Zyvox Phase IV Studies May Support Penicillin-Resistant Indications

Pharmacia will continue to seek additional indications for Zyvox (linezolid) in the treatment of antibiotic-resistant infections.

Pharmacia said it expects its Phase IV program for the oxazolidinone antibiotic will help the company gain approval for the treatment of infections due to penicillin-resistant Streptococcus pneumoniae.

Pharmacia is in continuing discussions with the agency to determine the scope of the studies that would be required in order to gain approval for additional indications.

Zyvox cleared FDA April 18 for the treatment of nosocomial pneumonia, including cases due to methicillin-resistant Staphylococcus aureus; complicated skin and skin structure infections, including those caused by MRSA; and uncomplicated skin and skin structure infections.

Zyvox was also approved for the treatment of community-acquired pneumonia, and infections associated with vancomycin-resistant Enterococcus faecium.

Among the 16 Phase IV commitments outlined in the agency's approval letter for Zyvox, Pharmacia is expected to submit additional clinical efficacy data for the treatment of infections due to penicillin-resistant S. pneumoniae.

The company is also expected to submit additional data for S. aureus infections, including MRSA, associated with bacteremia.

FDA did not grant indications Pharmacia sought for Zyvox in the treatment of either CAP due to PRSA or CAP due to MRSA.

FDA's approval of Zyvox was consistent with the recommendations of the agency's Antiviral Drugs Advisory Committee, which met March 24 to consider the Zyvox application.

The advisory committee was evenly split on the question of whether or not linezolid should be approved for CAP due to MRSA and voted 7-3 against indications for CAP and nosocomial pneumonia due to PRSP.

In addition to citing concern that there were not enough evaluable patients in Zyvox clinical trials to rigorously determine the safety and efficacy of linezolid in the treatment of infections due to pathogen resistance, some committee members at the meeting questioned the overall benefit of granting antibiotic products pathogen-resistant indications.

Some members argued that resistant indications might encourage overuse, ultimately leading to additional resistance, and suggested that general pathogen indications should suffice (¹ (Also see "Pathogen-Resistant Antibiotic Indications Questioned By FDA Cmte." - Pink Sheet, 3 Apr, 2000.)).

FDA approved linezolid for the treatment of complicated SSSIs due to MRSA, despite a split committee vote, but did not clear the antibiotic for the treatment of uncomplicated SSSIs due to MRSA.

Pharmacia anticipates launching the new product in late April or early May. Pricing is expected to be competitive with other antibiotic products for the treatment of Gram-positive infections, the company said.

Zyvox is the first product to be commercialized by the newly formed Pharmacia Corp. -formerly Pharmacia & Upjohn and Monsanto. Several hundred Pharmacia reps will detail Zyvox, drawing primarily on the former Pharmacia & Upjohn sales force, the company said.

The company will target patients in a hospital or institutional care setting for Zyvox treatment. Pharmacia estimates the potential patient population to be several million, noting that over 60% of all Gram-positive infections occur in a hospital setting.

Labeling advises that, "due to concerns about inappropriate use of antibiotics leading to an increase of resistant organisms, prescribers should carefully consider alternatives before initiating treatment with Zyvox in the outpatient setting."

On April 14, the American College of Physicians and the American Society of Internal Medicine announced its campaign against antibiotic resistance, issuing a list of "do's and don'ts" for physicians, parents and institutions to address growing antibiotic resistance.

Among other recommendations, the organizations call for the federal government to develop a system of electronic laboratory reporting by hospitals and laboratories, and the establishment of a communication link to public health and medical communities to provide timely updates on aggregate data and their interpretation.

Pharmacia's Phase IV commitments for Zyvox also include a study to further characterize the mechanism of resistance to linezolid, and establishment of a surveillance program to monitor development of resistance to linezolid as well as cross-resistance to other antimicrobials.

In clinical trials, Zyvox resistance developed in six patients infected with E. faecium. Among these patients, four had received 200 mg Zyvox b.i.d. -lower than the recommended dose - and two had received 600 mg b.i.d.

In a compassionate use program, eight patients with E. faecium and one patient with E. faecalis developed resistance to Zyvox. "All patients had either unremoved prosthetic devices or undrained abscesses," labeling notes.

Resistance to linezolid was not seen in clinical trials in patients infected with Staphylococcus spp. or Streptococcus spp., including S. pneumoniae, labeling continues.

Pharmacia has also committed to submit a study report to FDA providing additional microbiologic and clinical summary information on the development of resistance to linezolid observed during any ongoing clinical trials.

As another Phase IV commitment, FDA has requested Pharmacia submit additional pharmacokinetic data, clinical data and information on the safety of linezolid and its two metabolites in patients with renal insufficiency.

Linezolid metabolites PNU-142300 and PNU-142586 accumulate in patients with renal insufficiency, "with the amount of accumulation increasing with the severity of renal dysfunction," labeling states.

The label notes that the significance of accumulation of the two metabolites has not been determined, and does not recommend dose adjustment for these patients.

FDA found that for one metabolite (PNU-142300), total exposures to Zyvox were "53%, 631% and 3,516% greater in patients with moderate renal impairment, severe renal impairment and anuria, respectively. Exposure to the second metabolite was 68%, 566% and 4,744%, respectively (² (Also see "Zyvox Dose Adjustments Not Necessary For Renally Impaired Patients - P&U" - Pink Sheet, 3 Apr, 2000.)). The agency reported the figures in an FDA briefing document for the advisory committee meeting.

Zyvox labeling also cautions that linezolid is a reversible, nonselective inhibitor of monoamine oxidase, and has the potential for interaction with adrenergic and serotonergic agents.

The "Precautions" section of linezolid labeling notes that thrombocytopenia has been reported in patients receiving linezolid.

Labeling recommends monitoring of patients who are at increased risk for bleeding or who have pre-existing thrombocytopenia, and patients "who receive concomitant medications that may decrease platelet count or function, or who may require longer than two weeks of linezolid therapy."

Also among the company's Phase IV commitments is a call to provide additional information on the hematologic effects of linezolid, including definition of risk factors for thrombocytopenia, and in vitro studies to further characterize the effect of linezolid on platelets.

Pharmacia is conducting pediatric clinical trials for Zyvox, and has already received a pediatric written request from the agency. The company anticipates filing for a pediatric indication in the next few years.

The most common side effects reported in clinical studies were headache, nausea, diarrhea and vomiting.

Zyvox is available as an injectable, tablet and oral suspension. The company has touted the equivalent bioavailability of the oral and I.V. formulations of Zyvox for easier administration and switches.

The product is available in 200 mg, 400 mg and 600 mg I.V. bags; 400 mg and 600 mg tablets; and 100 mg powder for oral suspension.

The Zyvox NDA (21-130/131/132) was submitted in October 1999, and reviewed on a six-month priority schedule. The company reports that total development time for the antibiotic was under five years.