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Clinical Microbiology: Open Access Hama, Clin Microbiol 2015, 4:6
Cli

ISSN: 2327-5073 DOI: 10.4172/2327-5073.1000224

Review Article Open Access

The Mechanisms of Adverse Reactions to Oseltamivir: Part II. Delayed

Type Reactions
Rokuro Hama*
Japan Institute of Pharmacovigilance, Non-profit Organization, Osaka, Japan
*Corresponding author: Rokuro Hama, Japan Institute of Pharmacovigilance, Non-profit Organization, Osaka, Japan, Tel: +81-6-6771-6314; Fax: +81-6-6771-6347; E-
mail: [email protected]
Received date: October 16, 2015; Accepted date: November 21, 2015; Published date: November 28, 2015
Copyright: © 2015 Hama R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Oseltamivir is recommended for treatment and prophylaxis of Influenza in persons at higher risk for Influenza
complications such as individuals with diabetes, neuropsychiatric illnesses, and respiratory, cardiac, renal, hepatic or
hematological diseases. However, a recent systematic review reported that reduction of antibody production, renal
disorders, hyperglycemia, psychiatric disorders, and QT prolongation may be related to Oseltamivir use. The
underlying mechanisms of these effects are reviewed.

There is decisive evidence that administration of a clinically compatible dose of Oseltamivir in mice challenged by
a respiratory syncytial virus (RSV) that lacks a neuraminidase gene showed symptom-relieving effects and inhibition
of viral clearance. These effects were accompanied by decreased level of T cell surface sialoglycosphingolipid
(ganglioside) GM1 that is regulated by the endogenous neuraminidase in response to viral challenge. Clinical and
non-clinical evidence supports the view that the usual dose of Oseltamivir suppresses pro-inflammatory cytokines
such as interferon-gamma, interleukin-6, and tumor necrosis factor-alpha almost completely in experimentally
infected Influenza viruses in humans with partial suppression of viral shedding.

Animal toxicity tests support the clinical evidence with regard to renal and cardiac disorders (bradycardia and QT
prolongation) and do not disprove the metabolic effect. Reduction of antibody production and cytokine induction and
renal, metabolic, cardiac, and prolonged psychiatric disorders after Oseltamivir use may be related to inhibition of
the host’s endogenous neuraminidase. While the usual clinical dose of Zanamivir may not have this effect, a higher
dose or prolonged administration of Zanamivir and other neuraminidase inhibitors may induce similar delayed
reactions, including reduction of antibody and/or cytokine production.

Keywords: Antibody; Endogenous neuraminidase; Neuraminidase reduction in hospitalization was not shown for either NI. Oseltamivir
inhibitor; Neuropsychiatric adverse effects; Oseltamivir; Pro- did not reduce complications, including pneumonia classified as
inflammatory cytokines; QT prolongation; Renal impairment serious or which led to study withdrawal. Both NIs reduced
“laboratory confirmed symptomatic Influenza infection,” but not
Introduction Influenza-like illness. Oseltamivir increased risk of nausea, vomiting,
headache, psychiatric, renal, and diabetic/hyperglycemic events, and
Neuraminidase inhibitors (NIs) are expected to reduce pain in limbs, but Zanamivir did not. Oseltamivir reduced diarrhea
complications of Influenza, especially in persons at higher risk for and apparent cardiac events, but induced prolonged QTc time (Bazett
Influenza complications [1,2], and Oseltamivir is included in the correction) [9].
Model List of Essential Medicines [3]. Persons at higher risk include
those with diabetes, neuropsychiatric illnesses, and respiratory, This review discusses the biological base of adverse reactions, in
cardiac, renal, hepatic, or hematological diseases [1,2]. However, particular those of the delayed type.
serious neuropsychiatric adverse reactions to Oseltamivir, including
sudden deaths and abnormal behaviours leading to accidental death, Brief Description of Neuraminidase Inhibitors
have been reported since the drug was introduced into medicine [4-8].
In Japan, Oseltamivir has been contraindicated in principle for Neuraminidase inhibitors and medical use
children and adolescents aged 10 to 19 years since 2007 due to concern
about the risk of abnormal behaviours [4-7]. Adverse reactions to Neuraminidase inhibitors (NIs) comprise inhaled Zanamivir
Oseltamivir include sudden and delayed onset types and others [6,7]. (Relenza, GlaxoSmithKline), oral Oseltamivir (Tamiflu, Gilead
Sudden death is another concern about Oseltamivir use [5-8]. Sciences, F. Hoffman-La Roche and Chugai in Japan), parenteral
Peramivir [11] (BioCryst Ltd and Shionogi), inhaled laninamivir
The Cochrane’s neuraminidase inhibitors team showed in its latest (Daiichi Sankyo Co. Ltd) [12], and others still under development [13].
review [9] that neuraminidase inhibitors (NIs), including Oseltamivir Zanamivir and Oseltamivir have been marketed in the US since 1999,
and Zanamivir, have symptom-relieving effects in adults, but it is and subsequently in other countries including Japan. Peramivir and
unclear whether the same effects occur in children. Oseltamivir
reduced a four-fold increase in antibody titre [9,10]. Evidence of

Clin Microbiol Volume 4 • Issue 6 • 1000224

ISSN:2327-5073 CMO, an open access journal
Citation: Hama R (2015) The Mechanisms of Adverse Reactions to Oseltamivir: Part II. Delayed Type Reactions. Clin Microbiol 4: 224. doi:
10.4172/2327-5073.1000224

Page 2 of 10

Laninamivir were put on the market in Japan in January and When healthy adult volunteers were administered with 75 mg of OT
September 2010, respectively. (equivalent to 98.6 mg of OP), approximate average Cmax (ng/ml), Tmax
(h), AUC (ng.h/ml), and elimination half-life (t1/2:hs) of OP were as
F. Hoffman-La Roche (Roche) donated Oseltamivir to the World
follows, respectively: 60 ng/ml, 0.7-2 hs, 150-200 ng.h/ml, and 1.2
Health Organization (WHO), and the WHO decided to recommend
h-1.9 h. For OC, they were 200 ng/ml-300 ng/ml, 4-5 h, 3000 ng h/
stockpiling neuraminidase inhibitors (especially Oseltamivir) for use in
ml-4000 ng h/ml, and 5 h-10 h [29]. The pharmacokinetic (PK)
the event of a pandemic [14]. Prior to the emergence of Influenza A/
parameters in healthy children aged 3 years or older are not very
H1N1 in 2009, governments worldwide stockpiled 220 million
different from those in adults [29]. In the 5 patients with decreased
treatments of Oseltamivir, swelling sales since the start of 2003 to CHF
creatinine clearance (<30 ml/min), after 6 days administration of 100
7.6 billion [15]. The use of NIs has increased dramatically since the
mg of OT (as free form), PK parameters (± SD) of OC were as follows:
outbreak of A/H1N1 in April 2009.
Cmax: 4052 (± 1519) ng/ml, Tmax: 5.20 (± 1.11), AUC0-12:43086 ng
Between the first approval in the US and the 2006/2007 season, h/ml (± 18068), and t1/2:16.1 (± 2.69) [29].
approximately 48 million patients received a prescription for
In the 12 patients who were hemo-dialyzed, PK parameters (± SD)
Oseltamivir worldwide [16], while 4 million patients received a
after 75 mg of OT were as follows: Cmax: 2131 (± 533) ng/ml, Tmax:
prescription for Zanamivir [17]. Japan, the US, and the other countries
27.3 (± 6.9), AUC0-last: 106314 (± 26.029) ng h/ml, and t1/2: 159
consumed 76%, 21%, and 3% of the world total of Oseltamivir,
(these data were calculated before the next dialysis, 48 hours after the
respectively [16]. For children (suspension), 85% was consumed in
previous dialysis; SD was not given) [29]. Thus, almost all OC is
Japan [17].
secreted in urine, and dose adjustment is necessary if the patients’
Zanamivir was rarely prescribed (less than 1% of total antiviral creatinine clearance is less than 30 ml/min [24,29,30].
prescriptions for Influenza) in Japan before the Japanese Ministry of
Health, Labour and Welfare (MHLW) contraindicated Oseltamivir use Evidence on Adverse Reactions to Oseltamivir in
in patients aged 10 years to 19 years in March 2007 [4,6]. After this
Humans and in Other Animals
restriction, prescriptions of Oseltamivir decreased substantially. After
laninamivir was put on the market in Japan in September 2010, its To date, it is postulated that adverse effects of Oseltamivir include
share increased rapidly. In the 2013/14 season, the prescription shares sudden onset type, delayed onset type, and others [6,7]. This chapter
of Oseltamivir, Zanamivir, laninamivir, and peramivir were 36%, 19%, mainly summarizes the delayed onset type adverse reactions to
42%, and 3% in Japan, respectively [18]. Oseltamivir reported in the clinical trials and epidemiological studies,
which may help to explain possible adverse effects of other
Mode of Action and Pharmacokinetics in Non- neuraminidase inhibitors. A very brief review of the sudden onset type
neuropsychiatric adverse effects of Oseltamivir is also provided.
Infectious State
Although NIs may reduce the ability of the virus to penetrate the Sudden onset neuropsychiatric reactions
mucus in the very early stage of infection [19-24], their main
mechanism of action is thought to lie in their ability to interfere with The sudden onset type reactions include nausea, vomiting, and
the release and spread of progeny Influenza virus from infected host hypothermia, as well as neuropsychiatric reactions such as abnormal
cells by inhibiting neuraminidase of Influenza viruses [21,23,24]. It is behaviours, hallucination, and sudden respiratory arrest followed by
generally believed that Oseltamivir most likely reduces symptom cardiac arrest and death [6,7,31]. These appear very shortly (from less
duration by reducing viral load, and via the spread and release of than 1 hour to 12 hours at most) after the first dose of Oseltamivir, and
cytokines [25]. However, the full prescription information of disappear rapidly unless they induce respiratory arrest and sudden
Oseltamivir (revised in April 2010) states “The concentrations of death, or sequelae [6,7,31]. They may disappear even if Oseltamivir is
Oseltamivir carboxylate required for inhibition of Influenza virus in continuously taken, although symptoms may reappear if the drug is
cell culture were highly variable depending on the assay method used taken several times. The underlying mechanisms of sudden-onset type
and the virus tested. The relationship between the antiviral activity in reactions are discussed elswhere [6,31].
cell culture, inhibitory activity in the neuraminidase assay, and the
inhibition of Influenza virus replication in humans has not been Delayed onset reactions with prolonged time for recovery
established” [24]. It is not clearly stated that the mechanisms of
Delayed onset reactions include disorders of various organs and
symptom relief are derived from reduction of viral load.
systems such as renal, metabolic, cardiac, hepatic, hematological,
Oseltamivir phosphate (OP) is an ethyl ester prodrug that requires immune, nervous, psychiatric, and general systems (fatigue or
ester hydrolysis for its conversion to the active form of the malaise). Most of the reactions of this type appear at least a few days
neuraminidase inhibitor, Oseltamivir carboxylate (OC). The brand after commencement of Oseltamivir intake, although QTc
name drug of OP capsule (Tamiflu capsule) contains 75 mg of prolongation may be closely related to the plasma concentration of
Oseltamivir expressed as free base (OT), which is compatible with 98.6 Oseltamivir carboxylate, even at first dose (details described below).
mg of OP. OP dissociates in the gastrointestinal tract to form OT, Duration of symptoms from these reactions, especially
which is absorbed and metabolised into OC by hepatic neuropsychiatric ones, tends to be prolonged: for months or even years
carboxylesterase (hCE). [6].
In healthy volunteers, the area under the curve (AUC) of OP is 3%
to 5% that of OC. The penetration of OP across the blood-brain barrier Inhibition of antibody production and reinfection
(BBB) is restricted (less than 10%) by P-glycoprotein (P-gp) in mature Oseltamivir significantly reduced the odds of patients having a 4-
and non-infected animals [26-28]. fold antibody rise, by almost 20% (risk ratio by 8%), according to a

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Citation: Hama R (2015) The Mechanisms of Adverse Reactions to Oseltamivir: Part II. Delayed Type Reactions. Clin Microbiol 4: 224. doi:
10.4172/2327-5073.1000224

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meta-analysis of 8 reports (10 studies) [9,10]. Heterogeneity was not 38 mg/kg is 6.1 mg/kg converted by body surface area and 5.5 mg/kg
significant (I2=4%). converted by AUC level of OC. These are 2.4 and 2.2 times higher than
the usual dose for a person weighing 60 kg. Renal impairment in the
Attenuation of secretory IgA (sIgA) was more marked [32-35].
highest-dose group was accompanied by increased water intake,
Sawabuchi et al. reported that lower induction of sIgA against the
increased leukocyte count, and increased bilirubin, BUN, creatinine,
Influenza A virus was observed in children treated with Oseltamivir in
urine volume, and NAG/creatinine ratio.
comparison with children treated without Oseltamivir. The odds of a
child’s sIgA level increasing more than 5-fold were significantly lower *a: HED (human equivalent dose) [40]. According to the “Guidance
in children treated without Oseltamivir: OR=0.11 (95% CI: 0.02, 0.61, for Industry,” for a person weighing 60 kg, conversion factors for HED
p=0.008) [32]. Anti-Influenza A virus sIgA attenuation was observed for mouse, rat, ferret, marmoset monkey, rabbit, and dog are 12.3, 6.2,
in children treated both with Oseltamivir or with Zanamivir [33]. 5.3, 6.2, 3.1, and 1.8, respectively.
These findings are consistent with evidence from animal tests using Metabolic disorders: hyperglycemia and diabetes: Increased glucose
sub-clinical doses of Oseltamivir in Influenza A/H1N1 infected mice level in the highest dose group (1522 mg/kg) was observed in a rat oral
[34,35]. Non-significant slight reduction of hemagglutinin (HA) 2-week test. The data were not described, but this increased glucose
specific IgG antibody in the serum and spleen was reported, while HA level was accompanied by increased leukocyte count, dose-related
specific secretory IgA antibody (s-IgA Ab) in nasal wash and significant increase of BUN (p<0.01), increased weights of the kidney
bronchoalveolar fluids (BALF) was significantly reduced: by and the liver, mineralization of tubules of renal medulla (male: 8/10),
approximately 80% on day 12 [34]. and mild-to-moderate accumulation of lung alveolar macrophages
[29].
In human clinical trials, Zanamivir at the usual dosage did not
reduce antibody (anti-HA Ab) production [9], but attenuated sIgA Cardiac disorders: bradycardia and QT prolongation: Oseltamivir
antibody significantly [33]. In a double blind, placebo controlled trial decreased heart rate in the 9-month repeated toxicity test using
with healthy volunteers designed to investigate the effect of Zanamivir marmoset monkeys. The average heart rate during treatment period
treatment (20 mg/day for 14 days) on the humoral immune response with Oseltamivir was 328 beats/min, which was an 11% and 16%
to Influenza, the Zanamivir group responded with significantly lower decrease compared with the control group (368 beat/min) and the
antibody titres to the H1N1 [36]. Levels of pro-inflammatory cytokines average of baseline and recovery phase (392 beat/min), respectively
including IL-6, TNF-α, IFN-γ, and other chemokines were almost [29].
completely suppressed in the viral challenge RCT using a very high
In an experiment using beagle dogs to test the effects on cardiac
dose (600 mg) of intravenous Zanamivir before inoculation of
functions such as QT time [41], mean baseline QTc intervals (msec ±
Influenza virus in human adults [37].
SE) were 417 ± 16 in the control (vehicle) group (n=4) and 374 ± 2 in
Shinahara et al. [33] reported: “Even under the spread of a new virus the Oseltamivir carboxylate (OC) group (n=4). This difference was
subtype in 2009/2010, only 8.6% of the children of the no-treatment significant (p=0.0372) according to the summary data t-test. Other
group were re-infected. However, the proportions of children treated evidence suggested that variation was higher in the control group
the previous year with Oseltamivir and Zanamivir who developed re- (p=0.005; Bartlett’s test) [42]. The average ± standard error of QTc
infection in 2009-2010 were significantly higher at 37.3% and 45.0%, interval of anesthetized dogs intravenously infused with 100 mg/kg OC
respectively (P<0.01), than those of the no-treatment group.” over 30 minutes significantly increased (390 ± 4) compared with that
before infusion (376 ± 2). The average QTc recovered (374 ± 6) at 1.5
Several cases of re-infection with the same Influenza virus within
hours after discontinuation, but the standard error became larger. QTc
one season were reported [38,39]. Kopel et al. [38] reported a 13-year-
prolongation is closely related to the serum concentration of OC
old boy with cerebral palsy who 3 times had episodes of fevering with
[29,41,42]. The reasons for such large and systemic imbalances are not
positive 2009A/H1N1 Influenza detected by the RT-PCR method. He
known, but they are unlikely to have occurred by chance.
was treated with the standard dose (75 mg b.i.d for 5 days) of
Oseltamivir at the time of the first episode. A second course of Bradycardia and QT prolongation that occurred in the animal tests
Oseltamivir was administered for 10 days with the dosage adjusted for were also observed in the randomized controlled trials in humans, and
age and doubled from that of the previous regimen. His HI titres were the occurrence was closely related to the timing of the increase in the
high, but the level of secretory IgA was not determined. concentration of Oseltamivir carboxylate [9].
Renal impairment: Dose-related histological change in the renal Delayed type psychiatric symptoms: The author reported the
tubules, increased urine volume, and increased relative weights of the following case of psychiatric reaction [6]. A 15-year-old junior high
liver and kidneys were observed at various doses in various animals school boy with a body temperature of 39.2C due to Influenza B
treated for various periods [29]. diagnosed by rapid testing took Tamiflu 75 mg b.i.d. for 5 days. His
body temperature was normalized on day 5, but he felt lethargic. After
For example, in the 6-month rat toxicity test, renal weights (both
he took the last (10th) dose of Tamiflu in the morning on day 6, he
relative and absolute) increased, and histological examination revealed
went to school, sat on his desk, and began to sing loudly during a
degenerating and regenerating changes in the renal tubular epithelia,
lesson. He could not communicate with his classmates. He seemed to
basement membranes, and Bowman capsules; vacuolization in the
be delirious. 4 days after this episode, his parents took him to a general
renal tubular epithelia; and mineralization in the highest dose group
hospital. Before admission, he commented, “There are insects on my
(761 mg/kg). These histopathological findings were not reversed at 8
mask,” a sign of visual hallucinations. After admission, he tried to pull
weeks after cessation of Oseltamivir intake. In the medium-dose group
out his venous lines and attempted to go home, shouting “This is not a
(152 mg/kg: HED*a=24.5 mg/kg), renal relative and absolute weights
hospital but a nursing home for elderly people.” He could not wait until
increased, and vacuolization in the renal tubular epithelia was
his turn for examination and rushed out of the hospital into the street,
observed [29]. NOAEL for renal impairment was 38 mg/kg. HED for
where he narrowly avoided being run over by a car. On day 16 he was

Clin Microbiol Volume 4 • Issue 6 • 1000224

ISSN:2327-5073 CMO, an open access journal
Citation: Hama R (2015) The Mechanisms of Adverse Reactions to Oseltamivir: Part II. Delayed Type Reactions. Clin Microbiol 4: 224. doi:
10.4172/2327-5073.1000224

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discharged, and on days 19 and 20 he came to know that he had but she was found and transferred to hospital for medical treatment.
behaved abnormally from records on his mobile phone. It took 13 days Study medication was discontinued on study day 8. Paranoid
after the beginning of abnormal behaviour for his psychiatric schizophrenia of severe intensity was diagnosed. She subsequently
symptoms to be completely resolved [6]. absconded from the hospital and was found on study day 15 with
moderate concussion. She was again hospitalized, for 10 days. The
Among the four study reports of prophylaxis RCTs analysed in the
paranoid schizophrenia resolved within 68 days and was considered
systematic review [9], the case of longest recovery time was Subject
unrelated to study medication.
23639/3122 in trial WV15825 [43]. The narrative description on
module 1 of the clinical study report stated as follows: In the prophylaxis RCTs, 11 and 2 cases of psychiatric events with
late onset and prolonged recovery (14 days and longer) were reported
“This 69-year-old female was hospitalized on study day 8 because of
in the Oseltamivir and placebo groups, respectively. The pooled odds
paranoid schizophrenia. Her medical history included paranoid
ratio was 3.37 (95% CI: 1.11-10.23, p=0.032, I2=0%).
schizoaffective disorder, hypertension, and coronary artery disease.
Her medications included Ketoconazole, Amlodipine, Haloperidol and No animal study was performed to confirm the association of
Lorazepam. On study day 8 she ran away from her place of residence, psychotic reactions of delayed onset with prolonged recovery.

System Symptom group Symptoms and reactions

Sudden onset type reactions (by Oseltasmivir)

Digestive Gastrointestinal nausea, vomiting

Mild to moderate
hypothermia, sleep, headache, vomiting, vulging of fontanelle
symptoms

sensory disturbances, impairment of cognition, abnormal behaviour (suppressed or

Central nervous system Psychiatric symptoms excitatory), unconsciousness, paranoia, delusion, hallucination, psychosis, depression,
aggression, agitation, delirium, suisaidal (ideation, attempt, complete)

cyanosis, difficulty of breathing, hyperpnea, hypopnea, irregular breath, respiratory failure,

Respiratory suppression
respiratory arrest, cardiorespiratory arrest, and death

Delayed onset and/or prolonged type reactions

antibody reduction of antibody production, especially secretory IgA at respiratory tract

cytokine attenuated induction of cytokine and chemokines (IL-6, IFN-γ, TNF-α etc)
Immune/inflammatory/infectious
cell reduction of inflammatory cells in nasal wash and lung, reduction of CD8+ T cell in lung

reinfection etc reinfection of influenza, pneumonia and exacerbation of other infections

degenerating and regenerating changes in the renal tubular epithelia and Bowman capsules,
Renal histology/function
increased urine volume and kidney weight, proteinuria etc

Metabolic diabetic hyperglycemia, exacerbation of diabetes mellitus, new onset diabetes

Cardiac contraction decreased heart rate, bradycardia, QT prolongation

Neurological nociceptor pain in limbs or other parts of the body

delayed onset/ delayed onset psychiatric symtoms (abnormal behaviour, psycosis hallucination, delusion,
Psychiatric
prolonged type agitation, schizophrenic reactions, depression etc)

Digestive GI tract bleeding

Others bleeding (hepatic and/or hematological impairment)

Table 1: Spectrum of adverse reactions to neuraminidase inhibitors.

Other adverse effects (pneumonia, wheezing, gastric bleeding, and In the marmoset monkey 7-day oral toxicity studies, all 4 animals
others): 3 of 6 rats treated with intravenous OC (at 12 times higher treated with a 127-times-higher-than-HED dose of OT were sacrificed
level than clinical area under the curve) for 2 weeks developed acute within 4 days (1 on day 2 and 3 on day 4) because they were near death
alveolitis [29]. Of the 3, 1 exhibited wheezing on day 14 and was after severe vomiting, sleep, hypoactivity, and collapse. Macroscopic
sacrificed the next day. Diffuse hemorrhagic alveolitis (pneumonia) reddening of the stomach mucosa and histologically mucosal bleeding
and pulmonary microvascular thromboembolism were observed in with erosions, ulcers, and atrophy were observed in the stomachs of all
this animal. The safe level of intravenous OC dose is lower than twice animals.
the AUC of the usual clinical human dose.
The safety index (animal AUC0-24 with no toxicity by human
average AUC0-24 when taking 75 mg capsule b.i.d.) is 3 for the 4-week

Clin Microbiol Volume 4 • Issue 6 • 1000224

ISSN:2327-5073 CMO, an open access journal
Citation: Hama R (2015) The Mechanisms of Adverse Reactions to Oseltamivir: Part II. Delayed Type Reactions. Clin Microbiol 4: 224. doi:
10.4172/2327-5073.1000224

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toxicity studies in rats, 3 for the 6-month oral toxicity studies in rats, 8 “Adult ferrets (4 per group) were inoculated with a virulent
for the 2-week oral toxicity study in rats, and 10 for the marmoset Influenza strain. Ro-0796 was administered orally at a dose of either 5
monkey 7-day oral toxicity study. mg/kg or 25 mg/kg b.i.d. for 3 days starting 2 hours post exposure. A
control group of four ferrets received vehicle alone. In this experiment,
Potential adverse reactions to Oseltamivir and to other
Ro 64-0796 was shown to reduce the febrile response and reduce the
neuraminidase inhibitors: Potential adverse reactions to Oseltamivir
number of inflammatory cells in nasal washing in a dose dependent
and to the other neuraminidase inhibitors are summarised in Table 1.
manner. However, neither dose was demonstrated to reduce the viral
titres obtained from the lungs or nasal washings of infected animals.”
Mechanisms for Symptom Relief and the Host’s Ro-0796 refers to Oseltamivir phosphate.
Endogenous Neuraminidase
According to the published paper of Oseltamivir [49], the area
Mechanisms for symptom relief are mainly discussed in this section, under the curve (AUC) of the viral load of both 5 mg/kg/day and of 25
and those for delayed reactions are mainly discussed in the next mg/kg/day oral doses and peak viral load in the 5 mg/kg/day group
section. Both mechanisms seem to be related to inhibition of the host’s were not reduced significantly, although average peak viral titres of the
neuraminidase. 25 mg/kg/day group was reduced significantly.
In contrast, AUC of the febrile response was reduced significantly in
Inhibition of the host’s neuraminidase and symptom relief both Oseltamivir dose groups, dose-dependently. In addition, the total
Symptom relief in RSV-infected mice by Oseltamivir: Decisive number of inflammatory cells in nasal wash obtained from infected
evidence is shown by Moore et al. [44], who reported that animals in both Oseltamivir dose groups was continuously reduced for
administration of a clinically compatible dose of Oseltamivir in mice more than 96 hours.
challenged by a respiratory syncytial virus (RSV) that lacks a The conversion factor for ferret dose to human equivalent dose
neuraminidase gene showed symptom-relieving effects (decreased (HED) for a person weighing 60 kg in the “Guidance for Industry” [40]
weight loss) and inhibition of viral clearance. These effects were is 5.3. Therefore, 5 mg/kg and 25 mg/kg for adult ferrets correspond to
accompanied by decreased level of CD8+ T cell surface approximately 1 mg/kg and 5 mg/kg for humans. These are almost
sialoglycosphingolipid (ganglioside) GM1, which is regulated by the equivalent doses and 4 to 5 times higher than the human single dose of
endogenous sialidase/neuraminidase in response to viral challenge, Oseltamivir (75 mg/60 kg).
along with suppression of cytokines expression. To date, no such study
has been conducted for Zanamivir, Laninamivir, or Peramivir. Hence, the clinical dose of Oseltamivir may reduce febrile response
and the number of inflammatory cells in a nasal washing without
Decreased GM1 ganglioside and suppression of pro-inflammatory significant reduction of viral titres obtained from the lungs or nasal
cytokines: In the human phase II randomized controlled trial with washings of infected animals.
experimental infection [25], pro-inflammatory cytokines including
IL-6, TNF-α, and IFN-γ were completely suppressed by Oseltamivir *a: Module II of the most CSRs for adult treatment RCTs including
administered 28 hours after the experimental inoculation of the 2 pivotal RCTs (WV15670, WV15671) and others (WV15673/15697,
Influenza virus, while reduction of viral titre in nasal lavages was WV15707, WV15708, WV15730, WV15758, WV15759/15871,
partial. WV15799, WV15812/872, WV15819/15876/15978, WV15825), except
3 CSRs (M76001, WV16277 and ML16369). These full CSRs are
Attenuating induction of pro-inflammatory cytokines including available in ref [43] http://datadryad.org/resource/doi:10.5061/dryad.
IL-6, TNF-α, and IFN-γ is related to decreased secretion by immune 77471.
cells including dendritic cells [45], by polymorphonuclear leukocytes
[46], and by CD8+ T-cells [44,47]. Reduced cytokine induction is Mouse model: mild Influenza and lack of evidence of reduction of
derived from decreased expression of GM1 ganglioside in these cells viral load: Oral administration of 10 mg/kg of OP per day caused a
related to inhibition of the host’s endogenous neuraminidase (or 100-fold reduction in lung homogenate viral titres in mice infected
Sialidase) [44-47], especially Neu 3 (the third sub-type of with a 90% lethal dose of some strains of Influenza A or B viruses, and
neuraminidase mainly expressed in plasma membrane) [45]. enhanced survival [29,49]. Similar experiments were reported for
Peramivir [50-52].
Decreased GM1 ganglioside and pain: Crain et al. [48] reported that
Oseltamivir at 100 to 1000 times lower HED than the clinical dose may However, in a study by Wong et al. [53] using mice infected with
affect the host’s neuraminidase and reduce endogenous GM1 mild Influenza (inoculated with a non-lethal dose of Influenza virus),
ganglioside, leading to some reactions in the host. They suggest that which is a better model for testing the effects of Oseltamivir in human
“Clinical administration of Oseltamivir at doses that result in seasonal Influenza, a clinically compatible dose of Oseltamivir (10 mg/
inhibition of Influenza may also have an additional effect by decreasing kg=approximately 0.8 mg/kg as HED) administered (in 3 different
GM1 levels in nociceptive neurons” [48]. experiments) at 4 hours before inoculation, 24 hours after inoculation,
or 48 hours after inoculation showed no significant effect on viral titres
at day 5 post-inoculation.
Animal infection model: symptoms, inflammatory, cytokine
response, and viral load Wong et al. [53] observed that Oseltamivir markedly and
significantly reduced lung inflammatory cell response and induction of
Ferret model: reduction of febrile, inflammatory response with little pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β,
viral load change: The ferret model is one of the best animal models for IL-6, granulocyte–macrophage colony-stimulating factor (GM-CSF),
human Influenza infection. Roche used this model and reported as keratinocyte-derived chemokine (KC), Macrophage inflammatory
follows in the protocol (Module II) of most clinical study reports for protein-1α (MIP-1α), and Monocyte chemotactic protein-1 (MCP-1)
treatment randomized controlled trials [43*a]: whether administered prophylactically or therapeutically. However,

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these were accompanied by small non-significant effects on viral titres. Target of molecule (receptor etc.)/ Inhibition (% Inhibition (%
Based on these findings, the researchers discussed the possibility of method of assay control) control)
intrinsic anti-inflammatory effects of Oseltamivir [53].
Concentration of Concentration of
No animal study has been conducted of the infection model with OT OC
mild and non-lethal doses of the Influenza virus for Zanamivir,
3 μM 30 μM 3 μM 30 μM
Laninamivir, or Peramivir. Only animal studies of the infection model
using lethal doses of the Influenza virus are available. Adenosine A receptor 8 13 15 27

L-type Ca2+ channel (diltiazem site) 14 41 10 9

In vitro findings showing inhibitory effects on immune cells
Na+ channel (site 2) 11 38 n.i.d 9
Peripheral T-lymphocytes from healthy adult whole blood were
incubated with antigen presenting cells (APCs) pre-sensitized with NMDA-type glutamate receptor (PCP) 14 23 21 12
Influenza viruses and were tested for their proliferation ability with
and without Oseltamivir carboxylate. Proliferation of the T- AMPA-type glutamate receptor 4 17 n.i.d n.i.d
lymphocytes was suppressed by 15% and 20% when incubated with 1
Glycine-site on NMDAR (strychnine-
μM and 10 μM of Oseltamivir carboxylate, respectively, compared with insens.)
n.i.d n.i.d 1 24
the control. Concentration of Oseltamivir carboxylate (OC) of 1 μM is
compatible with the human clinical concentration of OC [29,30]. The Kainate-type glutamate receptor n.i.d 14 10 10
pharmaceuticals and medical devices agency (PMDA) and the
Muscarinic receptor M4 n.i.d n.i.d 1 10
summary basis of approval (SBA) did not refer to any published paper
for these findings [29,30]. No published papers with these data could Neuropeptide Y receptor Y1 8 6 n.i.d 11
be found.
Nociceptin receptor 9 8 8 16

Mechanism for Delayed Reactions Norepinephrine transporter n.i.d n.i.d 5 11

Nicotinic acetylchol receptor (α4β3, BGTX

Psychiatric and other nervous symptoms insens.)
5 n.i.d n.i.d 11

Psychiatric and nervous symptoms that occur in the very early hERG potassium channel (Kv11.1) n.i.d 17 8 16
phase of treatment such as acute behavioural change and respiratory
depression leading to death may be due to the effects of unmetabolized Sigma receptor (non-selective) 9 34 n.i.d 3
Oseltamivir phosphate (OP) on the central nervous system (CNS). If GABA transporter 15 15 n.i.d 17
OP has affinity to NMDA receptors [31,54,55] and is used for an
extended period of time, it may induce schizophrenic reactions in Serotonin 5-HT2A receptor 4 13 15 n.i.d
humans, as shown in the prophylaxis RCTs of Oseltamivir [9,43], by a
Serotonin 5-HT4e receptor n.i.d 13 n.i.d n.i.d
mechanism similar to that of the sudden onset type reactions.
Chemokine receptor 1 (CD191) 3 2 2 8
The symptoms that occur in the late phase of treatment with
prolonged duration, such as psychosis, confusion, and aggression, and Chemokine receptor 3 (CD193) 10 18 15 12
are frequently observed in the prophylaxis trials (shown in section
3.2.6) may also be due to the effects of Oseltamivir carboxylate (OC) CXC chemokine receptor 2 (IL-8B) 1 2 11 16
on CNS. Pain in the limbs [9] may also be induced by both
mechanisms. Table 2: Activity of OP and OC against molecular targets of high
Izumi et al reported that systemic injection of Oseltamivir (50 relevance for mood, cognition and behavior in binding or functional
mg/kg i.p.) significantly altered the duration of loss of lightning reflex assay (data are extracted from ref [58]).
following ethanol injection in rats. Ethanol injection in the presence of
Muraki et al. [55] demonstrated that Oseltamivir, but not
Oseltamivir also resulted in enhanced hypothermia [56]. Izumi et al
Oseltamivir carboxylate, directly blocks human neuronal nAChRs.
also reported that combination of Oseltamivir with other
Hiasa et al. [59] found that Oseltamivir, but not Oseltamivir
neurostimulants may alter synaptic plasticity and this may contribute
carboxylate, competitively and selectively inhibited human MAO-A.
to behavioural changes associated with the drug [57].
They estimated the Ki value to be 25 to 28 μM, and IC50 was shown to
As described in section 3.2.4, QT prolongation is closely related to be between 50 to 100 μM in their paper, while Lindeman et al reported
the plasma concentration of Oseltamivir carboxylate. that both Oseltamivir and Oseltamivir carboxylate lacked clinically
relevant pharmacological activities on a panel of 155 other molecular
Taking these into account, it may be possible that Oseltamivir
targets, including MAO-A. Differing results between the study by
carboxylate directly alters the cell excitability of both neurons and
Lindeman et al and those by Muraki et al or Hiasa et al. may be derived
heart muscles, although it is not known whether the alteration is
from the different assay methods used.
derived from inhibition of the host’s endogenous neuraminidase or
from other mechanisms, including effects on other receptors or Accordingly, it is possible that there exist target receptors or
enzymes. Among receptors or enzymes that were tested by Lindeman enzymes that Oseltamivir carboxylate specifically acts on.
et al. [58], those that showed apparent dose-related increase are listed
in Table 2.

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Attenuated antibody production, immune suppression, and neuraminidase inhibitors. These include not only inhibition of
re-infection antibody and pro-inflammatory cytokine induction, but also
prolonged neuropsychiatric reactions, hyperglycemia, renal and
Attenuated antibody production [32-34] may be derived from the hepatic impairment, pneumonia, and exacerbation of infection, such
same mechanisms as those for reduction of cytokine induction related as re-infection of Influenza, gastrointestinal tract hemorrhage, and
to inhibition of the host’s neuraminidase due to decreased expression others.
of GM1 ganglioside in various immune cells [44-47]. These findings
are supported by the fact that both Oseltamivir and Zanamivir reduce
antibody production at certain doses both in humans and other
Difference between Oseltamivir and Other
animals. Neuraminidase Inhibitors in Delayed Reactions
Marois et al [47] demonstrated that Influenza specific CD8+ effector Sufficient plasma concentration of Oseltamivir carboxylate, a
T cell recruitment was reduced up to 81% in the lungs of mice treated metabolite of orally administered Oseltamivir phosphate, acts on the
with Oseltamivir (5 or 50 mg/kg twice daily; EC50 49 nM in vitro) host’s endogenous neuraminidase to reduce (or suppress) the immune
compared to saline controls. They also showed that Oseltamivir response even at the dose of 20 mg b.i.d. for 5 days [25]. However,
administration significantly decreased the pools of tissue-resident and bioavailability of inhaled Zanamivir is 11%, estimated using the data of
circulating effector memory (93.7%) and central memory CD8+Tcells area under the curve (AUC) from inhalation and intravenous
(45%) compared to saline controls. During heterologous secondary administration over 30 minutes while peak concentration (Cmax) was
infection, a decreased memory CD8+ T cell pool combined with 3.1% of that of intravenously administered Zanamivir [63]. According
reduced generation of secondary Influenza-specific effectors in the to the data from the summary basis of approval of Zanamivir in Japan
lymph nodes resulted in 10-fold decreased CD8+Tcell recall responses, [64], bioavailability of inhaled Zanamivir is calculated to be
which increased mouse morbidity and delayed viral clearance. approximately 9% to 72% (geometric mean=25%). The low
Furthermore, they reported that antiviral administration led to a bioavailability of Zanamivir may be the major reason why reduction of
significant 5.7-fold decreased production of functional anti-Influenza antibody rise was not observed in the systematic review of Zanamivir
antibodies. They summarized that Oseltamivir treatment affects the [9].
kinetics, magnitude, and nature of innate, adaptive, and memory However, if Zanamivir is administered at a high dose or for an
immune responses during PR8 (H1N1) Influenza infection in the extended period, or if the patient is very susceptible, inhaled
mouse model. They suggested that administration of Oseltamivir in Zanamivir might reach a concentration high enough to reduce the
infected individuals might reduce the generation of protective immune response. In fact, 20 mg/day of Zanamivir for 14 days showed
immunity against reinfection and, thus, lead to the development of significant reduction of antibody titres to the H1N1 compared with a
disease [47]. placebo [36]. Levels of various pro-inflammatory cytokines and
The evidence of re-infection in the subsequent season [33] or within chemokines were almost completely suppressed in the viral challenge
the same season [38,39] supports the adverse effect of both RCT using a very high dose (600 mg) of intravenous Zanamivir before
neuraminidase inhibitors on the immune system. inoculation of Influenza virus in human adults [37].

These findings are also consistent with the evidence on the Although no report on the suppression of cytokine induction by
mechanism of action of Oseltamivir from animal models [49,53], a laninamivir was found in either published papers or the summary
randomized controlled experimental human Influenza study [25], and basis of approval [65], several reports indicated that pro-inflammatory
in vitro findings showing inhibitory effects on immune cells [29]. cytokine induction was suppressed by peramivir administration in the
animal models of lethal Influenza virus infection [49-51]. Prolonged
Other adverse reactions: renal, metabolic, cardiac, prolonged median survival was reported in these animal infection models with
almost 100% mortality. However, prolonged survival was not stated in
psychiatric and bleeding disorders, pneumonia, etc.
the ferret infection model of Laninamivir [65]. Moreover, viral titres in
In mammalian cells, 4 types of sialidase (neuraminidase) have been the nasal wash were higher at 72 hours after inoculation of Influenza
identified. They are classified according to their major intracellular virus in ferrets administered with inhaled laninamivir 4 hours after
localization as intralysosomal sialidase (NEU1), cytosolic sialidase inoculation compared with vehicle control, while they were lower at 24
(NEU2), plasma membrane-associated sialidases (NEU3), and hours and 48 hours after inoculation [65].
mitochondrial sialidase (NEU4) [60,61].
The AUC at the maximum animal dose of Zanamivir (191 μgh/ml
Hepatic NEU3 may be associated with sensitivity to insulin and after intravenous 90 mg/kg) [64] in rats was only 2.2 times higher than
glucose tolerance through modification of ganglioside composition that of healthy male adults [63] (86.6 μgh/ml after intravenous
and peroxisome proliferator-activated receptor gamma signaling [62]. administration of 600 mg over 30 minutes). The maximum dose of
inhaled Laninamivir in the toxicity tests was 7.4 times higher than the
Clinical administration of Oseltamivir at doses that result in
usual clinical dose based on the AUC [65]. Hence, it may be hard to
inhibition of Influenza may also have an additional effect by decreasing
detect renal toxicity of Zanamivir and Laninamivir using existing
GM1 levels in various cells, including immune cells [44-47],
animal toxicity studies.
nociceptive neurons [48], insulin or peroxisome proliferator-activated
receptor gamma signaling [62], and possibly other important cells in According to the Japanese summary basis of approval [66], the
the kidney, liver, heart, or central nervous system. kidney is a toxic target organ of Peramivir. NOAEL of peramivir for
renal toxicity in rabbits was 100 mg/kg, which is 32 mg/kg in HED
The evidence from these reports suggests that reduction of human
(conversion factor 3.1) or 2.7 times higher than the maximum clinical
endogenous sialidase (neuraminidase) activity by Oseltamivir
dose of Peramivir (600 mg/50 kg). The safety margin for renal toxicity
carboxylate may cause delayed type adverse reactions to
was estimated at 3.0 and 2.1 based on the AUC in single-dose and

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multiple-dose (7 days) oral rabbit toxicity studies [66]. It is very 4. Maxwell SRJ (2007) Tamiflu and neuropsychiatric disturbance in
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Inhibitory effects on antibody production have been reported for Prefecture.
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cell functions, including effects on ganglioside GM1, have not been be related to central suppression. BMJ. 335: 59.
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in general may act as inhibitors of the host’s endogenous Neuraminidase inhibitors for preventing and treating Influenza in healthy
neuraminidase and thereby induce various delayed type reactions as adults and children. Cochrane Database Syst Rev 4: CD008965.
shown in the case of Oseltamivir. 10. Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, et al (2012)
Neuraminidase inhibitors for preventing and treating Influenza in healthy
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Summary and Conclusion
11. Kohno S, Yen MY, Cheong HJ, Hirotsu N, Ishida T, et al. (2011)Clinical
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Influenza symptoms by inhibiting the neuraminidase of the Influenza single-dose intravenous peramivir with oral Oseltamivir in patients with
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laninamivir octanoate (CS-8958) versus Oseltamivir as treatment for
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symptom relief without significant reduction of viral load. They also S1.
cause attenuated antibody production of secretory IgA antibodies and 14. Roche. Media release (2006) Roche donates a further 2 million treatment
plasma HI antibodies of Influenza, and may be the cause of re- courses of antiviral Tamiflu to the WHO for regional stockpiling.
infection of Influenza within the same or the subsequent seasons. 15. Jack A (2009) Roche steps up production of Tamiflu after virus scare.

Mechanisms for delayed onset reactions with prolonged course, 16. FDA Pediatric Advisory Committee Meeting (2007) Relenza®
(Zanamivir) Inhalation Powder NDA 21-036. Glaxosmithkline.
such as psychosis and other psychiatric reactions, and renal, metabolic
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2007-4325b_02_16_Sponsor%20Background%20Package%20GSK.pdf
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18. http://www.mhlw.go.jp/file/05-Shingikai-11121000-
Iyakushokuhinkyoku-Soumuka/0000063406.pdf
Conflict of Interest 19. Bhatia A, Kast RE (2007) How Influenza’s neuraminidase promotes
virulence and creates localized lung mucosa immunodeficiency. Cell Mol
Rokuro Hama was a co-recipient of a UK National Institute for Biol Lett 12: 111-119.
Health Research grant (HTA 10/80/01, Update and amalgamation of 20. Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk H (2004)
two Cochrane reviews: neuraminidase inhibitors for preventing and Neuraminidase is important for the initiation of Influenza virus infection
treating Influenza in healthy adults and children (www.nets.nihr.ac.uk/ in human airway epithelium. J Virol 78: 12665-12667.
projects/hta/108001). RH wrote two books published in 2008 about the 21. Moscona A (2005) Neuraminidase inhibitors for Influenza. N Engl J Med
harm of Oseltamivir and antipyretics. He provided scientific opinions 353: 1363-1373.
and expert testimony on 14 adverse reaction cases related to 22. Ohuchi M, Asaoka N, Sakai T, Ohuchi R (2006) Roles of neuraminidase
Oseltamivir for the applications by their families for adverse reaction in the initial stage of Influenza virus infection. Microbes and Infection 8:
relief by PMDA (Pharmaceuticals and Medical Devices Agency) and in 1287-1293.
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these reactions. Most of the cases were reported in reference [6]. virus neuraminidase does not play a role in viral entry, replication,
assembly, or budding. J Virol. 69:1099–1106.
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of Mines, USA.

Clin Microbiol Volume 4 • Issue 6 • 1000224

ISSN:2327-5073 CMO, an open access journal