Oseltamivir: early use and late use are both related to harmful effects especially in hypercytokinemia in patients with or without risk
Cochrane team [1] and Freemantle and Calvert [2] did not discuss in
detail the harmful effects of Tamiflu. However, early use and late use of
Tamiflu may both be related to serious outcomes including death in influenza
infection. In this rapid response I would like to describe the
effect of late use of oseltamivir on survival of hospitalized patients.
One of the most important mechanisms of reactions with serious
outcome including death related to early use and late use of Tamiflu is
depression of the central nervous system, leading to respiratory
depression, neuropsychiatric symptoms and sudden death [3].
Unchanged oseltamivir (OT) easily enters the brain [3-8], if the
function of blood-brain barrier (BBB) decreased related to the low
activity of p-glycoprotein (p-gp), a major efflux transporter of OT [6-8].
Hypofunction of BBB is observed in animals before weaning (including human
infants) [5, 7] and under hypercytokinemia [9]. In vitro, BBB p-gp
activity is downregulated after short-term exposure to inflammatory
mediators [9] Of course, hypercytokinemia is observed in early phase of
influenza (around peak of fever). Inflammatory activation occurs modestly
with term labour, but much more robustly in preterm delivery, particularly
in the presence of intrauterine infection [10].
Moreover, hypercytokinemia is observed among the late presenters,
which correlated with hypercytokinemia [11]. It is easy to assume that
late presenters those presenting after day 3 might have treated themselves
with OTC antipyretics. If OTC antipyretics were non-steroidal anti-
inflammatory drugs (NSAIDs), they may promote induction of proinflammatory
cytokines resulting ARDS, encephalopathy with hepatic failure and
collectively multi-organ failure (MOF), while no study discussed the
harmful effect of NSAIDs in influenza [12, 13]
On the other hand, neuraminidase contributes to the maintenance of
normal human immune and repair systems [14] which might be impaired by the
neuraminidase inhibitor and could cause renal damage, glucose intolerance
[2, 14] and MOF [3].
2009 Pandemic Influenza A (H1N1) Hospitalizations Investigation Team
of CDC [16] reported that of the 268 patients for whom data were available
regarding the use of antiviral drugs, 200 (75%) received such drugs. Of
these patients, 188 received oseltamivir. They reported that the use of
antiviral drugs was beneficial in hospitalized patients, especially when
such therapy was initiated early (within 48 hour of onset). This is based
on the data, Of the 205 patients who were not admitted to an ICU and
survived, 62 (30 %) received antiviral therapy within 48 hours after the
onset of symptoms and of the 67 patients who were admitted to an ICU or
died 13 (20 %) received it.
However, if you look at another aspects of these data, of the 19
patients who died, 17 (90%) received antiviral treatment after 48 hours or
at unknown time after the onset of symptoms and of the 205 patients who
were not admitted to an ICU and survived 82 (40 %) received antiviral
therapy during the same period. Odds ratio was 12.75 (95% CI: 2.88-115.6,
p<_0.0001. p="p"/> I could find two other reports [17, 18] by which relation of late
initiation of oseltamivir and outcomes could be analysed: the first report
from Mexico [17] to which I already commented [19] and another CDC report
on the pregnant women [18].
In the former study [17] all seven fatal cases received Tamiflu,
while among 11 survived 7 received. Four patients who survived did not
receive oseltamivir. All 18 presented hospitals after 4 days after the
onset of symptoms and treatment by Tamiflu initiated after admission [17].
In the latter study [18] CDC reported all the 6 pregnant women who
died received Tamiflu at least after 6 days after the onset of symptoms.
They did not report how many pregnant women received Tamiflu and how many
did not. Anyway, number of pregnant women who did not receive Tamiflu and
died was zero. From the trend of increase of infected patients and
increase of proportion of Tamiflu takers, number of pregnant women who
received and did not received Tamiflu was estimated around 74 and 37
respectively.
Meta-analysis of these data from three reports by random effect model
yields odds ratio 10.90 (95%CI; 3.22-36.89, p<_0.0001 xmlns:_="urn:x-prefix:_" xmlns:ci="urn:x-prefix:ci" i2="0" _:_="_:_" _95="_95" ci:_="ci:_" _0-72.9="_0-72.9" figure="figure" which="which" indicates="indicates" that="that" late="late" initiated="initiated" oseltamivir="oseltamivir" might="might" be="be" related="related" to="to" death="death" of="of" the="the" hospitalized="hospitalized" patients.="patients." p="p"/> Patients who were admitted to an ICU and those who died were more
likely than patients who were not admitted to an ICU to have shortness of
breath, a neurologic disorder, radiographically confirmed pneumonia,
abnormality of laboratory data such as high creatine kinase, high
creatinine and high serum transaminase, ARDS, or sepsis [11, 16, 20].
Discussion on the harmful effect of Tamiflu to the mother themselves
and to the new born when used in pregnancy [21, 22] will be discussed in
the other rapid responses.
In conclusion, reanalysed data obtained from the observational
studies so far are consistent with the previous evidence on the
pharmacological and toxicological properties of Tamiflu. Both suggest the
harmful effects of Tamiflu in the exacerbation during late phase of
influenza probably after treatment by NSAIDs antipyretics. Tamiflu as
unchanged oseltamivir which enter the brain in hypercytokinemia in the
very early phase and in the relatively late exacerbation phase of
influenza infection may depress central nervous system, leading to
respiratory depression, neuropsychiatric symptoms and sudden death.
References
1. Tom Jefferson, Mark Jones, Peter Doshi, and Chris Del Mar
Neuraminidase inhibitors for preventing and treating influenza in healthy
adults: systematic review and meta-analysis. BMJ 2009;339:b5106, doi:
10.1136/bmj.b5106
2. Freemantle N and Calvert M. What can we learn from observational
studies of oseltamivir to treat influenza in healthy adults? BMJ 2009 339:
b5248.
3. Hama R. Fatal neuropsychiatric adverse reactions to oseltamivir?F
case series and overview of causal relationships. Internat J Risk Safety
Med 2008;20:5-36. : available at : http://npojip.org/english/no11.html
6. Morimoto K, Nakakariya M, Shirasaka Y, Kakinuma C, Fujita T, Tamai
I, Ogihara T. 2007. Oseltamivir (Tamiflu) efflux transport at the blood-
brain barrier via P-glycoprotein.
Drug Metab Dispos. (2008) 36(1):6-9. Epub 2007 Oct 16.
7. Ose A, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Fujita T,
Yamamoto A, Sugiyama Y. 2007. P-glycoprotein restricts the penetration of
oseltamivir across the blood-brain barrier. Drug Metab Dispos. (2008)
36(2):427-34. Epub 2007 Nov 26
9. Th¨¦ron D, Barraud de Lagerie S, Tardivel S, P¨¦lerin H, Demeuse
P, Mercier C, Mabondzo A, Farinotti R, Lacour B, Roux F, Gimenez F. 2003.
Influence of tumor necrosis factor-alpha on the expression and function of
P-glycoprotein in an immortalised rat brain capillary endothelial cell
line, GPNT. Biochem Pharmacol. 66: 579¨C587.
10. Keelan JA, Blumenstein M, Helliwell RJ, Sato TA, Marvin KW,
Mitchell MD. 2003. Cytokines, prostaglandins and parturition--a review.
Placenta. 24 Suppl A: S33-46.
11. Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral
treatment for patients hospitalized with severe influenza infection may
affect clinical outcomes. Clin Infect Dis 2008;46:1323-1324
12. Hama R. Rapid response. Potential harm of oseltamivir and NSAIDs
should be discussed, before the threat of a 2009A/H1N1 influenza-caused
pandemic is feared. www.bmj.com/cgi/eletters/338/may12_3/b1962#214206
13. Hama R. Rapid response. What can we learn from observational
studies of oseltamivir without examining NSAIDs use?
16. 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations
Investigation Team: Jain S, Kamimoto L, Bramley AM et al. Hospitalized
patients with 2009 H1N1 influenza in the United States, April-June 2009.
Engl J Med. 2009 Nov 12;361(20):1935-44. Epub 2009 Oct 8.
17. INER Working Group on Influenza: Perez-Padilla R, de la Rosa-
Zamboni D, Ponce de Leon S et al. Pneumonia and respiratory failure from
swine-origin influenza A (H1N1) in Mexico. N Engl J Med. 2009 Aug
13;361(7):680-9. Epub 2009 Jun 29.
18. Novel Influenza A (H1N1) Pregnancy Working Group. Jamieson DJ,
Honein MA, Rasmussen SA, H1N1 2009 influenza virus infection during
pregnancy in the USA.
Lancet. 2009 Aug 8;374(9688):451-8. Epub 2009 Jul 28.
19. Hama R. Rapid response: Re: Influenza treated with NSAIDs or
oseltamivir: case-control studies urgently needed. http://www.bmj.com/cgi/eletters/339/jul08_3/b2731
20. Dom¨ªnguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically
ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009;302:1880-
1887
21. Hama R. Oseltamivir (Tamiflu) is harmful for pregnant women (1).
The Informed Prescriber: 2009: 24 (6): 66-70.(in Japanese)
22. Hama R. Oseltamivir (Tamiflu) is harmful for pregnant women (2).
The Informed Prescriber: 2009: 24 (7): 77-82.(in Japanese)
Competing interests:
None declared
Competing interests:
No competing interests
14 December 2009
Rokuro Hama
Chairperson: Japan Institute of Pharmacovigilance, Editor: Kusuri-no-Check (a drug bulletin)
#902 Ueshio3-2-17, Tennoji-ku Osaka, Japan 543-0002
Rapid Response:
Oseltamivir: early use and late use are both related to harmful effects especially in hypercytokinemia in patients with or without risk
Cochrane team [1] and Freemantle and Calvert [2] did not discuss in
detail the harmful effects of Tamiflu. However, early use and late use of
Tamiflu may both be related to serious outcomes including death in influenza
infection. In this rapid response I would like to describe the
effect of late use of oseltamivir on survival of hospitalized patients.
One of the most important mechanisms of reactions with serious
outcome including death related to early use and late use of Tamiflu is
depression of the central nervous system, leading to respiratory
depression, neuropsychiatric symptoms and sudden death [3].
Unchanged oseltamivir (OT) easily enters the brain [3-8], if the
function of blood-brain barrier (BBB) decreased related to the low
activity of p-glycoprotein (p-gp), a major efflux transporter of OT [6-8].
Hypofunction of BBB is observed in animals before weaning (including human
infants) [5, 7] and under hypercytokinemia [9]. In vitro, BBB p-gp
activity is downregulated after short-term exposure to inflammatory
mediators [9] Of course, hypercytokinemia is observed in early phase of
influenza (around peak of fever). Inflammatory activation occurs modestly
with term labour, but much more robustly in preterm delivery, particularly
in the presence of intrauterine infection [10].
Moreover, hypercytokinemia is observed among the late presenters,
which correlated with hypercytokinemia [11]. It is easy to assume that
late presenters those presenting after day 3 might have treated themselves
with OTC antipyretics. If OTC antipyretics were non-steroidal anti-
inflammatory drugs (NSAIDs), they may promote induction of proinflammatory
cytokines resulting ARDS, encephalopathy with hepatic failure and
collectively multi-organ failure (MOF), while no study discussed the
harmful effect of NSAIDs in influenza [12, 13]
On the other hand, neuraminidase contributes to the maintenance of
normal human immune and repair systems [14] which might be impaired by the
neuraminidase inhibitor and could cause renal damage, glucose intolerance
[2, 14] and MOF [3].
2009 Pandemic Influenza A (H1N1) Hospitalizations Investigation Team
of CDC [16] reported that of the 268 patients for whom data were available
regarding the use of antiviral drugs, 200 (75%) received such drugs. Of
these patients, 188 received oseltamivir. They reported that the use of
antiviral drugs was beneficial in hospitalized patients, especially when
such therapy was initiated early (within 48 hour of onset). This is based
on the data, Of the 205 patients who were not admitted to an ICU and
survived, 62 (30 %) received antiviral therapy within 48 hours after the
onset of symptoms and of the 67 patients who were admitted to an ICU or
died 13 (20 %) received it.
However, if you look at another aspects of these data, of the 19
patients who died, 17 (90%) received antiviral treatment after 48 hours or
at unknown time after the onset of symptoms and of the 205 patients who
were not admitted to an ICU and survived 82 (40 %) received antiviral
therapy during the same period. Odds ratio was 12.75 (95% CI: 2.88-115.6,
p<_0.0001. p="p"/> I could find two other reports [17, 18] by which relation of late
initiation of oseltamivir and outcomes could be analysed: the first report
from Mexico [17] to which I already commented [19] and another CDC report
on the pregnant women [18].
In the former study [17] all seven fatal cases received Tamiflu,
while among 11 survived 7 received. Four patients who survived did not
receive oseltamivir. All 18 presented hospitals after 4 days after the
onset of symptoms and treatment by Tamiflu initiated after admission [17].
In the latter study [18] CDC reported all the 6 pregnant women who
died received Tamiflu at least after 6 days after the onset of symptoms.
They did not report how many pregnant women received Tamiflu and how many
did not. Anyway, number of pregnant women who did not receive Tamiflu and
died was zero. From the trend of increase of infected patients and
increase of proportion of Tamiflu takers, number of pregnant women who
received and did not received Tamiflu was estimated around 74 and 37
respectively.
Meta-analysis of these data from three reports by random effect model
yields odds ratio 10.90 (95%CI; 3.22-36.89, p<_0.0001 xmlns:_="urn:x-prefix:_" xmlns:ci="urn:x-prefix:ci" i2="0" _:_="_:_" _95="_95" ci:_="ci:_" _0-72.9="_0-72.9" figure="figure" which="which" indicates="indicates" that="that" late="late" initiated="initiated" oseltamivir="oseltamivir" might="might" be="be" related="related" to="to" death="death" of="of" the="the" hospitalized="hospitalized" patients.="patients." p="p"/> Patients who were admitted to an ICU and those who died were more
likely than patients who were not admitted to an ICU to have shortness of
breath, a neurologic disorder, radiographically confirmed pneumonia,
abnormality of laboratory data such as high creatine kinase, high
creatinine and high serum transaminase, ARDS, or sepsis [11, 16, 20].
Discussion on the harmful effect of Tamiflu to the mother themselves
and to the new born when used in pregnancy [21, 22] will be discussed in
the other rapid responses.
In conclusion, reanalysed data obtained from the observational
studies so far are consistent with the previous evidence on the
pharmacological and toxicological properties of Tamiflu. Both suggest the
harmful effects of Tamiflu in the exacerbation during late phase of
influenza probably after treatment by NSAIDs antipyretics. Tamiflu as
unchanged oseltamivir which enter the brain in hypercytokinemia in the
very early phase and in the relatively late exacerbation phase of
influenza infection may depress central nervous system, leading to
respiratory depression, neuropsychiatric symptoms and sudden death.
References
1. Tom Jefferson, Mark Jones, Peter Doshi, and Chris Del Mar
Neuraminidase inhibitors for preventing and treating influenza in healthy
adults: systematic review and meta-analysis. BMJ 2009;339:b5106, doi:
10.1136/bmj.b5106
2. Freemantle N and Calvert M. What can we learn from observational
studies of oseltamivir to treat influenza in healthy adults? BMJ 2009 339:
b5248.
3. Hama R. Fatal neuropsychiatric adverse reactions to oseltamivir?F
case series and overview of causal relationships. Internat J Risk Safety
Med 2008;20:5-36. : available at :
http://npojip.org/english/no11.html
4. Chugai Pharm Co 2004. New drug approval package (NAP) of
oseltmivir (in Japanese); Oseltamivir capsule for prevention (2004) (in
Japanese): available at:
http://211.132.8.246/shinyaku/g0407/g040703/index.html
5. Chugai Pharm Co. 2002. New drug approval package (NAP) of
oseltmivir (in Japanese); Tamiflu dry syrup (in Japanese): available at:
http://211.132.8.246/shinyaku/g0201/11/5303990_21400AMY00010.html
6. Morimoto K, Nakakariya M, Shirasaka Y, Kakinuma C, Fujita T, Tamai
I, Ogihara T. 2007. Oseltamivir (Tamiflu) efflux transport at the blood-
brain barrier via P-glycoprotein.
Drug Metab Dispos. (2008) 36(1):6-9. Epub 2007 Oct 16.
7. Ose A, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Fujita T,
Yamamoto A, Sugiyama Y. 2007. P-glycoprotein restricts the penetration of
oseltamivir across the blood-brain barrier. Drug Metab Dispos. (2008)
36(2):427-34. Epub 2007 Nov 26
8. Chugai Co. Ltd., Documents list for the fifth working panel for
drug safety in 2007, held on 25th December, 2007:
http://www.mhlw.go.jp/shingi/2007/12/s1225-7.html document-2-2;
on non-clinical studies ordered by the scientific working panel (part 1):
http://www.mhlw.go.jp/shingi/2007/12/dl/s1225-7b.pdf.
9. Th¨¦ron D, Barraud de Lagerie S, Tardivel S, P¨¦lerin H, Demeuse
P, Mercier C, Mabondzo A, Farinotti R, Lacour B, Roux F, Gimenez F. 2003.
Influence of tumor necrosis factor-alpha on the expression and function of
P-glycoprotein in an immortalised rat brain capillary endothelial cell
line, GPNT. Biochem Pharmacol. 66: 579¨C587.
10. Keelan JA, Blumenstein M, Helliwell RJ, Sato TA, Marvin KW,
Mitchell MD. 2003. Cytokines, prostaglandins and parturition--a review.
Placenta. 24 Suppl A: S33-46.
11. Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral
treatment for patients hospitalized with severe influenza infection may
affect clinical outcomes. Clin Infect Dis 2008;46:1323-1324
12. Hama R. Rapid response. Potential harm of oseltamivir and NSAIDs
should be discussed, before the threat of a 2009A/H1N1 influenza-caused
pandemic is feared.
www.bmj.com/cgi/eletters/338/may12_3/b1962#214206
13. Hama R. Rapid response. What can we learn from observational
studies of oseltamivir without examining NSAIDs use?
http://www.bmj.com/cgi/eletters/339/dec07_2/b5248#227268
14. Miyagi T, Wada T et al. Sialidase and malignancy: a minireview.
Glycoconj J 2004;20(3):189-98.
15. Hama R. Rapid response. Oseltamivir: psychotic and neurological
adverse reactions in the randomized controlled trials.
http://www.bmj.com/cgi/eletters/339/dec07_2/b5106#227187
16. 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations
Investigation Team: Jain S, Kamimoto L, Bramley AM et al. Hospitalized
patients with 2009 H1N1 influenza in the United States, April-June 2009.
Engl J Med. 2009 Nov 12;361(20):1935-44. Epub 2009 Oct 8.
17. INER Working Group on Influenza: Perez-Padilla R, de la Rosa-
Zamboni D, Ponce de Leon S et al. Pneumonia and respiratory failure from
swine-origin influenza A (H1N1) in Mexico. N Engl J Med. 2009 Aug
13;361(7):680-9. Epub 2009 Jun 29.
18. Novel Influenza A (H1N1) Pregnancy Working Group. Jamieson DJ,
Honein MA, Rasmussen SA, H1N1 2009 influenza virus infection during
pregnancy in the USA.
Lancet. 2009 Aug 8;374(9688):451-8. Epub 2009 Jul 28.
19. Hama R. Rapid response: Re: Influenza treated with NSAIDs or
oseltamivir: case-control studies urgently needed.
http://www.bmj.com/cgi/eletters/339/jul08_3/b2731
20. Dom¨ªnguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically
ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009;302:1880-
1887
21. Hama R. Oseltamivir (Tamiflu) is harmful for pregnant women (1).
The Informed Prescriber: 2009: 24 (6): 66-70.(in Japanese)
22. Hama R. Oseltamivir (Tamiflu) is harmful for pregnant women (2).
The Informed Prescriber: 2009: 24 (7): 77-82.(in Japanese)
Competing interests:
None declared
Competing interests: No competing interests