By Margaret Cronin Fisk and Elizabeth Lopatto
July 30 (Bloomberg) -- Eli Lilly & Co.'s current label warning on health risks linked to its antipsychotic Zyprexa may not be strong enough, according to court documents.
Lilly added a warning to its packaging in October 2007 saying that more than half of patients in 13 studies gained an average of 12 pounds after taking the drug for less than a year. It also says Zyprexa is more ``associated'' with higher blood- sugar levels -- a risk factor for diabetes -- than similar medications.
The warning, approved by the U.S. Food and Drug Administration, may need to be adjusted to link Zyprexa more directly to higher blood sugar and diabetes, according to a letter to the Indianapolis-based drugmaker from the agency. The document was produced for a lawsuit by the state of Alaska claiming the company withheld information on risks of Zyprexa, Lilly's top-selling drug with sales of $4.76 billion last year.
``We anticipate that additional labeling changes will be necessary when we have reviewed the results of the additional analyses that we have requested,'' FDA administrator Tom Laughren wrote to Lilly in an Aug. 28 letter.
The letter states: ``Given that you're completing these analyses and our review of them will take some time, we believe that it is in the best interest of the public health to make interim labeling changes now based on the data that we already have available.''
Zyprexa generates about a quarter of Lilly's revenue. Prescriptions for the drug didn't significantly decrease after its latest warning, according to data compiled by Bloomberg. A March 2004 warning about the risk of diabetes and high blood sugar spurred a 5 percent drop in sales in 2005.
Lilly hadn't submitted all the requested additional information to the agency by Dec. 11, two months after its latest labeling change, according to the documents. The documents were released yesterday after Bloomberg News filed a motion to unseal them.
``Have all the analyses been submitted to the FDA yet?'' Robin Wojcieszek, Lilly's associate director of regulatory affairs in the U.S., said in testimony that day, according to the documents, which she said also included analyses of studies dating back to 1996. ``No. they have not,'' she answered.
A lawyer for the state of Alaska read her the passage in the FDA letter that mentioned ``interim'' changes. ``There may be additional changes?'' he asked. ``That's correct,'' she said.
Lilly doesn't expect more label changes, company spokeswoman Marni Lemons said in an interview July 8. Lemons didn't immediately return messages after business hours yesterday.
``It is safe to assume that since this letter is dated August 2007, and we made a pro-active label change in October 2007 based on all the compiled data we have at the time, we feel very confident that our label is correct and accurate as it currently stands, based on all the information that we have, all of which has been made available to the FDA,'' Lemons said July 8.
Lemons referred to the FDA questions on whether the agency had finished the additional analyses referred to in the August letter. An FDA spokesman, Christopher Kelly, didn't immediately comment.
Another label change probably ``won't have a major impact on sales per se because a lot of this information has become fairly obvious, given the CATIE study and other kinds of data,'' Les Funtleyder, a Miller Tabak & Co. analyst in New York, said yesterday in a phone interview.
The CATIE study, by the National Institute of Mental Heath, reviewed the effectiveness of second-generation antipsychotics, including Zyprexa. That study found that Zyprexa's advantages over an older medicine were ``modest and must be weighed against increased side effects.''
Lilly rose 64 cents to $48.26 in New York Stock Exchange composite trading yesterday. The stock has last 9.6 percent this year.
The FDA letter was submitted as evidence in March by the state of Alaska in its Zyprexa lawsuit a few days before Lilly agreed to pay $15 million to settle the case. Lilly also paid $1.2 billion to resolve claims brought by more than 31,000 patients who said they weren't adequately warned that Zyprexa could cause weight gain, diabetes or pancreas inflammation, Lemons said.
Lilly faces Zyprexa suits filed by nine other states that claim the company failed to warn of all risks and engaged in improper marketing. Separate consumer-protection investigations continue in about 30 other states, the company said May 6 in a regulatory filing. The U.S. Attorney's Office in Philadelphia is investigating off-label marketing of the drug.
Patients suing Lilly claim the company downplayed risks for years to boost Zyprexa sales and prevent stronger warnings of possible side effects.
Lilly trained its sales force to downplay risks for Zyprexa and to encourage doctors to prescribe the drug beyond approved uses for schizophrenia and bipolar disorder, according to court documents.
Stronger warnings would have reduced the chance that state Medicaid programs would designate Zyprexa as a first-line drug for its patients, according to an undated document in the Alaska case titled ``Scenario and Contingency Planning Session, US Zyprexa Brand Team.''
Zyprexa would ``lose access and become primarily a 2nd or 3rd line treatment,'' the Lilly document states.
Studies have shown Zyprexa and similar medications known as atypical antipsychotics are associated with weight gain and an increased risk of diabetes. These studies prompted the FDA to require Lilly and other drugmakers to warn doctors of the risks in September 2003 and again in March 2004.
The FDA told Lilly in March 2007 that it wanted more information about weight gain and high levels of sugar and fat in the blood connected to Symbyax, a drug combining Zyprexa and Prozac.
``We do not feel that current labeling for either Symbyax or Zyprexa provides sufficient information on these risks,'' the FDA's Laughren wrote, according to Alaska trial documents.
In August, the FDA requested added warnings to Zyprexa's label about hyperglycemia, or high blood sugar, weight gain and hyperlipidemia, or high level of blood fats, the documents show. Lilly should add that Zyprexa was ``associated with a greater potential to induce hyperglycemia than other atypical antipsychotics,'' the FDA said in its Aug. 28 letter.
Lilly took out references to causation for high blood sugar in the language suggested by the FDA, Wojcieszek testified in December. ``We did not include that in our proposal,'' she said.
``To this day, Lilly denies that olanzapine can induce or cause hyperglycemia, correct?'' the lawyer for Alaska asked.
``We don't feel that the -- that we have data to support that particular statement that FDA included,'' she answered.
The case is Alaska v. Eli Lilly and Co., 3AN-06-05630 CI, Alaska Superior Court, Anchorage District.
To contact the reporters on this story: Margaret Cronin Fisk in Southfield, Michigan, at email@example.com; Elizabeth Lopatto in New York at firstname.lastname@example.org.
Last Updated: July 30, 2008 00:01 EDT
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