High-dose oseltamivir in critically ill patients provides no added benefit

The evidence does not support the administration of high-dose oseltamivir to critically ill patients, according to Gabrielle Gibson, PharmD, BCPS, a clinical pharmacist at Barnes-Jewish Hospital, St. Louis, Mo., who spoke at the 2015 ASHP Midyear Clinical Meeting in New Orleans.

In 2011 the Centers for Disease Control and Prevention (CDC) had recommended patients with influenza be treated with oseltamivir 75 mg PO twice daily for 5 days and that treatment should begin within 48 hours of symptom onset. The CDC suggested that for critically ill patients, a higher dose of 150 mg PO BID might be worthwhile and started at any time regardless of symptom onset. Longer oseltamivir treatments, such as 10 days, were also suggested, based on expert opinion, Gibson noted.

"The rationale for high-dose oseltamivir was due to the speculation that highly pathogenic influenza virus causes severe disease linked to high levels of viral replication," she noted. "It was speculated that maintaining higher plasma levels of oseltamivir carboxylate with higher doses may lead to improved outcomes in critically ill patients."

The 2011 MMWR guidelines suggested that this approach for severely critically ill patients with influenza A (H1N1) has been advocated as an appropriate strategy although the data is limited. One animal study supported a longer course of treatment and one supported a higher dose if treatment initiation was delayed.

Human studies

In a multicenter, double-blind, randomized study, published in 2013, 326 patients were randomized to standard oseltamivir (75 mg PO BID) or high-dose oseltamivir (150 mg PO BID) or the pediatric equivalent. The primary outcome was viral status on day 5 and the secondary outcomes were days on supplemental oxygen, ICU length of stay, and time on mechanical ventilation.

"The virological clearance was similar between the high-dose and standard-dose on day 5. Also, the high-dose oseltamivir didn't result in any improvement in the secondary outcomes," Gibson explained.

One of the limitations with the study was that more than 75% were children and only 19% required ICU admission and about 10% required mechanical ventilation, she noted.

In a prospective, open-label, intervention study of 157 adults, also published in 2013, 41 received high-dose oseltamivir (150 mg PO BID) and the rest were given the standard oseltamivir dose (75 mg PO BID). The primary outcome was viral status on day 5. The secondary outcomes included hospital length of stay, duration of supplemental oxygen, duration of fever >37.5°C, admission to the ICU, and mortality.

"There was no difference in RNA negativity between high and standard dose oseltamivir and no difference between doses in clinical outcomes," she said.  

In a retrospective, single-center, cohort study of 123 critically ill patients, published in 2015, 46 had received the standard dose of oseltamivir (75 mg PO BID) and 77 received the high dose of 150 mg PO BID. The primary outcome was the number of ICU-free days and the secondary outcomes included differences in ventilator-free days, time to return to pre-morbid oxygen requirements, hospital length of stay, and 28-day mortality.

"After accounting for baseline differences, high-dose therapy was not independently associated with a decreased time to ICU discharge or 28-day mortality. High-dose therapy showed no improvement in clinical outcomes compared to standard dose in the critically ill," Gibson said.

Although higher doses of oseltamivir are not associated with adverse events, based on limited data, higher doses cannot be supported.

In 2014 the manufacturer of oseltamivir revised the dosing recommendations for patients with renal dysfunction. Patients with a CrCl >30-60 mL/min should receive a 30 mg BID dose of oseltamivir and those with a CrCL >10-30 mL/min should receive a 30 mg dose daily. Those patients on hemodialysis should receive 30 mg after each hemodialysis, and those with CAPD should receive 30 mg after dialysis exchange. There were not recommendations for patients on continuous renal replacement therapy (CRRT).

"The new FDA-approved package insert [for oseltamivir] now includes recommendations for IHD and CAPD based on small, observational studies," she said. A 30-mg dose is recommended after each IHD session and for patients on CAPD, a 30-mg dose is recommended once weekly immediately after dialysis exchange.