A three-part investigative series by Knight Ridder Newspapers has found that patients nationwide are being harmed as doctors routinely prescribe drugs in ways the Food and Drug Administration has never approved as safe and effective. The study, based on a sample of top-selling drugs, found that the number of off-label prescriptions has nearly doubled in five years. The Knight Ridder analysis released today is perhaps the most comprehensive ever done of off-label prescribing.

The series by investigative reporters Alison Young and Chris Adams is based on interviews with patients, doctors, researchers and drug companies, and the review of thousands of records from lawsuits, government hearings and regulatory actions, medical records and scientific studies. The complete results will run over the next three days in Knight Ridder newspapers across the country.

Off-label prescribing is legal, widely accepted and defended by doctors and the American Medical Association. Victims of off-label prescribing interviewed by Knight Ridder have suffered heart attacks and strokes, had permanent nerve damage or lost their eyesight. Based on the FDA's own data, the report estimates that at least 8,000 people became seriously ill last year after taking some of the nation's most popular drugs for off-label purposes.

Among the report's findings on prevalence of off-label prescribing:

• 21 percent of the prescriptions examined were for off-label uses
• 115 million off-label prescriptions for the drugs analyzed by Knight Ridder were written in the U.S. last year, nearly double the number of five years ago
• As many as 90 percent of the prescriptions for some drugs were off-label uses.
• Three-quarters of anti-seizure medications are prescribed off-label, as are nearly two-thirds of antipsychotics and about one-quarter of antidepressants

The report tracks some of the most widely prescribed drugs in the U.S. It found that doctors are giving their patients epilepsy drugs for depression, hot flashes and to help them lose weight. They use antidepressants to treat premature ejaculation and pain, and powerful antipsychotics for insomnia and attention deficit disorder. High blood-pressure pills are prescribed for headaches and anxiety; antibiotics are used to treat viruses.

Eight out of 10 prescriptions for the epilepsy drug Topamax aren't for epilepsy. Thalidomide, the morning-sickness drug that caused horrible birth defects and ushered in today's FDA drug-safety rules, even is on the market, and 99 percent of its prescriptions are off-label.

To calculate how often drugs are prescribed off-label, Knight Ridder analyzed the three top-selling drugs in 15 classes of medications, comparing what doctors said they prescribed them for with the FDA's approval for each. The analysis looked at 900 million prescriptions written in 1998 and 2003 for more than 1,000 different ailments. Its estimate of the prevalence of off-label prescribing excluded cancer treatments or pediatric off-label uses, because they already are known to have a large percentage of off-label use.

To estimate how often patients are harmed by this practice, Knight Ridder reviewed the FDA's database of adverse drug reactions. The FDA estimates that only 1 to 10 percent of reactions are reported. Knight Ridder identified more than 800 reports filed during 2002 of serious reactions involving off-label prescriptions for its sample of 45 drugs. Experts say that means anywhere from 8,000 to 80,000 people probably were affected.