Clinical considerations in prescribing oseltamivir (Tamiflu, generics) for influenza

As of December 12, 2023, Part A pharmacists in Ontario were granted authorization to prescribe oseltamivir (Tamiflu, generics) for the treatment of influenza.1 This article provides answers to common questions regarding the clinical aspects of prescribing oseltamivir.1 Although the article focuses on regulations in Ontario, much of the clinical information would be applicable to other jurisdictions. In what situations can Ontario (Part A) pharmacists prescribe oseltamivir?An individual has documented instructions to obtain oseltamivir for influenza prophylaxis as directed by the local Public Health Unit or institutional Infection Prevention and Control (IPAC) in response to an outbreak and requires a therapeutic assessment for a prescription.An individual has a lab-confirmed influenza A or influenza B infection AND will be starting oseltamivir within two days of symptom onset (symptom onset day is considered day 0). An individual is suspected to have an influenza A or influenza B infection based on clinical judgment plus a negative COVID-19 test result AND will be starting oseltamivir within two days of symptom onset. (Suspicion of influenza A/B may include a combination of symptoms of influenza-like illness and a negative COVID-19 test result and/or influenza confirmed to be circulating in the Public Health Unit area).2What are the symptoms of influenza infection?Adults, older children and adolescents typically start with fever, respiratory symptoms such as a cough or sore throat, and systemic symptoms, such as myalgia, arthralgia and headache. Gastrointestinal symptoms, notably diarrhea, may occur but are more common in children with seasonal influenza A than in adults.3 When influenza is circulating in the community, the presence of cough and a temperature of ≥ 37.8 °C in an otherwise healthy adult has a positive predictive value of 86.8% for a laboratory-confirmed diagnosis of influenza.3Children < 10 years may experience atypical symptoms. The common presenting symptoms of fever, cough and rhinorrhea do not distinguish influenza illness from illness due to other respiratory viruses, especially among children younger than four years of age. As a result, arriving at a treatment decision must be guided by knowledge of whether influenza virus is circulating in the community as well as on a clinical assessment of the individual patient.3 Infants younger than six months are more likely to present with rhinorrhea and dehydration than with cough and pneumonia. Fever alone, or with dehydration, is a common presenting feature in children younger than three months.3Read: Ontario pharmacists, RPhTs granted new immunization, treatment authoritiesHow can I determine if influenza is circulating in my area of Ontario? Public Health Ontario routinely publishes the number of influenza and COVID cases circulating (https://www.publichealthontario.ca/en/Data-and-Analysis/Infectious-Disease/Respiratory-Virus-Tool). The Chief Medical Officer of Health suggests using high (> 25% influenza positivity) as the cut-off for test positivity. If influenza percent positivity is intermediate (10%–24.9%), or if activity is localized (rather than widespread) other indicators can be considered as well (e.g., outbreaks and increasing numbers compared to previous weeks).4 Does an individual need to have a negative COVID-19 rapid antigen or PCR test before an Ontario pharmacist can prescribe oseltamivir? Ruling out COVID-19 with a negative COVID-19 test prior to prescribing oseltamivir is required, as the symptoms of influenza and COVID-19 are indistinguishable, with both viruses causing a range of overlapping respiratory and systemic symptoms.4,5 However, a negative COVID-19 test result is not required for asymptomatic patients who require oseltamivir as directed by IPAC or a public health unit, or for patients who have a laboratory-confirmed influenza A or influenza B infection.4,6 However, in patients with a lab-confirmed influenza infection, it might be prudent to test for COVID-19 if the patient is also at high risk for severe COVID-19 (i.e., the patient might benefit from concomitant Paxlovid treatment if the COVID-19 test is positive).Can an Ontario pharmacist prescribe oseltamivir and Paxlovid (nirmatrelvir/ritonavir) for the same patient? Yes, Paxlovid and oseltamivir may be prescribed concurrently if any of the following conditions are met: The patient has a confirmed positive COVID-19 test result and a confirmed positive PCR influenza test result. The patient has a confirmed positive COVID-19 test result, and also requires prophylactic oseltamivir as directed by a local public health agency or their occupational health and safety department due to involvement in an influenza outbreak. The patient has a confirmed positive COVID-19 test result and is a direct contact of someone who has a PCR-confirmed influenza infection. NOTE: Knowing that influenza is or may be circulating in the community is insufficient cause to prescribe both Paxlovid and oseltamivir to a patient with a positive COVID-19 test. The COVID-19-positive patient must be a close contact of someone with a PCR-confirmed influenza infection before prescribing both Paxlovid and oseltamivir.4 What is the approved age range for oseltamivir use in Canada? In Canada, oseltamivir is authorized for the treatment of uncomplicated influenza A and B in patients one year of age or older who have been symptomatic for no more than two days. It is also authorized for the prevention of influenza A and B in adults and children one year of age or older who are in close contact with an individual with characteristic symptoms of influenza.7 Although not officially approved by Health Canada for younger children, AMMI Canada guidelines also provide suggested doses for children under one year of age.3 What is the recommended dosage of oseltamivir?3,7The following table summarizes dosing guidelines for oseltamivir. Doses do not need to be adjusted in adults with obesity, elderly or other patients with a creatinine clearance > 60 mL/min, or people with mild or moderate hepatic impairment.3,7Is a renal function assessment required before prescribing and/or dispensing oseltamivir?Oseltamivir may require a dose adjustment based on the patient’s renal function (see Table above).3,7 Ontario pharmacists should review the individual’s serum creatinine results (e.g., in the Ontario Laboratories Information System or other source), if available.4Read: A clearer link between RSV and childhood asthmaHow soon should oseltamivir be started after the onset of influenza symptoms?Ontario pharmacists can only prescribe oseltamivir if the drug will be started within two days of symptom onset (symptom onset day is considered day 0).2 Initiation of treatment within 36–48 hours of illness is effective in shortening symptom duration.3 Early treatment has also been shown to lead to fewer complications requiring antibiotics in adults and children.8 Optimal benefits are obtained if treatment is initiated as early as possible after the onset of symptoms. AMMI Canada states that starting treatment within 12 hours of illness onset should be a practice goal; the benefits of treatment are much greater when started at less than 12 hours than with initiation at 48 hours.3 AMMI Canada indicates that starting oseltamivir later than 48 hours after symptom onset can be considered in specific situations (e.g., hospitalized or at risk of severe disease; see details in reference #3).3 Which patients are candidates for early empiric treatment with oseltamivir? AMMI Canada recommends early empiric antiviral treatment for seasonal influenza based on an individual’s clinical presentation and their risk factors for developing complications. When influenza is circulating in the community, AMMI Canada recommends that influenza antivirals be used to treat adults and children with influenza-like illness who are at higher risk of complications of influenza; OR have severe, complicated or progressive illness; OR are hospitalized.9 Oseltamivir is recommended for the empiric treatment of seasonal influenza if the answer is “Yes” to all three of the following questions:Is influenza circulating in your community? Consult the Ontario Respiratory Virus Tool (https://www.publichealthontario.ca/en/Data-and-Analysis/Infectious-Disease/Respiratory-Virus-Tool) or your local public health unit (https://www.phdapps.health.gov.on.ca/phulocator/).Does your patient have symptoms of influenza-like illness? Symptoms can include: sudden onset of fever (may be absent in older adults), cough, headache, sore throat, muscle aches and fatigue. Is your patient at high risk for complications of influenza and/or does your patient have moderate, progressive, severe or complicated influenza (e.g., individuals who are hospitalized with influenza-like illness? Those at high risk for complications include adults ≥ 65 years of age, pregnant women and women up to four weeks post-partum, and those with underlying medical conditions.9 Additional details on high-risk individuals are available in reference #3. NOTE: If patients without risk factors for complications and without serious illness present within 48 hours of symptom onset, oseltamivir can be considered, but not routinely recommended, for those one to five years of age; and considered in those 18–64 years of age.5,9 When indicated, antiviral therapy should be prescribed as soon as possible, without waiting for laboratory-confirmation of influenza.5,9Should oseltamivir be used during pregnancy or when breastfeeding?Oseltamivir is considered safe to use during pregnancy.5 AMMI Canada recommends oseltamivir in standard doses for treatment of women with influenza during pregnancy and up to four weeks post-partum. This is based on epidemiological data demonstrating an association between pregnancy and the immediate post-partum period and an increased risk of severe influenza combined with data demonstrating the extensive safe use of oseltamivir to treat such patients during the 2009 H1N1 pandemic.3 Oseltamivir is the preferred antiviral for treatment of influenza in women who are breastfeeding.10How effective is oseltamivir?Controlled trials in otherwise healthy adults and children (≥ 1 year of age) have demonstrated that oseltamivir reduces the duration and severity of uncomplicated, self-limited laboratory-confirmed influenza, largely because of influenza A viruses.3 In adults, it shortens symptom duration by about one day.10 Oseltamivir also seems to reduce total influenza-related complications, including a reduction in the frequency of otitis media as a complication of influenza in children.3Treatment of hospitalized patients with seasonal influenza may reduce the duration of hospitalization and mortality,3 although the results of systematic reviews on the use of oseltamivir to prevent hospitalization have been mixed.8 The combined results of controlled trials, observational studies and meta-analyses show that early antiviral treatment of influenza in high-risk and hospitalized patients can reduce the risk of complications.10Read: Drug news—NovemberWhat adverse effects might occur with oseltamivir?Oral oseltamivir is generally well tolerated in adults. Mild, rapidly reversible nausea and vomiting occur approximately 5%–10% more often in persons taking oseltamivir compared to placebo. Nausea and vomiting occur in about 8%–11% of young adults taking 75 mg twice daily, compared with 3%–7% of those taking placebo.3 Headache has also been reported.10 Vomiting is the most frequently reported adverse event in children.3,7 Taking with food may improve tolerability in some patients.7 Neuropsychiatric events, including self-injury and delirium, have been reported in patients taking oseltamivir; however, a causal relationship has not been established and neuropsychiatric dysfunction can be a complication of influenza itself.3,10 Severe skin and hypersensitivity reactions, including anaphylaxis, have been reported.7,10 Oseltamivir has been associated with bradycardia in critically ill patients.10Does oseltamivir have any significant drug interactions?Clinically important drug interactions with oseltamivir are unlikely.3,7,10 This includes drug interactions involving competition for renal tubular secretion; however, the European Medicines Agency suggests that care should be taken when prescribing oseltamivir in patients taking co-excreted agents with a narrow therapeutic margin (e.g., methotrexate).11Oseltamivir has the potential to inhibit replication of live vaccine virus and reduce the efficacy of the intranasal live attenuated influenza vaccine (FluMist Quadrivalent). US prescribing information recommends avoiding administration of live attenuated influenza vaccine within two weeks before or 48 hours after oseltamivir administration.10,12 Inactivated influenza vaccine can be administered at any time relative to use of oseltamivir.12Are there any concerns about resistance developing to oseltamivir?The development of resistance of influenza A or B viruses to oseltamivir is uncommon during therapy or prophylaxis in immunocompetent individuals.3 More than 99% of the recently circulating influenza virus strains tested by the World Health Organization (WHO) have been susceptible to neuraminidase inhibitors, such as oseltamivir.10 However, in immunocompromised patients with influenza treated with oseltamivir, resistance has developed frequently and relatively early during therapy with resultant treatment failure.3 Reduced susceptibility of some influenza virus strains, particularly influenza A(H1N1) viruses, to oseltamivir can emerge during or after treatment, especially in young children and immunocompromised patients with prolonged viral shedding.10 Although oseltamivir resistance is not considered to be a significant concern at this time,5 AMMI Canada recommends that practitioners maintain an awareness of the Public Health Agency of Canada’s FluWatch reports (http://www.phac-aspc.gc.ca/fluwatch/) and reports from their provincial or territorial public health departments, in case oseltamivir-resistant seasonal influenza viruses appear.3In a 2023 update, AMMI Canada states that the use of chemoprophylaxis for influenza should be balanced against the recognized risk for the emergence of antiviral resistancewhen prophylactic oseltamivir is used for prolonged periods of time or when it is initiated late post-exposure. The importance of oseltamivir stewardship is underscored by the possibility of human infection with emerging zoonotic strains of influenza virus that have pandemic potential.8 Is documentation of any clinical information required when Ontario pharmacists prescribe oseltamivir?Yes. Pharmacists should document clinical information, including:date and result of the individual’s COVID-19 test (e.g., verbal confirmation from individual, test result obtained from the Ontario Laboratories Information System, test conducted in the pharmacy)date of onset of the individual’s influenza symptomsa care plan for the individual based on a review of the individual’s medical history, lab results, and current medications and how any potential drug interactions will be managed, follow-up/monitoring, and notification to the primary care provider, if applicable.4See references #2 and #4 for complete documentation requirements.If an Ontario pharmacist prescribes oseltamivir, do they have to notify the patient’s primary care provider? Yes. The pharmacist is expected to notify the patient’s primary care provider (if any) within a reasonable timeframe after prescribing oseltamivir and provide details about the prescription.2Where can I find answers to questions on nonclinical issues related to prescribing of oseltamivir by Ontario pharmacists?Answers to nonclinical questions about oseltamivir prescribing (e.g., billing for a therapeutic assessment, dispensing oseltamivir) can be found in references #2 and #4 below. References1. Ontario College of Pharmacists. Regulatory amendments that expand vaccine administration and treatment of influenza now in effect. December 13, 2023. https://www.ocpinfo.com/regulatory-amendments-that-expand-vaccine-administration-and-treatment-of-influenza-now-in-effect/ (accessed December 19, 2023).2. Ontario Ministry of Health. Executive officer notice: prescribing and dispensing oral antiviral treatments for respiratory viruses in Ontario pharmacies. Effective December 12, 2023. 3. Aoki FY, Allen UD, Mubareka S, et al. Use of antiviral drugs for seasonal influenza: foundation document for practitioners—Update 2019. J Assoc Med Microbiol Infect Dis Can 2019;4(2):60-82. https://jammi.utpjournals.press/doi/10.3138/jammi.2019.02.08 (accessed December 19, 2023).4. Ontario Ministry of Health. Prescribing and dispensing oral antiviral treatments for respiratory viruses in Ontario pharmacies – frequently asked questions. Effective December 12, 2023. 5. Aoki FY, Papenburg J, Mubareka S, et al. 2021–2022 AMMI Canada guidance on the use of antiviral drugs for influenza in the COVID-19 pandemic setting in Canada. J Assoc Med Microbiol Infect Dis Can. March 2022;7(1):1-7. https://jammi.utpjournals.press/doi/pdf/10.3138/jammi-2022-01-31 (accessed December 19, 2023).6. Health Programs and Delivery Division. Email correspondence, December 15, 2023.7. Hoffmann-La Roche Limited. Tamiflu (oseltamivir capsules and powder for oral suspension) product monograph. Mississauga, ON; September 9, 2022. https://pdf.hres.ca/dpd_pm/00067405.PDF(accessed December 19, 2023).8. Harrison R, Mubareka S, Papenburg J, et al. AMMI Canada 2023 update on influenza: management and emerging issues. J Assoc Med Microbiol Infect Dis Can 2023;8(3):176-86. https://jammi.utpjournals.press/doi/pdf/10.3138/jammi-2023-07-12 (accessed December 19, 2023).9. Public Health Ontario. Antiviral medications for the 2023-24 seasonal influenza: public health considerations. September 2023. https://www.publichealthontario.ca/-/media/Documents/A/2023/antiviral-medications-seasonal-influenza.pdf?rev=cf32ccda7ef74d839ef02a19c9ebe8a6&sc_lang=en (accessed December 19, 2023).10. Anon. Antiviral drugs for influenza for 2023-2024. Med Lett Drugs Ther 2023; November 13, 2023.11. European Medicines Agency. Tamiflu: summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/tamiflu-epar-product-information_en.pdf (accessed December 19, 2023).12. Tamiflu: highlights of prescribing information. Revised August, 2019. https://www.gene.com/download/pdf/tamiflu_prescribing.pdf (accessed December 19, 2023).

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