variations and their physiologic effects, the risks and benefits of more drugs will become better defined, and patients with high risk of side effects or high likelihood for responding to a medication will be better identified. In 2007,National Institute of Mental Health scientists found two genetic variations that significantly influence the emergence of suicidal thoughts upon starting citalopram, a selective serotonin reuptake inhibitor (Psychiatric News, October 19, 2007).

Pharmacologists have long been aware of variations in liver-enzyme genes that can affect how fast or slow drugs are metabolized in the body and are more frequently present in certain ethnic groups. These variations can lead to substantial differences in side effects and sometimes effectiveness, of the same dose of a drug in individual patients.

Since the FDA's 2004 approval of a genetic test, AmpliChip Cytochrome P450 Geno-typing, for detecting mutations that affect antidepressants, antipsychotics, and many other drugs, genetic concerns have gradually increased. For example, the FDA has issued warnings that some women with certain gene variations in liver enzymes that convert codeine into morphine more rapidly than most others may excrete unusually high levels of morphine in their breast milk and risk overdose when breast-feeding.

In August 2007 the labeling information for warfarin was updated and approved by the agency that recommends genetic tests to predict patients' variable response to the drug's effect on preventing blood clots.

"Driven by advances in genomics, emerging insight into each individual's unique susceptibility to disease promises to transform patient care," wrote James Evens, M.D., Ph.D., an associate professor in the Department of Genetics at the University of North Carolina, in a commentary in the December 12, 2007, JAMA. He argued that the growing knowledge in genetics will inevitably change medicine and the health care delivery system in a fundamental way. Pharmacogenomics, the study of how individual genetic variations affect people's response to drug therapy, will be increasingly applied in practice and change the "current practice of broad, somewhat random prescribing of a medication to everyone with a given disorder."

The announcement for the carbamazepine labeling change is posted at<www.fda.gov/cder/drug/infosheets/HCP/carbamazepineHCP.htm>. The FDA's consumer information on genomics and personalized medicine is posted at<www.fda.gov/fdac/features/2005/605_genomics.html>.▪