Pfizer, which purchased Wyeth last year, announced in a regulatory filing on February 26 that it was under investigation by the U.S. Attorney’s office for the Western District of Oklahoma. Pfizer officials did not provide any further details on the potential allegations, and federal prosecutors declined to comment on ongoing investigations.

Rapamune (sirolimus) is an immunosuppressant that prevents the body from rejecting organs after transplant surgery. The drug generated $376 million in sales in 2008.

It is most often used in kidney transplants for hemolytic-uremic syndrome, which can reoccur in a transplanted kidney. However, the drug is also commonly prescribed off-label for liver transplants as well. It is illegal for drug companies to promote medications for off-label uses, even though doctors can prescribe approved medications for any purpose they feel is appropriate.

The new charges come after Pfizer agreed last year to pay $2.3 billion to settle charges that it illegally marketed the painkiller Bextra and other drugs. That settlement included the largest criminal fine in U.S. history, $1.195 billion. The fine was specifically for off-label promotion charges.

That Pfizer settlement followed a four-year investigation into the company brought about after whistleblower lawsuits were filed alleging that Pfizer was defrauding the government. The agreement was reached in September, including a corporate integrity statement in which Pfizer promised federal prosecutors that the company would toe the line on off-label promotion restrictions.

In June 2009, the FDA issued a warning to transplant doctors that Rapamune side effects could increase the risk of death in liver transplant patients after a study found that the chance of liver rejection was “significantly higher” for stable liver transplant patients who switched from a calcineurin inhibitor (CNI)-based immunosuppressive treatment to Rapamune.

The FDA already requires that Rapamune carry a “Black Box” warning advising against its use immediately after a liver transplant.

Allergan Inc. filed the complaint Thursday in the U.S. District Court in Washington, D.C., saying that the FDA’s ban on “off-label” drug promotion by pharmaceutical companies violates their first amendment rights to free speech. The ban restricts Allergan from offering information about off-label use of Botox, an antiwrinkle drug that is used by many doctors for unapproved uses, such as treatment of muscle spaticity in children with cerebral palsy.

Although doctors are allowed to prescribe medications for non-approved uses, drug makers are prohibited from marketing those applications. Allergan says that the ban is unconstitutional and prevents them from offering truthful information and other data that could help doctors prescribe the drugs effectively and safely.

Botox contains extremely minute quantities of Botulinum Toxin A, which causes muscle paralysis. Although the medication is most commonly known for its cosmetic uses to remove wrinkles, it is also approved treat cervical dystonia, spasms of the eyelids and symptoms of severe underarm sweating.

One of the most common off-label Botox uses is among children with cerebral palsy, who are given much larger doses of the drug. The toxin is used to prevent muscles from involuntarily contracting, helping alleviate stiff, jerky and difficult movements commonly associated with cerebral palsy.

Earlier this year, the FDA required a black box warning for Botox about the risk of serious injury or death if the drug spreads from the area of the injection to other parts of the body. The warning was issued after the FDA received a number of reports of Botox problems, most commonly involving off-label use at higher doses.

Allergan claims that they should be permitted to provide doctors with dosing guidelines and instructions on injection techniques that could help reduce the risk associated with Botox off-label use and improve patient safety.

The effect of a successful overturn of the FDA ban on drug companies marketing off-label uses of their products could have far reaching effects. According to a 2006 study in the Archives of Internal Medicine, more than 20% of all drug prescriptions in the United States are already off-label, and this number could increase dramatically if drug companies are allowed to promote information about unapproved use.

Despite the ban, which has been in effect since 1938, many pharmaceutical companies have been accused of promoting drugs off-label, which can substantially increase sales. Last month, Pfizer agreed to pay $2.3 billion in fines to resolve claims that they promoted the recalled painkiller Bextra for unapproved uses. Government prosecutors said that Pfizer marketed Bextra for uses that would require larger doses even after learning that the health risks of the drug increased with dosage.

Last week, Eli Lilly & Co. agreed to pay $25.1 million to the state of Connecticut, on top of more than $1.4 billion in fines that were part of a January settlement over off-label promotion and hiding side effects associated with their antipsychotic drug Zyprexa.

AstraZeneca also faces allegations of off-label promotion for its antipsychotic drug Seroquel in lawsuits filed by nearly 20,000 plaintiffs who claim the drug maker failed to adequately warn about potential side effects of Seroquel that may increase the risk of diabetes, weight gain, hyperglycemia and a rare movement disorder known as tardive dyskinesia.

The deal between the pharmaceutical company and the U.S. Justice Department includes a $1.195 billion criminal fine to resolve claims that they promoted drugs for uses that were not approved by the FDA or established as safe and effective. The drug maker will also pay another $1 billion in civil penalties and make a five-year corporate integrity agreement with the U.S. Department of Health and Human Services.

The Pfizer settlement concludes a four-year investigation into the practices of the world’s largest drug company. The investigation was brought about after whistleblowers from several states filed lawsuits that alleged Pfizer was defrauding government health programs due to its illegal marketing practices. Under the terms of the deal, six whistleblowers will share in more than $100 million of the settlement.

Bextra (valdecoxib) was approved by FDA in 1991 for the treatment of arthritis and menstrual cramps. However, Pfizer marketed the drug to doctors for the treatment of acute pain, which was an “off-label” use. While doctors can prescribe drugs for non-approved uses, it is illegal for drug companies to market them that way. A Bextra recall was issued in April 2005 after it was found that it increased the risk of heart attack, stroke and a serious, potentially fatal skin reaction known as Stevens-Johnson syndrome.

Government prosecutors say that Pfizer marketed Bextra for uses that would require larger doses even after learning that the health risks of the drug increased with dosage. Prosecutors said that Pfizer also provided doctors with kickbacks and incentives including paying doctors for weekend meetings in resort locations. The government also accused Pfizer of illegally marketing the epilepsy drug Neurontin, the antipsychotic Geodon, and several other drugs.

The felony plea will be made by Pfizer subsidiary Pharmacia & Upjohn over its marketing of Bextra specifically. Pfizer has not admitted guilt in any of the civil charges brought against it by whistleblowers, although it is settling with them.

The “corporate integrity” settlement Pfizer is signing is a pledge of good behavior with the government, agreeing to reform its marketing practices. It is the third such pledge Pfizer has made in less than ten years. It signed an agreement in 2002 over its marketing of Lipitor, and again in 2004 over marketing practices for Neurontin.

Celebrex and Bextra are pain medications that were sold by Pfizer to millions of Americans. Also known as COX-2 enzyme inhibitors, the drugs reduce pain and inflammation in the back and neck and pain from arthritis. However, they have also been linked to increased cardiovascular risk, including heart attacks and strokes.

They are non-steroidal anti-inflammatory (NSAID) pain medications, which are part of the same class of medications as Vioxx, which was recalled in 2004 by Merck & Co. as a result of heart risks. Merck is currently in the process of finalizing about 50,000 Vioxx settlements for $4.8 billion.

Reports of Celebrex and Bextra settlements first began to surface in May 2008, when the Wall Street Journal reported that Pfizer was negotiating with lawyers who represent injured users of the drugs. However, Pfizer did not confirm the settlements until they issued a press release on October 17, 2008.

Pfizer indicates that they have agreed to set aside $894 million to pay Bextra and Celebrex settlements which have been reached on nearly all of the pending personal injury lawsuits that the company is aware of.

The drug maker indicates that $745 million will be used to settle injury lawsuits, $60 million will be applied to state attorney general settlements and $89 million will be applied to Celebrex and Bextra class action lawsuits alleging consumer fraud.

Although no specific figures were provided about the number of Bextra and Celebrex lawsuits settled or the value of each case, the May 2008 report in the Wall Street Journal indicated that lawyers negotiating the cases have been averaging about $200,000 for each Bextra settlement and between $40,000 and $50,000 per case for Celebrex settlements.

Pfizer issued a Bextra recall in April 2005 after it was linked to heart attacks, strokes, blood clots and other injuries such as the Stevens-Johnson Syndrome (SJS), which is a serious and potentially fatal skin reaction. The Bextra Stevens-Johnson Syndrome lawsuits were not included in the announced settlements, as most of these cases have already settled.

While Celebrex was also linked to the heart risks, Pfizer did not recall the medication and it is still on the market today with much stronger warnings.

Thousands of individuals have filed Celebrex lawsuits and Bextra lawsuits claiming that the COX-2 inhibitors caused an injury. Both drugs are in the same class of medications as Vioxx, which was recalled in September 2004 due to cardiovascular risks. In April 2005, Pfizer issued a Bextra recall, but they kept Celebrex on the market with much stronger warnings.

The report indicates that the Bextra settlement offers have averaged about $200,000.00 for each claim and the Celebrex settlement offers have averaged about $40,000.00 to $50,000 per case. Pfizer is negotiating the settlement of lawsuits on a firm-by-firm basis, instead of attempting to arrange a global settlement like Merck did with Vioxx last November.

According to lawyers representing individuals injured by Celebrex and Bextra, Pfizer’s attorneys have indicated that the pharmaceutical company is currently willing to pay as much as $500 million to resolve all outstanding cases. By contrast, Merck’s Vioxx settlement involved an agreement to pay $4.85 billion to resolve about twice as many lawsuits.

According to financial reports, Pfizer reported Celebrex sales of $611 million during the first three months of 2008. Therefore, the Bextra and Celebrex settlements are unlikely to have much of a financial impact on the drug maker.