Oseltamivir (Tamiflu) and Bradycardia
Oseltamivir is associated with clinically significant bradycardia in critically ill patients, with 43% experiencing heart rate ≤59 BPM or a decrease of ≥20 BPM from baseline, typically occurring within 51 hours of initiation. 1
Evidence of Association
The strongest evidence comes from a 2021 retrospective audit of 203 critically ill adults receiving oseltamivir for presumed influenza. 1 Key findings include:
- 88 patients (43.4%) developed bradycardia, defined as HR ≤59 BPM or a decrease of ≥20 BPM from baseline 1
- Time to onset averaged 51.4 ± 43 hours after the first dose 1
- Over half (54.6%) required interventions including increased inotropic/vasopressor doses, electrolyte replacement, ECG monitoring, medication discontinuation, cardiology consultation, oseltamivir discontinuation, or pacemaker placement 1
- Multivariate analysis identified risk factors: baseline heart rate, advanced age, neurological comorbidities, and positive influenza status 1
Proposed Mechanisms
Multiple mechanisms may explain oseltamivir-associated bradycardia:
- Direct cardiac effects: Oseltamivir may modulate Na+, K+, and Ca2+ channels in cardiac tissue 1
- Endogenous neuraminidase inhibition: The drug may suppress the host's endogenous neuraminidase, affecting cardiac function and causing QT prolongation 2
- Cytokine suppression: Oseltamivir suppresses pro-inflammatory cytokines (interferon-gamma, interleukin-6, tumor necrosis factor-alpha) which may indirectly affect cardiac conduction 2
Animal toxicity studies support clinical evidence regarding cardiac disorders including bradycardia and QT prolongation. 2
Clinical Context
It is important to distinguish oseltamivir-induced bradycardia from influenza-associated cardiac arrhythmias:
- Influenza infection itself can cause cardiac conduction disorders through IL-6 and TNF-alpha mediated inflammation, sympathetic overactivation, focal myocarditis, and ACE2 protein cleavage 3
- Ventricular arrhythmias are the most common influenza-associated arrhythmias, though complete heart block can occur (usually temporary) 3
- The 2021 study controlled for influenza status and still found oseltamivir independently associated with bradycardia 1
Monitoring Recommendations
Clinicians should closely monitor heart rate in all patients receiving oseltamivir, particularly in:
- Critically ill patients 1
- Elderly patients 1
- Patients with baseline bradycardia 1
- Patients with neurological comorbidities 1
- Patients on concurrent medications that affect cardiac conduction 4
Monitor continuously from hours 6 through 126 after initiation, as significant differences in actual and lowest heart rate occur throughout this period. 1
Drug Interaction Considerations
While major cardiac guidelines discuss bradycardia from antiarrhythmic agents (amiodarone, sotalol, dofetilide) 4, they do not specifically address oseltamivir. However, the 2011 ACC/AHA/HRS guidelines note that amiodarone, class IA or IC agents, or sotalol can be associated with bradycardia requiring permanent pacemaker implantation. 4 This precedent supports vigilance when using oseltamivir, particularly in combination with these agents.
The EASL hepatitis C guidelines note that sofosbuvir-based regimens (which share P-glycoprotein interactions with oseltamivir) are contraindicated with amiodarone due to risk of life-threatening bradycardia, with cases occurring within hours to days but sometimes up to 2 weeks after initiation. 4 This mechanism may be relevant to oseltamivir given its P-glycoprotein substrate properties.
Common Pitfalls
- Assuming bradycardia is solely due to influenza infection rather than considering oseltamivir as a contributing factor 1, 3
- Failing to monitor heart rate closely in the first 5 days of therapy when bradycardia typically manifests 1
- Not recognizing that over half of patients with oseltamivir-associated bradycardia require intervention 1
- Overlooking the dose-response relationship in critically ill patients, particularly those on hemodialysis or with renal impairment 5