DID - Feb. 7, 2008 Issue

Vol. 7 No. 26

Injectable Zyprexa Is Safe, Has Somnolence Risk, Advisory Committee Says

A longer-lasting injectable version of Eli Lilly’s schizophrenia drug Zyprexa would be safe for use under some circumstances despite cases of severe somnolence in patients using the product, an FDA advisory committee says.

Approximately 1.2 percent of patients receiving olanzapine pamoate depot in clinical trials had episodes of profound sedation, a “relatively common” occurrence, Jing Zhang, the FDA’s clinical reviewer of the drug’s new drug application, said. A total of 25 events occurred in 24 of 1,915 patients.

The sedation episodes tended to be severe, hospitalizing 20 of the 24 patients. The episodes included five cases of altered consciousness, two comas and two patients requiring intubation. Most sedation episodes typically happened within 1–3 hours after injection, according to the FDA. The exact cause of the sedation events is unknown.

Most patients who experienced sedation events stayed in the clinical trials and continued to receive the drug, the FDA said. All patients reportedly recovered within 3–72 hours.

The FDA’s Pyschopharmacologic Drugs Advisory Committee voted unanimously, 11–0, in two separate votes that olanzapine pamoate depot was effective in both the maintenance treatment of schizophrenia and the acute exacerbation of schizophrenia.

The committee voted 10–0 with one abstention on two questions: the drug could be acceptably safe both to treat acute exacerbation of schizophrenia and to maintain treatment of schizophrenia. The committee, however, changed the original question posed by the FDA, which was whether the drug was shown to be acceptably safe for the treatment of acute exacerbation or maintenance of schizophrenia. 

Eli Lilly maintains the drug’s benefits outweigh its risks as an important alternative for schizophrenic patients, many of whom do not take oral medications regularly. Failing to treat schizophrenia can be catastrophic, the company said.

Advisory committee members debated potential restrictions for the drug, such as whether it could only be indicated for patients with a documented history of nonadherence to other medications. They also questioned if the drug’s labeling could suggest a mandatory monitoring period of patients after receiving the drug.

The committee also discussed the public health consequences of approving an antipsychotic that led to profound sedation in 1 percent or more of patients. Members agreed there was value in seeking to manage and prevent the severe sedation episodes to handle the significant public health concern. 

In addition, the committee said it endorses the company’s plan to further study and better understand this problem.

Eli Lilly representatives said they would include cautions about using Zyprexa in its marketing activities if the drug were approved. — Emily Ethridge


NIH Study Casts Doubt on Avandia Risks

Newly released information from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study produced no evidence of increased risk of death from GlaxoSmithKline’s (GSK) controversial drug Avandia, the National Heart, Lung and Blood Institute (NHLBI) announced.

The study at sites in the U.S. and Canada included 10,251 adults at especially high risk for heart attack and stroke with Type 2 diabetes in two treatment groups. An intensive treatment group had 257 people die compared with 203 in a standard treatment group. The 54 death difference amounts to three per 1,000 participants each year over an average of almost four years of treatment, the NHLBI said. The death rates in both groups were lower than in similar populations in other studies.

“Because of the recent concerns with rosiglitazone [Avandia], our extensive analysis included a specific review to determine whether there was any link between this particular medication and the increased deaths. We found no link,” William Friedewald, chair of the ACCORD Steering Committee and clinical professor of medicine and public health at Columbia University, said.

The trial, which involves all major classes of diabetes medications, attempted to intensively lower blood glucose below current recommendations in the intensive treatment group, but because this increased the risk of death compared with a less-intensive standard treatment strategy, the study’s data safety monitoring board recommended stopping the former group. Participants in that arm of the study will now receive the standard treatment, the NHLBI said.

The FDA, which asked GSK last year to add a black box warning about the possibility of heart failure to Avandia’s label, said it could not comment on the revised analysis (DID, Aug. 15, 2007). — Martin Gidron


Waxman Wants Information on Mifepristone Exporter Investigations 

House Oversight and Government Reform Committee Chairman Henry Waxman (D-Calif.) is looking into FDA inspections of a Chinese manufacturer under investigation for tainted drugs.

The Chinese government is conducting a criminal investigation into tainted leukemia drugs produced by Shanghai Hualian, a division of Shanghai Pharmaceutical, Waxman said. He asked FDA Commissioner Andrew von Eschenbach for a briefing on FDA inspections of Shanghai Pharmaceutical facilities.

Shanghai Hualian exports mifepristone, which is used for the termination of early pregnancy, to the U.S. However, that drug is not manufactured at the facility the Chinese government is investigating, Waxman said.

Waxman is concerned the corporation will sell more drugs intended for export to the U.S. He cited a New York Times article about the investigation saying another company division intends to sell at least five active pharmaceutical ingredients to manufacturers for sale in the U.S.

China’s State Food and Drug Administration (SFDA) signed an agreement with HHS last year to improve drug safety by sharing more information with the U.S. (DID, Dec. 12, 2007). The agreement developed after negotiations by the Interagency Working Group on Import Safety, established by President Bush and led by HHS Secretary Mike Leavitt.

Under the agreement, the SFDA is supposed to share information about manufacturers with the FDA, including a list of manufacturers who do not meet SFDA standards. However, the agreement does not yet cover manufacturers of mifepristone.

Waxman urged von Eschenbach to complete FDA inspections of the facilities as quickly as possible. He requested a briefing on the oversight of all FDA-approved Shanghai Pharmaceutical facilities.

The briefing should be scheduled before Feb. 22, Waxman said. The letter can be seen at oversight.house.gov/documents/20080201162401.pdf. — Emily Ethridge


Administration: FDA, Lawmakers Should Collaborate on Follow-On Biologics Proposal

HHS Secretary Mike Leavitt has endorsed Sen. Charles Schumer’s (D-N.Y.) suggestion that the FDA and Congress work together to formulate proposed legislation for creating a follow-on biologics approval pathway.

The Senate Finance Committee held a hearing on the HHS budget request days after the Bush administration announced a proposed 5.7 percent increase in the FDA’s budget for fiscal 2009 that includes funding for a follow-on biologics approval pathway (DID, Feb. 5).

Schumer said FDA Commissioner Andrew von Eschenbach inquired at his office this week about crafting a joint proposal for follow-on biologics legislation, and after Leavitt agreed with the approach during the hearing, Schumer said he would start work immediately.

“It is an encouraging sign that the administration not only included this proposal in its budget but is prepared to sit down with Congress to figure out how to make the approval process work for manufacturers and the American people,” Schumer said.

The senator said he was willing to support the administration’s proposal that the follow-on biologics pathway be funded by user fees as long as the pathway allows for products to be approved as interchangeable and grants innovator products “a reasonable period of exclusivity” so biosimilars can be brought to market quickly, he said.

Schumer, Sen. Hillary Rodham Clinton (D-N.Y.) and others sponsored the Biologics Price Competition and Innovation Act, S. 1695, to establish a follow-on biologics approval pathway that was passed by the Senate Health, Education, Labor and Pensions Committee last year. But lawmakers were unsuccessful in attaching it to the FDA Amendments Act (DID, Sept. 19, 2007).

On the House side, Rep. Henry Waxman (D-Calif.) and others have introduced competing bills, and Energy and Commerce Committee members are still discussing the legislation.

S. 1695 is available at thomas.loc.gov/cgi-bin/bdquery/z?d110:s.01695:, and Waxman’s bill, H.R. 1038, is available at thomas.loc.gov/cgi-bin/bdquery/z?d110:h.r.01038:. — Breda Lund


Schering-Plough’s Vicriviroc Holds Promise for HIV Patients

Schering-Plough said its CCR5 antagonist vicriviroc in its Phase II VICTOR-E1 trial demonstrated potent and sustained viral suppression in treatment-experienced patients when administered in combination with an optimized ritonavir-boosted protease inhibitor-containing antiretroviral regimen.

The company discussed these findings during an oral presentation at the 15th Conference on Retroviruses and Opportunistic Infections Feb. 4.

A total of 116 patients with R5-type virus were randomized to receive 30 or 20 mg of vicriviroc plus an optimized background therapy (OBT) or OBT alone. After 48 weeks, 56 percent of patients in the 30-mg vicriviroc group had fully suppressed HIV-RNA compared with 14 percent of patients receiving new OBT alone, according to Schering-Plough. 

The 30-mg dose is being used in two ongoing Phase III studies which will enroll approximately 375 patients each.

Last August, the FDA approved Pfizer’s CCR5 antagonist Selzentry (maraviroc). The approval came two months after the agency had issued an approvable letter for the drug over physician labeling (DID, June 22, 2007).

Both vicriviroc and Selzentry have faced scrutiny for safety. Vicriviroc has shown a potential safety issue for lymphoma, and physician labeling for Selzentry carries a black box warning for chemically induced liver failure (DID, Aug. 8, 2007). — Elizabeth Jones


New Type of RA Drug Up for Review

The FDA has accepted UCB’s biologics license application (BLA) for Cimzia, a potential treatment for active rheumatoid arthritis (RA).

The BLA includes data from three multicenter, placebo-controlled Phase III trials. In two of these studies, Cimzia (certolizumab pegol) given in combination with methotrexate was more effective than methotrexate alone for inhibiting the progress of joint damage in patients with active RA.

In the third trial, the drug demonstrated efficacy as a monotherapy in patients who had failed at least one course of disease-modifying anti-rheumatic drug therapy.

If approved, Cimzia will be the first PEGylated antitumor necrosis factor biologic therapy for RA, according to UCB. The company also plans to submit a marketing authorization application for Cimzia to the European Medicines Agency (EMEA) for this indication.

Last November, the EMEA’s Committee for Medicinal Products for Human Use recommended against approving Cimzia for the treatment of moderate to severe Crohn’s disease. The committee questioned the drug’s effectiveness and expressed concern about the lack of evidence of the drug’s long-term effects because the study of maintenance treatment did not last long enough.

The firm announced in March 2007 that it would begin a short-term clinical study of Cimzia following receipt of an FDA complete response letter for the Crohn’s indication. The company filed its response to the letter the following month (DID, April 19, 2007). — Elizabeth Jones


FDA Approves Ranbaxy’s Generic Ceftin

Indian generic drug manufacturer Ranbaxy Laboratories has received approval from the FDA’s Office of Generic Drugs to manufacture and market a pediatric formulation of the antibiotic cefuroxime axetil, which is marketed by GlaxoSmithKline (GSK) under the brand name Ceftin.

The drug is indicated for the treatment of mild to moderate pharyngitis/tonsillitis, acute bacterial otitis media and impetigo in patients 3 months to 12 years old. The FDA has approved Ranbaxy to market both the 125-mg/5mL and the 250-mg/5mL doses.

Total annual sales of the drug were $28.7 million last year, according to the company.

In 2004, the U.S. District Court for the District of New Jersey ruled that Ranbaxy’s generic version of cefuroxime axetil, which it had begun marketing in the U.S. in 2001, does not infringe on GSK’s patents for Ceftin (DID, April 9, 2004). — Martin Gidron

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