Aug. 27 (Bloomberg) -- Eli Lilly & Co. and Amylin Pharmaceuticals Inc. may have to add tougher warnings to prescribing instructions for their diabetes drug Byetta after four more patients taking the medicine died from pancreatitis.

The deaths announced by the companies today bring the total to six after the U.S. Food and Drug Administration announced two last week. No definite relationship between Byetta and the additional deaths has been proved, and the FDA was aware of them when it made its announcement last week, Amylin Chief Executive Officer Dan Bradbury said by telephone yesterday.

Byetta, available in the U.S. since June 2005, is Amylin's leading product, with global sales that rose 25 percent in the second quarter to $194.7 million from a year earlier. Indianapolis-based Lilly and Amylin, of San Diego agreed to warn of the risk of pancreatitis in October, after 30 milder cases were reported. The company is talking with the FDA about the possibility of additional warnings.

``We expect prescription declines for Byetta,'' said Jon Paul Lecroy, an analyst with Natixis Bleichroeder Inc., in New York, in a phone interview yesterday. ``It also puts in jeopardy the long-acting version'' that Lilly and Amylin plan to submit within nine months for U.S. approval, he said.

Sales of the approved version could decline 5 percent this week compared with last week, Lecroy said, and then drop further if the FDA requires the companies to display stronger, so-called ``black-box'' warnings.

`Very Rare'

Diabetes patients have a threefold risk of pancreatitis, or inflamed pancreas, and as many as 20 percent of patients with the condition develop complications, Amylin's Bradbury said in a telephone interview. Patients taking Byetta weren't at a greater risk for complications or death, he said.

``It is very important that people understand that in those four cases, there is no association with the pancreatitis and the deaths,'' Bradbury said. ``We're talking about an event that is very rare in a population that is at higher risk. The nature of cases are in line with what we would expect with this population.''

The companies' next version of the drug, Byetta LAR, is designed to be taken weekly instead of the standard injections given twice daily.

Because the drug stays in the body longer and can't be neutralized if pancreatitis develops, the FDA may have concerns when it considers it for approval, said Tim Anderson, an analyst at Sanford C. Bernstein & Co. in New York, in a note to investors last week. He still estimates approval in 2010 and U.S. sales of $1.5 billion of the new drug by 2015.

`Increased Severity'

Donald Therasse, Amylin's vice president of global patient safety, told analysts yesterday on a conference call that the company doesn't expect any ``increased severity of pancreatitis'' in the once-weekly version.

``These cases are all similar to those seen in the general population,'' Therasse said.

Amylin is discussing with the FDA possible changes to Byetta's prescribing information that may include raising the advisory to a warning from a precaution or changing the wording, said Orville Kolterman, Amylin's vice president of clinical and regulatory affairs. The company wouldn't estimate when a change could take place.

To contact the reporter on this story: Tom Randall in New York at trandall6@bloomberg.net; Shannon Pettypiece in New York at ro spettypiece@bloomberg.net

Last Updated: August 27, 2008 00:00 EDT