Influenza antivial medications

◼ Seasonal influenza epidemics can cause febrile illnesses that range in
severity from mild to debilitating and can lead in some instances to
hospitalization and even cause death.
◼ Persons infected by influenza virus may be asymptomatic or present with
self-limited acute febrile respiratory symptoms , with recovery in 3-7 days.
◼ However, those presenting with severe illness may have significant morbidity
and mortality, such a presentation has been found to be associated with
high-risk patients.

◼ Influenza is a self limited illness ,For patients in low-risk groups who
do not develop complications, prognosis is good and a full recovery
is expected.
◼ Patients in high-risk groups have an increased incidence of severe
illness, hospitalization, and death.

• Uncomplicated
influenza (Mild ILI)
• Complicated
influenza (Severe ILI)
▪ Fever
▪ Cough
▪ Sore throat
▪ Muscle pain
▪ Malaise
▪ No dyspnea and
shortness of breath
▪ GIT symptom (vomiting
& diarrhea)
▪ Shortness of breath and
dyspnea
▪ Lower RTI (pneumonia)
▪ CNS involvement
(confusion)
▪ Severe dehydration
▪ Secondary complications
▪ COPD–asthma exacerbation

How to recognize patients with severe or
complicated illness (Severe ILI)?

▪ Patients with mild influenza like illness (Mild ILI) who present with an
uncomplicated febrile illness typically do not require antiviral treatment
unless they are at higher risk for serious influenza complications.
▪ Patients with complicated or severe influenza like illness should be
hospitalized & treated with antivirals .

◼ Antiviral treatment is recommended as early as possible for any
patient with confirmed or suspected influenza who :
1. is hospitalized
2. has severe, complicated, or progressive illness
3. is at higher risk for influenza complications.
Most people who are otherwise healthy and get the flu do not need
to be treated with antiviral drugs .

◼ Adamantanes and Rimantadine are M2 ion channel blockers; they
interfere with hydrogen ion channel activity of the influenza A virus
and prevent viral uncoating.
◼ M2 proton channel blockers protect only against the A viruses,
however they are ineffective against all currently circulating influenza
virus strains.

◼ Neuraminidase, is an enzyme, breaks the bonds that hold new virus
particles to the outside of an infected cell.
◼ Once the enzyme breaks these bonds, this sets free new viruses that
can infect other cells and spread infection.
◼ Neuraminidase inhibitors block the enzyme's activity & prevent new
virus particles from being released, thereby limiting the spread of
infection.

◼ Neuraminidase inhibitors block viral neuraminidase enzyme, which is
critical in releasing virions from the infected host's cells. These drugs
are active against influenza A and B.
◼ Neuraminidase inhibitors, are not cures and do not kill the virus but
interfere with the way the virus multiplies , they shorten flu episodes by
a couple of days, reduce the risk of complications and possibly lower the
likelihood that someone will pass on the virus.

◼ Neuraminidase inhibitors do not ‘kill’ the flu virus but merely slow the
virus replication down to a level where the immune system can more
easily destroy it.
◼ Thus they can reduce the severity and shorten duration of a flu illness.
◼ Ideally, they should be given as early as possible especially within 48
hours of influenza illness onset.

◼ There are three FDA-approved influenza antiviral drugs (Neuraminidase
inhibitors), recommended by CDC this season to treat influenza:
1. Oseltamivir (trade name Tamiflu®)
2. Zanamivir (trade name Relenza®)
3. Peramivir (trade name Rapivab®).

◼ Due to high levels of resistance, Amantadine and Rimantadine are not
recommended for antiviral treatment or chemoprophylaxis of currently
circulating influenza A viruses.
◼ WHO recommends neuraminidase inhibitors as the first-line treatment
for people requiring influenza antiviral therapy.

◼ Neuraminidase inhibitors are effective against all strains of influenza,
unlike vaccines which are specific only to the strains for which they were
designed.
◼ Antiviral resistance to oseltamivir, zanamivir, and peramivir among
circulating influenza viruses is currently low, but this can change.

Influenza Diagnosis and Management
◼ Influenza testing is not needed for all patients with signs & symptoms of
influenza to make antiviral treatment decisions.
◼ In general, in the context of a community outbreak of influenza, testing
for influenza is not indicated.
◼ If testing is done, it is recommended that RT-PCR (Reverse Transcriptase
Polymerase Chain Reaction) tests be performed from nasopharyngeal
swabs or throat swabs.

◼ When influenza viruses are known to be circulating in a community,
patients presenting with features of uncomplicated influenza with
or without high risk factors of developing severe or complicated
illness can be diagnosed on clinical and epidemiological grounds,
will not require influenza laboratory confirmation.

◼ The clinical diagnosis of influenza can be made for outpatients with
signs and symptoms consistent with influenza , results of diagnostic
testing are not available in a timely manner to inform clinical decision
making.
◼ The use of rapid tests is not recommended, due to their low sensitivity.
◼ Influenza testing is appropriate for hospitalized inpatients, especially
if a positive test would result in a change in clinical management.

◼ Patients with mild influenza like illness who present with an uncomplicated
febrile illness typically do not require antiviral treatment unless they are at
higher risk for serious influenza complications.
◼ Patients with complicated or severe influenza like illness (Severe ILI) should
be hospitalized & treated with antivirals.

◼ Clinical judgment is important when making antiviral treatment decisions.
◼ For Decisions to start antiviral treatment,you should not wait for laboratory
confirmation of influenza because laboratory testing can delay treatment
and because a negative rapid influenza diagnostic test result does not
rule out influenza.

◼ When indicated, Clinical benefit is greatest when antiviral treatment is
administered early, ideally within 48 hours of influenza illness onset.
◼ Clinical trials & observational data show that early antiviral treatment can
shorten the duration of fever and illness symptoms, and may reduce the
risk of complications from influenza .

◼ Antiviral treatment for influenza might have benefits in patients with
severe, complicated or progressive illness (Severe ILI) in hospitalized
patients even, when started after 48 hs of illness onset (up to 4 or 5
days after illness onset).

For outpatients with uncomplicated influenza (Mild ILI):
◼ Oral oseltamivir, inhaled zanamivir, or intravenous peramivir may be
used for treatment.
◼ The recommended treatment course for uncomplicated influenza is
two doses per day of oral Oseltamivir or inhaled Zanamivir for 5 days,
OR one dose of intravenous Peramivir for 1 day.

◼ For hospitalized patients and patients with severe or complicated
illness, (Severe ILI): treatment with oral or enterically administered
Oseltamivir is recommended.
◼ Inhaled Zanamivir is not recommended because of the lack of data for use
in patients with severe influenza disease.
◼ There is insufficient data regarding efficacy of IV Peramivir for hospitalized
patients .
▪

◼ The optimal duration and dosing are uncertain for severe or complicated
influenza.
◼ Treatment regimens might need to be altered to fit the clinical situation,
For example, clinical judgment should be the guide regarding the need
to extend daily treatment regimens longer than 5 days for patients
whose illness is prolonged.

◼ Hospitalized patients with suspected influenza should be treated empirically
with Neuraminidase Inhibitors, which will provide protection, effective against
both influenza A & B viruses .
◼ A higher dose of oral or enterically administered oseltamivir (Tamifu) has been
recommended by (e.g.150 mg twice daily in adults with normal renal function)
for the treatment of influenza in immunocompromised patients & in severely
ill hospitalized patients.

◼ Patients with severe, progressive or complicated illness consistent with
a diagnosis of influenza (Severe ILI) should be treated empirically with
neuraminidase inhibitors Oseltamivir as soon as possible, irrespective
of the presence of underlying comorbidities & even if the time elapsed
between symptom onset and first opportunity to treat is >48hrs.

◼ All patients with complicated influenza should receive treatment, often in
hospital.
◼ Treatment should be started as early as possible; do not wait for laboratory
confirmation of influenza virus infection.
◼ Clinical judgment is an important factor in antiviral treatment decisions,the
duration of therapy depends on clinical response.

◼ Evidence indicates that the greatest benefit is derived from early
oseltamivir treatment. Therefore, suitable preparations of oral
oseltamivir need to be available at the point of care.

Pharmacokinetics & Absorption:
◼ Oseltamivir is absorbed from the gastrointestinal tract after oral administration
& is extensively converted predominantly by hepatic esterases to the active
metabolite.
◼ Neither oseltamivir nor its active metabolite (Oseltamivir carboxylate) are
substrates for or inhibitors of cytochrome P450 isoforms.
◼ Plasma concentrations of active metabolite are proportional to dose and are
not significantly affected by co-administration with food .

◼ The capsules and oral suspension may be taken with or without food;
however, tolerability may be enhanced if Tamiflu is taken with food.
◼ Excretion: The active metabolite is not further metabolized and is
eliminated in the urine.

Drug interaction
◼ Oseltamivir has limited potential for clinically relevant interactions
with commonly co-administered drugs.
◼ Oseltamivir is extensively converted to oseltamivir carboxylate by
esterases, located predominantly in the liver. Drug interactions
involving competition for esterases have not been extensively
reported in literature.

◼ Nov 9, 2006 (CIDRAP News) – A laboratory study indicates that the
antiplatelet drug clopidogrel (Plavix) may limit the action of the antiviral
oseltamivir (Tamiflu).
◼ "Concurrent use of both drugs would inhibit the activation of oseltamivir . .
thus making this antiviral agent therapeutically inactive“.
◼ Tamiflu must be hydrolyzed in the body to be effective.. But in the presence
of clopidogrel , the hydrolysis of Tamiflu was inhibited as much as 90% ,
according to the report.

◼ "The study suggests that Plavix can prevent metabolic conversion of Tamiflu
to the active drug.
◼ it's not known whether the drug interaction observed in the lab study would
occur to the same extent in the human body.
◼ "The main limitation is that it's unclear how well this finding translates into a
clinical situation (ie, it might not be as concerning, as the inhibition of Tamiflu
conversion might not be as great).

◼ The study by itself does not prove there is a clinically relevant interaction
between clopidogrel and oseltamivir.
◼ "Roche has made a preliminary review of this publication and concludes
that "The clinical conclusions are made based on in vitro data from a limited
dataset.

◼ Oseltamivir administered orally or by oro/naso gastric tube is well absorbed
in critically ill influenza patients, including those in the intensive care unit,
on continuous renal replacement therapy, and/or on extracorporeal
membrane oxygenation.
◼ Intubated patients with influenza illness should receive oseltamivir through
a nasogastric tube .

◼ Children over one year of age and adults with swallowing difficulties
and those receiving nasogastric oseltamivir , should use capsules
which are opened and mixed into an appropriate sugary liquid as
oseltamivir has a very bitter taste.

◼ Oseltamivir and Zanamivir are "Pregnancy Category C" medications .
◼ No adverse effects have been reported among women who received
Oseltamivir or Zanamivir during pregnancy or with their babies.
◼ When considering antiviral treatment, pregnancy should not be
considered as contraindication to Oseltamivir use.

◼ Oral oseltamivir is preferred for treatment of pregnant women because
it has the most studies available to suggest that it is safe and beneficial.
◼ Oral oseltamivir is recommended for women at all stages of pregnancy
to prevent serious complications from the flu.
◼ Pregnant women are recommended to receive the same antiviral dosing
as nonpregnant women

◼ Tamiflu is probably compatible with breastfeeding , Levels of oseltamivir
in milk (39 ng/mL) are very low and would be subclinical to an infant.
◼ Limited data indicate that oseltamivir and its active metabolite are
poorly excreted into breastmilk.
◼ The infant would receive only about 0.5% of the mothers dose. The
CDC considers oseltamivir safe to use in breastfeeding mothers.

◼ No dose adjustment is needed in obese patients
either for Oseltamivir or Zanamivir.
◼ Studies indicate that the exposure to oseltamivir carboxylate (the active
metabolite of oseltamivir) is similar between obese and non-obese
subjects for both 75 mg and 150 mg doses given twice daily.

◼ Dose modification of oseltamivir should be considered in patients
with impaired renal function as serum concentrations of oseltamivir
carboxylate, the active metabolite of oseltamivir, will increase with
declining renal function .
◼ Duration of treatment and chemoprophylaxis is the same as that
recommended for patients with normal renal function.

◼ Dose adjustment of oseltamivir is recommended for patients with creatinine
clearance between 10 and 60 mL/min and patients with end-stage renal
disease (ESRD) undergoing hemodialysis or continuous peritoneal dialysis
receiving oseltamivir for the treatment or chemoprophylaxis of influenza.
◼ Oseltamivir is not recommended for patients with ESRD not undergoing
dialysis.

◼ In hepatically impaired patients, oseltamivir (75 µg, od) is adequately
metabolised, well tolerated and should result in no loss of clinical benefit.
◼ Therefore, no dose adjustment is required in patients with mild and
moderate hepatic impairment receiving oseltamivir for either treatment
or prevention of influenza.

• Influenza is a major cause of severe respiratory infections leading to
excessive hospitalizations and deaths globally:
 1) Annual epidemics (e.g., A/H3N2, A/H1N1, B; due to antigenic
drift)
1. 2) Pandemics (e.g., A/H1N1pdm09;due to antigenic shift - genetic
re-assortment)
2. 3) Sporadic/endemic avian Influenza virus infections (e.g., A/H5N1,
A/H7N9; adapted for limited human transmission)

◼ Oseltamivir is recommended by the World Health Organization for use
in the clinical management of pandemic and seasonal influenza of
varying severity, and as the primary antiviral agent for treatment
of avian H5N1 influenza infection in humans.

◼ Inhaled zanamivir via Diskhaler® may not be an effective delivery
route in some patients, including those unable to administer the
Diskhaler® and patients with severe underlying respiratory disease.
◼ Inhaled Zanamivir is not licensed for use in children less than five
years.

◼ Some patients have had bronchospasm (wheezing) or serious breathing
problems when they used zanamivir.
◼ Zanamivir is not recommended for people with chronic respiratory
diseases such as asthma or chronic obstructive pulmonary disease.

◼ Zanamivir powder for inhalation should NEVER be made into nebuliser
solution or administered to a mechanically ventilated patient.
◼ Zanamivir powder for inhalation should NOT be nebulised by dissolving
the capsules in water. This practice has been linked to deaths in ICU
believed to be due to blockage of ventilator tubes.

◼ No dose adjustment is recommended for inhaled Zanamivir for a 5-day
course of treatment for patients with renal impairment.
◼ No dose adjustment is required in patients with mild and moderate hepatic
impairment receiving Zanamivir for either treatment or prevention of
influenza.

◼ Transient neuropsychiatric events (self-injury or delirium) have been
reported postmarketing among persons taking oseltamivir; the
majority of reports were among Japanese adolescents and adults .
◼ Several recent analyses and reviews have found that oseltamivir is
not associated with an increased risk for neuropsychiatric events .

Post exposure Chemoprophylaxis
◼ According to the CDC, antiviral chemoprophylaxis generally should be
reserved for persons at higher risk for influenza-related complications
who have had contact with someone likely to have been infected with
influenza.
◼ Antiviral chemoprophylaxis is not appropriate for healthy children or
adults based on potential exposure in the community

◼ Exposure Antiviral chemoprophylaxis is not generally recommended if
more than 48 hours have elapsed since the last contact with an infectious
person.
◼ Patients receiving post exposure chemoprophylaxis should be informed
that Chemoprophylaxis lowers but does not eliminate the risk for influenza.
◼ Susceptibility to influenza returns once the antiviral medication is stopped.

◼ Patients receiving post exposure chemoprophylaxis should be encouraged
to seek medical evaluation ,as soon as they develop a febrile respiratory
illness suggestive of influenza because influenza virus infection still can
occur while a patient is on antiviral chemoprophylaxis .

▪ An emphasis on close monitoring and early initiation of antiviral
treatment is an alternative to chemoprophylaxis for some patients
who have had contact with someone likely to have been infectious
with influenza.
▪ Clinical judgment is an important factor in treatment decisions.

◼ Indiscriminate use of antiviral chemoprophylaxis might promote
resistance to antiviral medications or reduce antiviral medication
availability for treatment of persons at higher risk for influenza
complications or who are severely ill.

◼ CDC does not recommend widespread or routine use of influenza
antiviral medications for chemoprophylaxis so as to limit the
possibilities that antiviral resistant viruses could emerge.
◼ Influenza Antiviral chemoprophylaxis is currently NOT recommended
by the WHO.

▪ Chemoprophylaxis with antiviral medications is not a substitute for
influenza vaccination (Oseltamivir is not a substitute for the flu shot) .
▪ Annual influenza vaccination is the best way to prevent influenza and
its related complications.

Duration of Chemoprophylaxis
▪ Postexposure chemoprophylaxis is typically administered for a total
of no more than 10 days after the most recent known exposure to
a close contact known to have influenza.

Influenza Vaccines and Use of Influenza Antiviral Medications
◼ Administration of inactivated influenza vaccine to persons receiving
influenza antiviral drugs for treatment or chemoprophylaxis is acceptable.
◼ Inactivated influenza vaccine can be administered at any time relative to
use of TAMIFLU.

◼ Live-attenuated influenza vaccine should not be administered until 48
hours after cessation of influenza antiviral therapy., because antiviral
drugs reduce & inhibit replication of live vaccine virus and possibly
reduce the efficacy of LAIV.
◼ If influenza antiviral medications are administered within 2 weeks after
receipt of live-attenuated influenza vaccine, the vaccine dose should be
repeated 48 or more hours after the last dose of antiviral medication.

Influenza antivial medications

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