DID - Oct. 8, 2007 Issue

Vol. 6 No. 197

Eli Lilly Adds Warnings to Zyprexa and Symbyax Labels

Eli Lilly has added new warnings to the U.S. product labels for its atypical antipsychotic drugs Zyprexa and Symbyax.

The changed labels include new warnings for both drugs concerning weight gain and hyperlipidemia (elevation of triglycerides and cholesterol) and updated information in the warning for hyperglycemia (elevated blood sugar), including additional detail on a greater association of increases in glucose levels with olanzapine than with some other atypical antipsychotics.

Eli Lilly said the added warnings reflect recently completed pooled analyses of the company’s own clinical trial data on adults and adolescents, as well as information from two large external studies of atypical antipsychotics and discussions with the FDA.

The company is informing U.S. physicians about the new warnings through a Dear Healthcare Practitioner letter, as well as informing consumer and professional associations and regulatory agencies outside the U.S. The drug firm said it is continuing to work with the FDA and will provide additional data and analyses when they become available.

Before the new warnings were added, Zyprexa (olanzapine) and Symbyax (olanzapine/fluoxetine HCl) labels contained information on the risks of weight gain and elevated blood sugar and lipids. These metabolic changes and weight gain have been reported as adverse events since Zyprexa’s approval in the U.S. in 1996 and Symbyax’s approval in 2003, Eli Lilly said. Since 2003, the Zyprexa and Symbyax labels have also contained an FDA-mandated antipsychotic class warning, which recommends monitoring patients for elevated blood sugar and diabetes.

“Lilly continues to recommend that clinicians consult expert guidelines for treating people with antipsychotics, particularly the monitoring of lipids and blood glucose, regardless of the medication prescribed,” Sara Corya, Eli Lilly’s global medical director, said. “Over the last several years, the company has been actively informing healthcare professionals about these recommendations.”

At the end of last year, Eli Lilly denied a series of articles in The New York Times that claimed the company’s internal data showed a higher rate of diabetes in patients taking Zyprexa than had been documented in the information it provided to doctors (DID, Dec. 27, 2006). — Martin Gidron


Kentucky Officials Suing Purdue for Misrepresenting OxyContin Risks

Kentucky officials are suing Purdue Pharma for misrepresenting the risks of its painkiller OxyContin, Kentucky Attorney General Greg Stumbo said.

The lawsuit, filed by Stumbo and Pike County officials, alleges that the company misled pharmacists, physicians and patients about OxyContin’s (oxycodone) addictive potential and seeks to recover damages related to “widespread addiction” to the drug.

Pike County has reported 40 deaths related to OxyContin abuse and addictions, the attorney general’s office said. The county will represent a class of Kentucky counties that were affected by the overprescribing of OxyContin because of Purdue’s alleged misrepresentation of the drug’s risks.

“As a result of the company’s attempts to con consumers about this powerful painkiller, unsuspecting people are being exposed to the risk of severe and disabling addiction,” Stumbo said.

The lawsuit alleges fraud, conspiracy, negligence and public nuisance on the company’s part. It seeks restitution for state and county government costs related to drug abuse programs and payments through Medicaid and the Kentucky Pharmaceutical Assistance Program. It was filed in Pike County Circuit Court for the Commonwealth of Kentucky.

From December 1995 to June 2001, some Purdue employees promoted OxyContin as less addictive, less subject to abuse and less likely to cause withdrawal symptoms than other painkillers, the attorney general’s office said. The company provided some of its sales managers with false data, so sales representatives gave misleading information to pharmacists.

“Purdue used a systematic approach to mislead pharmacists, physicians and patients about the addictive nature of OxyContin,” Stumbo said.

Purdue Pharma and three current and former company executives pleaded guilty to mislabeling OxyContin earlier this year in the U.S. District Court for the Western District of Virginia (DID, May 11). The company agreed to pay $19.5 million to 26 states and the District of Columbia to settle complaints that it encouraged physicians to overprescribe the drug (DID, May 9).

The FDA’s Office of Criminal Investigations said the company engaged in “an extensive, long-term conspiracy” to generate higher sales through illegal schemes. Purdue said it accepted responsibility for the misleading statements its employees made.

The Kentucky lawsuit also demands that the court establish a medical monitoring program, funded by Purdue Pharma, to diagnose and treat addiction problems in the state. — Emily Ethridge


UCB, Mylan Settle Keppra Litigation

UCB announced last week that it has reached agreements with three generic drugmakers to settle patent litigation involving its epilepsy drug, Keppra.

The agreements settle pending lawsuits in the U.S. District Court for the Northern District of Georgia involving Mylan, Dr. Reddy’s Laboratories and Cobalt Pharmaceuticals, UCB said.

Under the agreement with Mylan, the company will be allowed to sell its generic Keppra (levetiracetam) 250-, 500- and 750-mg tablets effective Nov. 1, 2008, before the expiration of UCB’s market exclusivity, provided the FDA approves Mylan’s product and UCB obtains pediatric exclusivity for Keppra, the companies said. Mylan could enter the market sooner if UCB does not get pediatric exclusivity, UCB said.

Keppra tablets had U.S. sales of approximately $742 million during the 12-month period that ended in June, Mylan said.

The remaining terms of the Mylan settlement agreement and the agreements with Dr. Reddy’s and Cobalt are confidential, UCB said. Dr. Reddy’s and Cobalt could not be reached for comment. The agreements are subject to review by the Department of Justice and the FTC.

Settlement agreements face heightened FTC scrutiny as the agency monitors possible reverse-payment agreements, David Balto, former policy director in the FTC’s Bureau of Competition, said last month at the Third Annual FDA Regulatory and Compliance Symposium at Harvard University.

Some red flags include agreements where the generic drugmaker receives a payment not to market its product or agreements that restrict the generic company’s 180-day exclusivity period, Balto said.

Howard Morse, a partner with Drinker Biddle & Reath, told DID it is impossible to tell what kind of agreement this is, although there is no indication of a payment. He also noted that the FTC has said that simply “splitting the patent life” without a payment is not problematic. — Breda Lund


Novartis’ Prexige Withdrawn in Canada, Reclast Gets Nod in Europe

Health Canada announced it will revoke the market authorization for Novartis’ Prexige due to the potential for serious liver-related adverse events. Novartis said it has complied with the agency’s request to cease sales and marketing of the drug.

Prexige (lumiracoxib), a Cox-2 inhibitor, was approved in Canada in November 2006 for treating the signs and symptoms of osteoarthritis in adults at a maximum daily dose of 100 mg, the agency said.

Novartis said Health Canada’s approval of Prexige was based on clinical trial data from approximately 40,000 patients.

In August, Health Canada said it would review the safety after the drug was withdrawn from the Australian market (DID, Aug. 20). Australian reports of serious liver adverse events were linked with 200- and 400-mg doses of the drug, Health Canada noted.

Since Prexige was approved in Canada, there have been two Canadian cases of serious liver-related adverse events associated with the drug, Health Canada said. The agency has concluded that the risk of serious liver-related adverse events with Prexige cannot be safely and effectively managed at the 100-mg dose.

Last month, the FDA issued a not-approvable letter to Novartis for Prexige in the treatment of osteoarthritic pain (DID, Sept. 28). The 200- and 400-mg strengths of the drug were withdrawn in New Zealand in August (DID, Aug. 24).

Novartis also announced last week that the European Commission has approved its once-yearly treatment for postmenopausal osteoporosis, which is marketed as Reclast (zoledronic acid) in the U.S. but will be called Aclasta in Europe.

The FDA approved the treatment in August (DID, Aug. 21). Reclast is the only treatment approved in the U.S. and Europe to reduce the risk of fractures in areas of the body typically affected by osteoporosis, including the hip, spine, wrist and rib.

The FDA recently said it is planning to review new safety data related to reports of atrial fibrillation in patients taking bisphosphonates, which includes Reclast (DID, Oct. 3).

A study in the May 3 issue of the New England Journal of Medicine reported increased rates of serious atrial fibrillation in patients taking Reclast and Fosamax (alendronate sodium), the agency said. However, the FDA does not recommend that healthcare professionals change their prescribing habits of bisphosphonates or that patients change their use of the drugs. — Breda Lund


Novartis and MIT Enter Into Partnership to Improve Manufacturing Efficiencies

Novartis will fund a $65 million joint-research program with the Massachusetts Institute of Technology (MIT) aimed at developing new technologies to improve pharmaceutical manufacturing efficiencies, the company and university announced last week.

The 10-year research program will focus on changing current pharmaceutical production methods from a batch-based system to a continuous manufacturing process, Novartis and MIT said.

Under a batch-based production process, active pharmaceutical ingredients (APIs) are synthesized at one facility then transferred to another for conversion into pills, liquids or creams. The problem with batch-production processes is each batch may take weeks to produce and involves several steps, Novartis and MIT said.

Under a continuous manufacturing process, there is no interruption of production from one step to the next, MIT told DID.

“One benefit of constant throughput is that equipment, infrastructure and buildings can be significantly reduced in size, which in turn saves investment costs. Operation of smaller units requires less energy and raw material consumption. Furthermore, due to the continuous flow of product, no interruption of the process occurs while assuring quality with real time, online analysis,” MIT said.

Bernhardt Trout, an associate professor of chemical engineering at MIT, said a major goal of the program is to eliminate the development time of manufacturing process scale-up for new drugs. By integrating the manufacturing process in one operation, from API manufacture to finished-dose production, scale up times and manufacturing shutdowns and startups could be reduced.

Another benefit of the program includes the possibility of reducing the number of excipients used in pharmaceutical production and more efficiently utilizing raw materials, Trout said.

Integrating API and finished-dose production will require new technologies and equipment. Under the joint-research program, MIT will develop the technologies on a small scale during the first five years of the project, then transfer the technology and process to a Novartis facility for large-scale production, Trout said.  

In other Novartis-related news, the firm’s dipeptidyl peptidase-4 (DPP-4) inhibitor Galvus (vildagliptin) was approved in Europe for the treatment of Type II diabetes in combination with metformin, sulfonylureas or thiazolidinediones, such as GlaxoSmithKline’s Avandia (rosiglitazone maleate).

The product, now the second DPP-4 inhibitor approved for use in the European Union, is pending at FDA. The agency issued an approvable for Galvus earlier this year requesting an additional study to assess the safety of the product in patients with impaired kidney function (DID, Feb. 27).

During an investor conference last month, Novartis CEO Daniel Vasella said he does not expect the FDA to take action on Galvus until 2009 (DID, Sept. 18). — Christopher Hollis

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Reporters: Martin Gidron, Emily Ethridge, April Astor, Breda Lund, Christopher Hollis

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