Phase II data suggest IV zanamivir safe for severe flu in kids

NEW ORLEANS – The investigational intravenous formulation of the neuraminidase inhibitor zanamivir appears to be a safe influenza treatment for hospitalized children and adolescents at high risk of complications who can’t tolerate enteral therapy, according to findings from an open-label, multicenter, phase II study.

In 71 such patients with laboratory-confirmed flu, who presented within 7 days of illness onset and who received intravenous zanamivir (IVZ) for 5-10 days, 72% experienced adverse events (AEs), 21% experienced serious adverse events, and 5 deaths occurred, but none were considered by the investigators to be attributable to IVZ, Jeffrey Blumer, MD, reported at IDWeek, an annual scientific meeting on infectious diseases.

Rather, the adverse events were “fairly diverse. ... the kinds of things normally seen in critically ill pediatric populations,” he said.

The patients, who had a mean age of 7 years, were treated with IVZ doses selected to provide exposures comparable to 600 mg in adults – a dosage shown in prior studies to be safe and well-tolerated in adults. Patients aged 6 months to under age 6 years received twice-daily doses of 14 mg/kg, and those aged 6 years to less than 18 years received twice-daily doses of 12 mg/kg, not to exceed 600 mg. Doses were adjusted for renal function.

Patients were enrolled from five countries, and most (69%) had received prior treatment with oseltamivir. More than half (56%) had chronic medical conditions.

The median time from symptom onset to IVZ treatment was 4 days, Dr. Blumer of the University of Toledo (Ohio) said at the combined annual meetings of the Infectious Diseases Society of America, the Society of Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Infiltrate on chest x-ray was seen in 59% of patients, mechanical ventilation was required in 34% of patients, and extracorporeal membrane oxygenation was required in 6% of patients. Treatment in the intensive care unit was required in 65% of patients, and cumulative mortality was 4% at 14 days, and 7% at 28 days.

“Overall, the [IVZ] exposure and then the elimination profiles were consistent across the entire age cohort – unusual for most drugs, but it seemed to hold true, which makes zanamivir a lot easier for us to work with in pediatrics,” Dr. Blumer said.

While the numbers are small, exposure and response delineation didn’t seem to be impacted by mechanical ventilation, by extracorporeal membrane oxygenation, or by continuous renal replacement therapy, which is a good sign, he noted.

“So we generally had good, consistent experience here. ... Overall, 64 of the 71 patients survived, got better, left the ICU, and left the hospital,” Dr. Blumer said.

Of note, a treatment-emergent resistance substitution, E119G, was detected in a day 5 H1N1 isolate from an immunocompetent patient who improved clinically while on IVZ, he said, adding that no phenotype data were available as the sample could not be cultured.

The findings are important, because while zanamivir is currently labeled for patients older than 7 years, and the intravenous formulation currently in development has been shown to be safe for adults, there is a critical unmet need for an effective parenteral treatment for severe flu in children at high risk of complications who cannot tolerate enteral therapy.

“We need a drug that is available for the critically ill. We need a drug available for kids who are unable to take oral therapy, and for treatment of oseltamivir-resistant strains,” he said, adding that the current findings suggest that IVZ – with dose selection based on age, weight, and renal function – is a suitable treatment option for such patients.

“In conclusion, what we saw in this open-label trial was that the dose selection that we utilized gave us the kind of exposure we’d expect, and it seems it was an appropriate way to approach pediatric patients,” he said. “There wasn’t any safety signal attributable to the drug, and the overall pattern was more that of serious influenza, rather than of drug exposure.”

Dr. Blumer reported receiving research support from GlaxoSmithKline, which sponsored the study.

[email protected]

NEW ORLEANS – The investigational intravenous formulation of the neuraminidase inhibitor zanamivir appears to be a safe influenza treatment for hospitalized children and adolescents at high risk of complications who can’t tolerate enteral therapy, according to findings from an open-label, multicenter, phase II study.

In 71 such patients with laboratory-confirmed flu, who presented within 7 days of illness onset and who received intravenous zanamivir (IVZ) for 5-10 days, 72% experienced adverse events (AEs), 21% experienced serious adverse events, and 5 deaths occurred, but none were considered by the investigators to be attributable to IVZ, Jeffrey Blumer, MD, reported at IDWeek, an annual scientific meeting on infectious diseases.

Rather, the adverse events were “fairly diverse. ... the kinds of things normally seen in critically ill pediatric populations,” he said.

The patients, who had a mean age of 7 years, were treated with IVZ doses selected to provide exposures comparable to 600 mg in adults – a dosage shown in prior studies to be safe and well-tolerated in adults. Patients aged 6 months to under age 6 years received twice-daily doses of 14 mg/kg, and those aged 6 years to less than 18 years received twice-daily doses of 12 mg/kg, not to exceed 600 mg. Doses were adjusted for renal function.

Patients were enrolled from five countries, and most (69%) had received prior treatment with oseltamivir. More than half (56%) had chronic medical conditions.

The median time from symptom onset to IVZ treatment was 4 days, Dr. Blumer of the University of Toledo (Ohio) said at the combined annual meetings of the Infectious Diseases Society of America, the Society of Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Infiltrate on chest x-ray was seen in 59% of patients, mechanical ventilation was required in 34% of patients, and extracorporeal membrane oxygenation was required in 6% of patients. Treatment in the intensive care unit was required in 65% of patients, and cumulative mortality was 4% at 14 days, and 7% at 28 days.

“Overall, the [IVZ] exposure and then the elimination profiles were consistent across the entire age cohort – unusual for most drugs, but it seemed to hold true, which makes zanamivir a lot easier for us to work with in pediatrics,” Dr. Blumer said.

While the numbers are small, exposure and response delineation didn’t seem to be impacted by mechanical ventilation, by extracorporeal membrane oxygenation, or by continuous renal replacement therapy, which is a good sign, he noted.

“So we generally had good, consistent experience here. ... Overall, 64 of the 71 patients survived, got better, left the ICU, and left the hospital,” Dr. Blumer said.

Of note, a treatment-emergent resistance substitution, E119G, was detected in a day 5 H1N1 isolate from an immunocompetent patient who improved clinically while on IVZ, he said, adding that no phenotype data were available as the sample could not be cultured.

The findings are important, because while zanamivir is currently labeled for patients older than 7 years, and the intravenous formulation currently in development has been shown to be safe for adults, there is a critical unmet need for an effective parenteral treatment for severe flu in children at high risk of complications who cannot tolerate enteral therapy.

“We need a drug that is available for the critically ill. We need a drug available for kids who are unable to take oral therapy, and for treatment of oseltamivir-resistant strains,” he said, adding that the current findings suggest that IVZ – with dose selection based on age, weight, and renal function – is a suitable treatment option for such patients.

“In conclusion, what we saw in this open-label trial was that the dose selection that we utilized gave us the kind of exposure we’d expect, and it seems it was an appropriate way to approach pediatric patients,” he said. “There wasn’t any safety signal attributable to the drug, and the overall pattern was more that of serious influenza, rather than of drug exposure.”

Dr. Blumer reported receiving research support from GlaxoSmithKline, which sponsored the study.

[email protected]

NEW ORLEANS – The investigational intravenous formulation of the neuraminidase inhibitor zanamivir appears to be a safe influenza treatment for hospitalized children and adolescents at high risk of complications who can’t tolerate enteral therapy, according to findings from an open-label, multicenter, phase II study.

In 71 such patients with laboratory-confirmed flu, who presented within 7 days of illness onset and who received intravenous zanamivir (IVZ) for 5-10 days, 72% experienced adverse events (AEs), 21% experienced serious adverse events, and 5 deaths occurred, but none were considered by the investigators to be attributable to IVZ, Jeffrey Blumer, MD, reported at IDWeek, an annual scientific meeting on infectious diseases.

Rather, the adverse events were “fairly diverse. ... the kinds of things normally seen in critically ill pediatric populations,” he said.

The patients, who had a mean age of 7 years, were treated with IVZ doses selected to provide exposures comparable to 600 mg in adults – a dosage shown in prior studies to be safe and well-tolerated in adults. Patients aged 6 months to under age 6 years received twice-daily doses of 14 mg/kg, and those aged 6 years to less than 18 years received twice-daily doses of 12 mg/kg, not to exceed 600 mg. Doses were adjusted for renal function.

Patients were enrolled from five countries, and most (69%) had received prior treatment with oseltamivir. More than half (56%) had chronic medical conditions.

The median time from symptom onset to IVZ treatment was 4 days, Dr. Blumer of the University of Toledo (Ohio) said at the combined annual meetings of the Infectious Diseases Society of America, the Society of Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Infiltrate on chest x-ray was seen in 59% of patients, mechanical ventilation was required in 34% of patients, and extracorporeal membrane oxygenation was required in 6% of patients. Treatment in the intensive care unit was required in 65% of patients, and cumulative mortality was 4% at 14 days, and 7% at 28 days.

“Overall, the [IVZ] exposure and then the elimination profiles were consistent across the entire age cohort – unusual for most drugs, but it seemed to hold true, which makes zanamivir a lot easier for us to work with in pediatrics,” Dr. Blumer said.

While the numbers are small, exposure and response delineation didn’t seem to be impacted by mechanical ventilation, by extracorporeal membrane oxygenation, or by continuous renal replacement therapy, which is a good sign, he noted.

“So we generally had good, consistent experience here. ... Overall, 64 of the 71 patients survived, got better, left the ICU, and left the hospital,” Dr. Blumer said.

Of note, a treatment-emergent resistance substitution, E119G, was detected in a day 5 H1N1 isolate from an immunocompetent patient who improved clinically while on IVZ, he said, adding that no phenotype data were available as the sample could not be cultured.

The findings are important, because while zanamivir is currently labeled for patients older than 7 years, and the intravenous formulation currently in development has been shown to be safe for adults, there is a critical unmet need for an effective parenteral treatment for severe flu in children at high risk of complications who cannot tolerate enteral therapy.

“We need a drug that is available for the critically ill. We need a drug available for kids who are unable to take oral therapy, and for treatment of oseltamivir-resistant strains,” he said, adding that the current findings suggest that IVZ – with dose selection based on age, weight, and renal function – is a suitable treatment option for such patients.

“In conclusion, what we saw in this open-label trial was that the dose selection that we utilized gave us the kind of exposure we’d expect, and it seems it was an appropriate way to approach pediatric patients,” he said. “There wasn’t any safety signal attributable to the drug, and the overall pattern was more that of serious influenza, rather than of drug exposure.”

Dr. Blumer reported receiving research support from GlaxoSmithKline, which sponsored the study.

[email protected]