DID - Nov. 11, 2008 Issue

Vol. 7 No. 221

California Reverses Decision in Reglan Case

A California appeals court has reversed a favorable decision for Wyeth in a product liability case involving the heartburn drug Reglan.

In its decision, the Court of Appeal of the State of California, First Appellate District, ruled 3–0 that the plaintiff in the case, Elizabeth Conte, provided evidence that her physician relied on Wyeth’s product information when he prescribed a generic version of Reglan (metoclopramide). But she did not prove that he relied on information provided by manufacturers of the drug’s generic versions — Pliva, Teva and Purepac — the court ruled, upholding a decision in their favor made by the City and County of San Francisco Superior Court.

Conte says in her complaint that she developed tardive dyskinesia, a neurological disorder, after taking a generic version of Reglan from August 2000 to April 2004. She claims the defendants knew or should have known of the widespread misprescribing of Reglan and its generic equivalents for periods of 12 months or longer even though the medication was approved for only 12 weeks of use, according to court documents.

The superior court had ruled that Conte did not show that she and her physician had relied on warnings or product labeling produced by Wyeth. It also said brand-drug makers have no obligation to patients who take generic versions of their drugs, according to court documents.

The appeals court disagreed, saying, “Wyeth’s common-law duty to use due care in formulating its product warnings extends to patients whose doctors foreseeably rely on its product information when prescribing metoclopramide, whether the prescription is written for and/or filled with Reglan or its generic equivalent.”

Decision Favors Generic-Drug Makers

The appeals court refused to overturn the decision in favor of Pliva, Teva and Purepac because Conte did not prove that any of them was responsible for her injury. It points to her appellate brief in making its decision: “No evidence indicates that the generic defendants disseminated any information concerning their metocloramide products aside from price lists (distributed to pharmacies) and package inserts, distributed with wholesale shipments,” according to court documents.

Furthermore, there is no evidence her physician “relied on either the price lists or the package inserts for generic metoclopramide, if and when he ordered or wrote Ms. Conte’s Reglan prescription.”

The appellate court also determined it would be “an inappropriate use of judicial resources” to review the trial court’s ruling in favor of generic companies on the basis of preemption, according to court documents.

The California decision comes weeks after the U.S. District Court for the Western District of Kentucky dismissed an individual’s Reglan product liability lawsuit against Teva Pharmaceuticals USA, UDL Laboratories, Pliva and Morton Grove Pharmaceuticals, citing federal preemption.

The original suit, filed by Dennis Morris in October 2007, named Wyeth, Pliva, Actavis Elizabeth, Morton Grove, Schwarz Pharma, Teva Pharmaceuticals USA and UDL Laboratories. Morris maintained that his use of metoclopramide from March 1993 until October 2005 caused him to develop tardive dyskinesia, according to court documents.

Russell had dismissed claims against Actavis in June. The judge separately dismissed claims against Wyeth and Schwarz June 30. Schwarz won its motion for summary judgment because the plaintiff had never taken its product, and claims against Wyeth caused by a generic Reglan product were dismissed, but other claims against the drugmaker remain.

The plaintiff’s claims under Kentucky law include liability, negligence and breach of implied warranty. His allegation that the defendants failed to warn him adequately when they knew that continued use of Reglan increased the risk of tardive dyskinesia was central to his claims. He also claimed the drugmakers failed to propose a labeling change as required by federal law.

In the Kentucky decision, Judge Thomas Russell found that it is up to the FDA to decide whether a drugmaker has failed to comply with agency regulations regarding adverse event reporting and proposed labeling changes. Whether they failed to recommend labeling changes had no bearing on the court’s federal preemption determination or Morris’ state law claims, according to court documents (DID, Oct. 29). — Elizabeth Jones


FDA Delays Action on Discovery’s Surfaxin Until April

Discovery Laboratories was dealt another setback for its investigational synthetic surfactant drug Surfaxin when the FDA designated the company’s complete response to the product’s third approvable letter as a Class 2 resubmission, giving the agency six months to act on the filing. 

When Discovery submitted the complete response last month, the company expected the filing to be designated as a Class 1 resubmission, which would have had a 60-day review period.

Discovery does not market any products and has been struggling for years to get Surfaxin approved for the prevention of respiratory distress syndrome in premature infants.

If approved, Surfaxin would be the only synthetic surfactant on the market and would compete with Abbott Laboratories’ market-leading surfactant Survanta (beractant), which is derived from cows and is a $100 million product in the U.S., Discovery has said.

Surfaxin’s development has been plagued with manufacturing problems (DID, May 5). Many of the manufacturing issues the FDA had with the application have been resolved, and the company’s production operations passed a preapproval inspection. 

The third approvable letter, which was issued after the successful inspection, cited documentation issues and requested that the firm tighten specifications, for which additional clinical testing was not required, according to the company.

Discovery’s complete response includes preclinical data from a biological activity test at a different dosage and data on reducing impurities in the product’s ingredients to satisfy International Conference for Harmonisation guidelines for lipid-related impurities for two phospholipids in the drug (DID, Aug. 7).

During an investor conference held Monday to discuss the FDA’s classification of the response filing, Chief Financial Officer John Cooper said the company has about $33 million in cash and will burn $8 million in the fourth quarter of 2008 and $7 million during the first quarter of 2009. Discovery may have to issue equity shares to maintain its cash position before introducing the product, he indicated. — Christopher Hollis


‘Dramatic’ Cardiovascular Risk Reduction Seen in Crestor Study

AstraZeneca’s statin drug Crestor reduced major cardiovascular events — the combined risk of heart attack, stroke, arterial revascularization, hospitalization for unstable angina or death from cardiovascular causes — by 44 percent compared with placebo in a study of 17,802 patients.

This result applied to male and female patients who had elevated high-sensitivity C-reactive protein but low-to-normal cholesterol levels and took 20-mg Crestor (rosuvastatin calcium), AstraZeneca says in a statement.

In the study, christened JUPITER — Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin — nearly 9,000 patients who got the drug had a 54 percent reduction in the risk of heart attack, a 48 percent reduction in the risk of stroke, a 20 percent reduction in total mortality and a 47 percent reduction in the combined risk of heart attack, stroke or cardiovascular death. The trial was halted early because of the drug’s effectiveness (DID, April 1).

Patients on Crestor also showed a median 50 percent reduction in “bad” LDL-C cholesterol and tolerated the drug well with no difference in major adverse events such as cancer or myopathy between the treatment groups, the company says. However, there was a small increase in physician-reported diabetes, which was “consistent with data from other large placebo-controlled statin trials,” AstraZeneca says.

The company expects to file a regulatory submission including the JUPITER data in the first half of 2009 to begin new promotional activities, subject to approved labeling. — Martin Gidron


GSK Withdraws NDA for Gabapentin Reformulation

GlaxoSmithKline (GSK) had to withdraw its NDA for its reformulated version of gabapentin Solzira for the treatment of restless leg syndrome. 

The FDA requested that data in a single study be reformatted, leading GSK to withdraw the application, the company and its partner XenoPort say in a statement Monday.

“GSK will conduct a review of other trial data sets taking this input into account,” the companies say. “The withdrawal does not relate to the content of the filing. GSK plans to resubmit the NDA quickly once this work is complete.”

GSK is not providing a time frame for the resubmission. But the company told DID resubmitting the Solzira (gabapentin enacarbil) NDA is a top priority, and it will do so as soon as possible.

XenoPort sold GSK rights to the product last year. The filing delay means XenoPort will not get $23 million in milestone payments from GSK and Astellas Pharma, which owns rights to the drug in Japan.

Solzira is a new chemical entity and is reformulated to improve the pharmacokinetics of gabapentin. — Christopher Hollis


Ethex Recalls Lots of Generic Drugs

Ethex, a subsidiary of KV Pharmaceutical, voluntarily recalled several lots of generic products because they may contain oversized tablets.

The affected tablets may contain more than the intended levels of the active ingredient, which could result in patients receiving as much as twice the expected dosage of these drugs.

Overdoses of products involved in the recall — propafenone HCl, isosorbide mononitrate, morphine sulfate and dextroamphetamine sulfate — could have serious or life-threatening consequences, including low blood pressure, arrhythmias and respiratory depression.

The lots involved in the recall were shipped prior to May 22:

  • Propafenone HCl tablets, 150 mg: Lots 73761, 78184, 79373, 81240, 81241, 81242, 83470, 84357, 90525 and 90526 with expiration dates ranging from March 2009 to March 2011;
  • Propafenone HCl tablets, 225 mg: Lots 71720, 74831, 76014-15, 81243-45, 89731, 90527-29 and 90657 with expiration dates ranging from March 2009 to February 2011;
  • Propafenone HCl tablets, 300 mg: Lots 72834, 76016-18, 81246, 89092, 89732, 90530, 90532 and 91641-42 with expiration dates ranging from June 2009 to March 2011;
  • Isosorbide mononitrate extended-release tablets, 30 mg: Lots 62355, 66423 and 68102 with expiration dates ranging from November 2008 to August 2009;
  • Isosorbide mononitrate extended-release tablets, 60 mg: Lots 63466, 66034, 67351 and 67354 with expiration dates ranging from December 2008 to November 2009;
  • Morphine sulfate extended-release tablets, 15 mg: Lots 81175, 82514-16, 89660, 89664, 89667, 90249-51 and 91687 with expiration dates ranging from December 2008 to February 2010;
  • Morphine sulfate immediate-release tablets, 15 mg: Lots 77852-54, 81746, 82519-20, 84113 and 90276-78 with expiration dates ranging from September 2009 to January 2011;
  • Morphine sulfate immediate-release tablets, 30 mg: Lots 75093, 77855-57, 82297, 82521-22, 87239, 88925 and 90288-98 with expiration dates ranging from August 2009 to March 2011; and
  • Dextroamphetamine sulfate tablets, 10 mg: Lots 73934, 75892, 77945, 81137 and 86320 with expiration dates ranging from June 2009 to May 2011.

In June, the firm recalled one lot of 60-mg morphine sulfate tablets because of a report that tablets were twice the appropriate thickness (DID, June 11). It then recalled 48 additional lots of 60-mg morphine sulfate and 15 lots of morphine sulfate ER 30-mg tablets in the same month. No reports of side effects or injury were received before the recalls.

Last month, the firm recalled three lots of its generic 5-mg dextroamphetamine sulfate tablets because some were larger than the product’s standard size and contained as much as twice the amount of amphetamine listed on the label. — Elizabeth Jones


J&J Reports Rivaroxaban Success, Plans Phase III Trial

Johnson & Johnson’s (J&J) Phase II clinical trial of the experimental anticoagulant rivaroxaban yielded encouraging response rates as a treatment for acute coronary syndrome (ACS).

The company is planning a Phase III trial of the drug starting next month for the secondary prevention of ACS, enrolling as many as 16,000 patients, according to a statement. It will test only twice-daily doses of 2.5 mg and 5 mg.

The completed Phase II trial was designed to test the safety and efficacy of rivaroxaban in eight daily regimens of doses from 5 mg to 20 mg versus placebo. Almost 3,500 patients were enrolled, all of whom received standard antiplatelet therapy of low-dose aspirin and, at the physician’s discretion, a thienopyridine, such as Sanofi-Aventis and Bristol-Myers Squibb’s Plavix (clopidogrel).

Rivaroxaban was associated with a 21 percent relative risk reduction for the primary efficacy endpoint of death, heart attack, stroke or severe recurrent ischemia requiring revascularization.

Patients taking rivaroxaban suffered more often from “clinically significant bleeding” than those on placebo, with rates ranging from 6.1 percent for those on the 5-mg dose to 15.3 percent for those on the 20-mg dose versus 3.3 percent of placebo patients. J&J said the results were expected and added that no study arm was halted due to increased bleeding. — Martin Gidron


FDA Adds New CMPs, Increases Maximum Fine Amounts

The FDA increased the maximum amounts of civil money penalties (CMPs) it may impose, and it added new fines to its regulations under the FDA Amendments Act (FDAAA).

The agency would impose the new penalties for some violations related to the submission of certifications or clinical trial information to the clinical trial data bank; other violations concern postmarketing studies, clinical trial requirements, and risk evaluation and mitigation strategies for drugs, as well as dissemination of direct-to-consumer advertisements for approved drugs or biological products, according to a final rule published in Monday’s Federal Register.

The agency increased the maximum CMP amounts by as much as 9.1 percent to adjust for inflation as required by the Federal Civil Penalties Inflation Adjustment Act of 1990 (FCPIAA). The FDA last adjusted the CMPs July 20, 2004, when it identified 14 fines for drug and medical device rule violations that fall within its jurisdiction under the FCPIAA.

The agency is not adjusting the civil money provisions enacted by the FDAAA, according to the final rule, which it issued at the same time as a proposed rule calling for comments because it expects there will be no significant adverse comments.

“If significant adverse comments are received, we will withdraw this final rule and address the comments in a subsequent final rule,” the agency says.

“These technical changes, required by law, do not substantively alter the existing regulatory framework, nor do they in any way affect the terms under which civil penalties are assessed by FDA. The formula for the amount of the penalty adjustment is prescribed by Congress in the FCPIAA,” the final rule states.

The adjusted penalties are the following:

Adjusted Maximum CMP Amounts for Drug-Related Violations

USC Section

Former Maximum
CMP Amount

Assessment Method

New Maximum

21 USC 333(b)(2)(A)


Drug sample distribution: Each of first two violations in a 10-yr. period


21 USC 333(b)(2)(B)


Drug sample distribution: Each violation after second conviction in one 10-yr. period


21 USC 333(b)(3)


Drug sample distribution: Per violation


21 USC 335b(a)


Drug development or approval: Per violation for an individual


21 USC 335b(a)


Drug development or approval: Per violation for “any other person”


21 USC 360pp(b)(1)


Recordkeeping: For related series of violations


42 USC 300aa-28(b)(1)


Vaccine recordkeeping and reporting: Per occurrence


Source: Civil Monetary Authorities Administered by FDA and Adjusted Maximum Penalty Amounts, from Federal Register final rule displayed 11/10/08.

The final rule is available at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-N-0561-nfr.pdf. — David Grant

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