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〈Original Article〉

Comparative analysis of laninamivir octanoate hydrate
in inhalation suspension set and other anti-influenza
drugs in treating influenza in children
Soichiro Ando
Ando Clinic(Received for publication July 14, 2022)

Purpose: Laninamivir octanoate hydrate is a long-acting neuraminidase inhibitor
but may not be eﬀective in infants, who generally experience inhalation diﬃculty.
No study has compared the clinical proﬁles of Laninamivir Nebulizer, the inhalationsuspension set form of this drug, and other anti-inﬂuenza drugs and diﬀerent patient
statuses. Here, we compared the eﬀectiveness and adverse events of Laninamivir
Nebulizer inhalation and treatment with those of other anti-inﬂuenza drugs.
Patients and Methods: One hundred twenty-six children with inﬂuenza weredivided into the following groups according to their therapeutic scheme:
Laninamivir Nebulizer, all other drugs except for Laninamivir Nebulizer,
Laninamivir, and Oseltamivir. The primary endpoints of the present study were time
to resolution of fever and rates of household members with secondary infection.
Adverse events were also analyzed.
Results: According to the Log rank test results, the mean time to resolution offever for the Laninamivir Nebulizer group did not signiﬁcantly diﬀer from that for
the Other drugs, Laninamivir, and Oseltamivir groups for both inﬂuenza A and B
subtypes. The hazard ratio of the time to resolution of fever for the Laninamivir
Nebulizer group did not signiﬁcantly diﬀer from that for the Other drugs,
Laninamivir, and Oseltamivir groups for both inﬂuenza A and B and in the inﬂuenza
A cohort. However, the mean time to resolution of fever for the Laninamivir
Nebulizer group was signiﬁcantly shorter than that for the Other drugs (Laninamivir
Nebulizer vs. Other drugs groups ＝ 51.1 ± 4.8 and 70.8 ± 8.1 h, respectively,
p ＝ 0.0133 * ), Laninamivir (Laninamivir Nebulizer vs. Laninamivirgroups ＝ 51.2 ± 4.8 and 71.8 ± 10.0 h, respectively, p ＝ 0.0454*), and Oseltamivir
Correspondence author: Soichiro Ando, Ando Clinic, 4–6–7 Mimomi, Narashino City, Chiba 275–0002, Japan, Tel.: ＋81–
47–476–1111, Fax: ＋81–47–476–1124, E-mail: ando.clinic@nifty.com

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Dec. 2022(Laninamivir Nebulizer vs. Oseltamivir group ＝ 51.1 ± 4.8 and 94.5 ± 14.2 h,respectively, p ＝ 0.0015*) groups in the inﬂuenza B cohort. The hazard ratio for time
to resolution for the Laninamivir Nebulizer group was signiﬁcantly greater than thatfor the Other drugs (Laninamivir Nebulizer group ＝ 1.87 [95% CI: 1.05–3.35],
p ＝ 0.0347*] and Oseltamivir (Laninamivir Nebulizer group ＝ 3.38 [95% CI: 1.27–
9.00], p ＝ 0.0151*] groups in the inﬂuenza B cohort. Both the hazard ratio of therate of household members with secondary infection and the odds ratio did not
signiﬁcantly diﬀer between the Laninamivir Nebulizer and other drug treatmentgroups. Although 11.8% (6/51) of the patients cried during nebulizer-mediatedinhalation in the Laninamivir Nebulizer group, effectiveness, household
transmission, and adverse events did not signiﬁcantly diﬀer between patients whocried and those who did not during nebulizer-mediated inhalation.
Conclusions: Clinical proﬁles of the Laninamivir Nebulizer group wereequivalent to those of other anti-inﬂuenza drug treatment groups. Laninamivir
Nebulizer may be a good therapeutic option for infants with inﬂuenza and inhalationdiﬃculty.
Key words : Laninamivir octanoate hydrate, inhalation, nebulizer, inﬂuenza, children

Introduction
In Japan, in the last three winters (2016/2017, 2017/2018, and 2019/2020 seasons), approximately 10–20 million people contracted inﬂuenza, and nearly 10% of them comprised children
aged less than 5 years1–3). Among the children with inﬂuenza treated at Ando Clinic (Narashino
City, Chiba, Japan), nearly 35–50% were less than 5–7 years of age4–6). Children are usuallytreated with oseltamivir since it is a classic conventional drug and can be administered in dry
powdered form. However, small children frequently cannot take this dry powder because of its
taste. Moreover, oseltamivir-resistant viruses have been reported7,8). Laninamivir octanoate hydrate (laninamivir) is an octanoyl prodrug and a neuraminidase inhibitor eﬀective against both inﬂuenza A and B viruses as well as highly pathogenic avian H5N1 and oseltamivir-resistant viruses7,8). A single dose of laninamivir inhaled using a dry powder inhaler is eﬀective and welltolerated by both children and adults for treatment9,10) and prophylaxis11,12) of inﬂuenza. A proper
inhalation technique is crucial for eﬀective inhalation of laninamivir. Ensuring eﬀective delivery
is challenging without training. Therefore, laninamivir may not be suﬃciently eﬀective in patients with inhalation diﬃculty, such as infants. For laninamivir, an inhalation suspension set(Laninamivir Nebulizer) is available as a kit using a nebulizer, which was launched on October25, 201913). This form of laninamivir is easy to inhale for patients such as infants, who are generally non-cooperative during the administration of other forms of drugs. However, only one study

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concerning the use of Laninamivir Nebulizer among adults, primarily examining its pharmacokinetics, has been published so far14). A study on the safety and eﬃcacy of Laninamivir Nebulizer
in children under the age of 5 years based on post-market surveillance data was recently published13). However, no study has compared the eﬃcacy of Laninamivir Nebulizer with that ofother anti-inﬂuenza drugs. In this study, Laninamivir Nebulizer was compared with other neuraminidase inhibitors used for treating inﬂuenza in terms of eﬀectiveness, household transmissionof secondary inﬂuenza virus infection, and adverse events during the 2019–2020 ﬂu season. Additionally, the eﬀectiveness of Laninamivir Nebulizer in the context of patientsʼ statuses (crying
or non-crying) was prospectively examined because it may be diﬃcult for small, crying patientsto properly inhale laninamivir.

Patients and Methods
Patients and data collection
This study was designed as a prospective cohort study. The patients and/or their parents were
informed of the study design. Included were children diagnosed positive for inﬂuenza after a
rapid inﬂuenza diagnostic test (RIDT) at the Ando Clinic (Narashino City, Chiba, Japan) during
the 2019–2020 ﬂu season. Excluded were patients who had already began treatment for inﬂuenza
in another hospital. The patients were divided into the following four groups: 1) Laninamivir
Nebulizer—patients treated with Laninamivir Nebulizer; 2) Other drugs—patients treated withother anti-inﬂuenza drugs, namely laninamivir and oseltamivir powder; 3) Laninamivir — patientstreated with laninamivir; and 4) Oseltamivir—patients treated with oseltamivir phosphate (Oseltamivir). Patients treated with anti-inﬂuenza drugs other than those mentioned above were not analyzed owing to the small sample size. During presentation, the following clinical information
was collected: sex, age, type of inﬂuenza, vaccination status for the quadrivalent inﬂuenza vaccine, comorbidities, body temperature, time from onset, and type of anti-inﬂuenza drugs administered. Comorbidities were deﬁned as conditions that may aﬀect the immune status15). The following comorbidities were considered: chronic pulmonary, cardiovascular (excluding hypertension),
renal, liver, hematologic, and neurological disorders, diabetes mellitus, autoimmune disorders,congenital anomaly, and cancer15). Data regarding time to resolution of fever, adverse events ofanti-inﬂuenza drugs, and household members with secondary inﬂuenza virus infection were collected at follow-up or by telephone interview.
Diagnosis of inﬂuenza
Nasopharyngeal swabs were obtained from all patients and tested using the ImunoAceTM Flu
test kit (TAUNS Laboratories, Inc., Shizuoka, Japan). The ImunoAceTM Flu test can detect anddiﬀerentiate between inﬂuenza A and B virus, with high positive (inﬂuenza A: 100%, inﬂuenza B:

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100%) and negative (inﬂuenza A: 98.7%, inﬂuenza B: 99.3%) concordance rates, as demonstrated using a viral isolation culture (from package insert)6).
Anti-inﬂuenza drugs
Laninamivir Nebulizer was administered as one dose at 160 mg suspended in 2 mL saline
using a nebulizer on day 1 in an isolated examination room. Laninamivir was administered as one
dose of 20 mg (＜10 years) or 40 mg (≥10 years) by inhalation in powder form on day 1. Oseltamivir was administered in two doses of 3 mg/kg (＜1 year) or 2 mg/kg (≥ 1 year, maximum dose:
75 mg) orally on days 1–5. Zanamivir hydrate (zanamivir) was administered in two doses of
10 mg by inhalation on days 1–5. Peramivir hydrate (peramivir) was administered as one dose of
10 mg/kg intravenously for more than 15 mins on day 1 (maximum dose: 600 mg/day). Baloxavir
marboxil (baloxavir) was administered as one dose of 10 mg (＜12 years: bodyweight ≥10 kg and＜20 kg), 20 mg (＜12 years: bodyweight ≥20 kg and ＜40 kg), or 40 mg (≥12 years: bodyweight≥40 kg) orally on day 1.
Analysis of drug eﬀectivenessThe primary endpoint for treatment eﬀectiveness was time to resolution of fever. Time toresolution of fever was deﬁned as the time from the patientʼs ﬁrst presentation to the time atwhich the body temperature of the patient returned to less than 37.5°C (or in which the body temperature of each patient returned to the normal range) and remained stable for at least 24 h. Patients who required withdrawal and drug change owing to ineﬀectiveness or adverse events related to anti-inﬂuenza drugs were excluded from the analysis of household transmission. Patients
who consulted a secondary hospital owing to ineﬀectiveness or adverse events of anti-inﬂuenza
drugs were also excluded from the analysis of household transmission. A drug was regarded as
ineﬀective when fever and symptoms continued for more than 72 h. When the patients could not
be followed up at the clinic before the resolution of fever or symptoms, they were not included inthis analysis.
Analysis of household transmission of inﬂuenza virus infection
Household transmission was deﬁned as the occurrence of secondary infection among residual uninfected household members within the time interval from the presentation of the ﬁrst patient to the occurrence of secondary infection, which was ≥ 1 day and ≤ 7 days, respectively16,17).
The risk of household transmission anti-inﬂuenza drug intake was estimated based on the household transmission rate, deﬁned as the number of secondarily infected household members divided
by the number of residual uninfected household members×10016). Index patients were deﬁned as
the ﬁrst patient from each household diagnosed with inﬂuenza in the 2019–2020 ﬂu season at theAndo Clinic. Patients meeting the following criteria were included: those diagnosed positive forDec. 2022

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inﬂuenza after RIDT and treated with anti-inﬂuenza drugs.
The following patients were excluded: 1) index patients with household members already diagnosed with inﬂuenza 2 weeks before the ﬁrst visit; 2) patients who were a family member ofthe index patient (since the analysis in this study was based on the family as a unit); 3) patients
who required withdrawal and change of drugs owing to ineﬀectiveness of or adverse events
caused by anti-inﬂuenza drugs; 4) patients with no residual family member; and 5) patients who
could not be followed up before the resolution of fever or symptoms (these cases were regarded
as dropped).
Statistical analyses
Sample-size calculation was not performed. The Mann–Whitney U test was used to compare
continuous variables (i.e., age, body temperature, and time from onset) between groups. Fisherʼsexact test was used to compare nominal variables (i.e., sex, type of inﬂuenza, and presence or absence of both vaccination and comorbidities). For analyses of time to resolution of fever and rate ofhousehold transmission, a Log rank test was used to compare the Laninamivir Nebulizer and Other
drugs groups. Cox proportional hazards regression was used for multivariable analysis. Hazard ratios were adjusted for sex, age, and the subtype of inﬂuenza (A and B). To analyze the prevalence ofadverse events, Fisherʼs exact test was used. Logistic regression analysis was used for calculating
the odds ratio of adverse events. Odds ratios of adverse events were adjusted for sex, age, and subtype of inﬂuenza (A and B). Any adverse events during the clinical course, including delirium, confusion, hallucinations, vomiting, diarrhea, anorexia, eyelid function disorder, chest pain, and/or rash
maculopapular, were recorded for all patients. The nomenclature was in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (along with Medical Dictionary for Regulatory Activities: MedDRA version 21.0)18). The prevalence of adverse events was deﬁned as the number of cases with adverse events divided by the total number of cases. Odds ratios
of adverse events were adjusted for sex and age and subtype of inﬂuenza (A and B). Overlapping
was permitted (i.e., multiple adverse events could be associated with one case). A two-sided P-value＜ 0.05 indicated statistical signiﬁcance. Statistical analyses were performed using JMP® 15.2 (Statistical Analysis Software, SAS Institute Inc., Cary, NC, USA).
Ethical statement
This study was conducted according to the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patients, their parents, or both. Participants were recruited
prospectively. The study design was approved by the Joint Institutional Review Board, and all patients were part of a previous study on inﬂuenza vaccine eﬀectiveness (approval number:
14000050.20191220-4830)19).

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Results
Patient characteristics
From December 21, 2019, to March 2, 2020, 126 patients with inﬂuenza were enrolled. As
shown in Figs. 1 and 2 and Table 2, 126 cases of inﬂuenza were analyzed.
Patient characteristics are summarized in Table 1. Anti-inﬂuenza drugs were administered asfollows: Laninamivir Nebulizer, 51 patients; Other drugs, 75 patients (laninamivir [33], oseltamivir [28], zanamivir [7], peramivir [3], and baloxavir [4]).
Patients treated with Laninamivir Nebulizer (Laninamivir Nebulizer group) were signiﬁcantly younger than those treated with other drugs (Other drugs group; median age of Laninamivir Nebulizer vs. Other drugs groups ＝ 6 years vs. 9 years, p ＝ 0.0003) and those treated withlaninamivir (Laninamivir group; mean age of Laninamivir Nebulizer vs. Laninamivir groups ＝ 6
vs. 10 years, p＜0.0001). The Laninamivir Nebulizer group had a signiﬁcantly higher proportionof female patients than the Other drugs group (male : female ratio ＝ 24 : 27 vs. 49 : 26,
p ＝ 0.0456). Furthermore, the Laninamivir Nebulizer group had a signiﬁcantly higher proportionof inﬂuenza B patients than the Other drugs (inﬂuenza A : B ratio of Laninamivir Nebulizer vs.
Other drugs groups ＝ 18 : 33 vs. 51 : 24, p ＝ 0.0005), Laninamivir (inﬂuenza A : B of Laninamivir Nebulizer vs. Other drugs groups ＝ 18 : 33 vs. 22 : 11, p ＝ 0.0071) and Oseltamivir (inﬂuenza
A : B of Laninamivir Nebulizer vs. Other drugs groups ＝ 18 : 33 vs. 20 : 8, p ＝ 0.0025) groups.
Other clinical factors (inﬂuenza vaccination status, presence or absence of comorbidities, bodyFig. 1. Flowchart of the study

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Table 1. Patient characteristics
1) Laninamivir Nebulizer vs. Other drugs groups
Anti-inﬂuenza drugs
Total

Laninamivir Nebulizera

Other drugsb

126

51

75

P-value—

8 (0.5–15)

6 (0.5–14)

9 (1–15)0.0003*Sex (male : female)

73 : 53

24 : 27

49 : 26

0.0456*

Type of inﬂuenza (A : B)

69 : 57

18 : 33

51 : 240.0005*

Vaccination (yes : no)53 : 73

19 : 32

34 : 410.4624

Comorbidityd (yes : no)13 : 113

4 : 47

9 : 66

0.5585

Body temperaturee (℃ )39.1 ± 0.1

39.1 ± 0.1

39.2 ± 0.1

0.650523.3 ± 1.5

25.5 ± 2.4

21.8 ± 2.0

0.9444Characteristics
Number (n)Median agec (years) (range)eTime from onset (hours)

2) Laninamivir Nebulizer vs. Laninamivir groups
Anti-inﬂuenza drugs
Characteristics
Number (n)Median agec (range)

Total

Laninamivir Nebulizera

Laninamivir

84

51

33

P-value—

8 (0.5–15)

6 (0.5–14)

10 (7–15)＜0.0001*

Sex (male : female)

46 : 38

24 : 27

22 : 110.1158Type of inﬂuenza (A : B)

40 : 44

18 : 33

22 : 110.0071*

Vaccination (yes : no)33 : 51

19 : 32

14 : 190.6544

Comorbidityd (yes : no)6 : 784 : 47

2 : 311.0000Body temperature (℃ )39.1 ± 0.1

39.1 ± 0.1

39.2 ± 0.1

0.7479Time from onset (hours)

24.4 ± 2.0

25.5 ± 2.5

22.8 ± 3.2

0.6832

3) Laninamivir Nebulizer vs. Oseltamivir groups
Anti-inﬂuenza drugs
Total

Laninamivir Nebulizera

Oseltamivir

79

51

28

P-value—

Mean agec (range)

6 (0.5–14)

6 (0.5–14)

5.5 (1–12)

0.2835Sex (male : female)

42 : 37

24 : 27

18 : 100.1638Type of inﬂuenza (A : B)

38 : 41

18 : 33

20 : 80.0025*

Vaccination (yes : no)33 : 46

19 : 32

14 : 140.3420Characteristics
Number (n)dComorbidity (yes : no)9 : 704 : 47

5 : 230.2670Body temperature (℃ )39.2±0.1

39.1±0.1

39.2±0.1

0.4083Time from onset (hours)

24.3±2.225.5±2.722.1±3.7

0.8817

Laninamivir: Laninamivir octanoate hydrate
Oseltamivir: Oseltamivir phosphateaLaninamivir nebulizer: Laninamivir octanoate hydrate inhalation using a nebulizerb
Other drugs include: 33: Laninamivir octanoate hydrate, 28: Oseltamivir phosphate, 7: Zanamivir hydrate, 3: Peramivir
hydrate, and 4: Baloxavir marboxil.
c
In the Laninamivir nebulizer group, there were two patients under 1 year of age (one patient was 6 months old and another was
9 months old).
dComorbidities included bronchial asthma in 13 patients.
e
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temperature, and time from onset) did not signiﬁcantly diﬀer between the Laninamivir Nebulizer
and the other three groups (Table 1).

EﬀectivenessTime to resolution of feverOf the 125 patients, one patient was excluded for the analysis of time to resolution of fever
because of mixed infection with adenovirus (Fig. 1). There were six censored cases because of
the following reasons: four required a change of drugs before resolution of fever, and two consulted a secondary hospital before resolution of fever. These patients were included in the statistical analyses as censored cases.
The mean time to resolution of fever for the Laninamivir Nebulizer group did not signiﬁcantly diﬀer from that for the Other drugs, Laninamivir, and Oseltamivir groups for both inﬂuenza A and B subtypes and in the inﬂuenza A cohort (Fig. 2a). The hazard ratio (referring to theadjusted hazard ratio in the following sentences) of time to resolution of fever for the Laninamivir Nebulizer group did not signiﬁcantly diﬀer from that for the Other drugs, Laninamivir, andOseltamivir groups for both inﬂuenza A and B and in the inﬂuenza A cohort (Fig. 2a–b).
However, the mean time to resolution of fever for the Laninamivir Nebulizer group was signiﬁcantly lower than that for the Other drugs (Laninamivir Nebulizer vs. Other drugs
groups ＝ 51.1 ± 4.8 and 70.8 ± 8.1 h, respectively, p ＝ 0.0133*), Laninamivir (Laninamivir Nebulizer vs. Laninamivir groups ＝ 51.2 ± 4.8 and 71.8 ± 10.0 h, respectively, p ＝ 0.0454*) and Oseltamivir (Laninamivir Nebulizer vs. Oseltamivir groups ＝ 51.1 ± 4.8 and 94.5 ± 14.2 h, respectively, p ＝ 0.0015*) groups in the inﬂuenza B cohort (Fig. 2c). The hazard ratio for time toresolution for the Laninamivir Nebulizer group was signiﬁcantly greater than that for the Other
drugs (Laninamivir Nebulizer group ＝ 1.87 [95% CI: 1.05–3.35], p ＝ 0.0347*] and Oseltamivir(Laninamivir Nebulizer group ＝ 3.38 [95% CI: 1.27–9.00], p ＝ 0.0151*] groups in the inﬂuenza
B cohort. The hazard ratio for time to resolution for the Laninamivir Nebulizer group did not signiﬁcantly diﬀer from that for the Laninamivir (Laninamivir Nebulizer group ＝ 1.72 [95% CI:
0.78–3.80], p＝ 0.1815] group in the inﬂuenza B cohort (Fig. 2c).
Household transmission of inﬂuenza infection
The rate of household members with secondary infection in the Laninamivir Nebulizer group
did not signiﬁcantly diﬀer from that in the Other drugs (Laninamivir Nebulizer vs. Other drugs
groups ＝ 7.0 ± 2.4 vs. 12.4 ± 3.1, p ＝ 0.3811), Laninamivir (Laninamivir Nebulizer vs. Laninamivir groups ＝ 7.0 ± 2.4 vs. 13.7 ± 5.1, p ＝ 0.4064), and Oseltamivir (Laninamivir Nebulizer vs.
Oseltamivir groups ＝ 7.0 ± 2.4 vs. 15.5 ± 5.3, p ＝ 0.1509) groups for both inﬂuenza A and B(Table 2).

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Fig. 2a 1) Time to resolution of fever in Laninamivir Nebulizer vs. Other drugs (any inﬂuenza)groupsFig. 2a 2) Time to resolution of fever in Laninamivir Nebulizer vs. Laninamivir (any inﬂuenza)groups72（ 10 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Fig. 2a 3) Time to resolution of fever in Laninamivir Nebulizer vs. Oseltamivir (any inﬂuenza)groupsFig. 2b 1) Time to resolution of fever in Laninamivir Nebulizer vs. Other drugs (inﬂuenza A)groupsDec. 2022

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Fig. 2c 1) Time to resolution of fever in Laninamivir Nebulizer vs. Other drugs (inﬂuenza B)
groupsFig. 2c 2) Time to resolution of fever in Laninamivir Nebulizer vs. Laninamivir (inﬂuenza B)
groupsDec. 2022

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groups

The hazard ratio for the rate of household members with secondary infection in the Laninamivir Nebulizer group did not signiﬁcantly diﬀer from that in the Other drugs (Laninamivir Nebulizer group ＝ 1.21 [95% CI: 0.77–1.90], p ＝ 0.4041), Laninamivir (Laninamivir Nebulizer
group ＝ 1.19 [95% CI: 0.60–2.34], p ＝ 0.6172), and Oseltamivir (Laninamivir Nebulizer
group ＝ 1.26 [95% CI: 0.71–2.24], p ＝ 0.4352) groups for both inﬂuenza A and B (Table 2).
The rate of household members with secondary infection in the Laninamivir Nebulizer group
did not signiﬁcantly diﬀer from that in the Other drugs (Laninamivir Nebulizer vs. Other drugs
groups ＝ 10.3 ± 5.8 vs. 10.3 ± 3.3, p ＝ 0.9279), Laninamivir (Laninamivir Nebulizer vs. Laninamivir groups ＝ 10.3 ± 5.8 vs. 13.8 ± 5.9, p ＝ 0.7423), and Oseltamivir (Laninamivir Nebulizer
vs. Oseltamivir groups ＝ 10.3 ± 5.8 vs. 10.9 ± 5.3, p ＝ 0.9302) groups in the inﬂuenza A cohort(Table 2).
The hazard ratio of the rate of household members with secondary infection in the Laninamivir Nebulizer group did not signiﬁcantly diﬀer from that in the Other drugs (Laninamivir Nebulizer group ＝ 0.99 [95% CI: 0.47–2.08], p ＝ 0.9713), Laninamivir (Laninamivir Nebulizer
group ＝ 1.48 [95% CI: 0.19–11.30], p ＝ 0.7061), and Oseltamivir (Laninamivir Nebulizer
group ＝ 1.03 [95% CI: 0.48–2.21], p ＝ 0.9356] groups for inﬂuenza A (Table 2).
The rate of household members with secondary infection in the Laninamivir Nebulizer group
did not signiﬁcantly diﬀer from that in the Other drugs (Laninamivir Nebulizer group vs. Other
drugs group ＝ 5.6±2.3 vs. 17.2±6.7, p ＝ 0.1711) and Laninamivir (Laninamivir Nebulizer76（ 14 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Table 2. Risk of secondary household transmission with anti-inﬂuenza drugs
Rate of household memberswith secondary infectiona (%)

Any inﬂuenza
Laninamivir Nebulizerc vs. Other drugs groupd
Laninamivir Nebulizerc vs. Laninamivir group
Laninamivir Nebulizerc vs. Oseltamivir group

Hazard ratio of the rate of household
members
with secondary infectionb
Hazard ratio(95% conﬁdence interval)nMean ± standard error

P-value

43 vs. 64
43 vs. 30
43 vs. 21

7.0 ± 2.4 vs. 12.4 ± 3.1
7.0 ± 2.4 vs. 13.7 ± 5.1
7.0 ± 2.4 vs. 15.5 ± 5.3

0.38110.40640.15091.21 (0.77–1.90)
1.19 (0.60–2.34)
1.26 (0.71–2.24)

0.40410.61720.4352

13 vs. 44
13 vs. 20
13 vs. 16

10.3 ± 5.8 vs. 10.3 ± 3.3
10.3 ± 5.8 vs. 13.8 ± 5.9
10.3 ± 5.8 vs. 10.9 ± 5.3

0.92790.74230.93020.99 (0.47–2.08)
1.48 (0.19–11.30)
1.03 (0.48–2.21)

0.97130.70610.935630 vs. 20
30 vs. 10
30 vs. 5

5.6 ± 2.3 vs. 17.2 ± 6.7
5.6 ± 2.3 vs. 13.3 ± 10.2
5.6 ± 2.3 vs. 30.0 ± 13.3

0.17110.72270.0165 ＊1.40 (0.75–2.60)
1.14 (0.51–2.51)
2.15 (0.63–7.28)

0.28770.75430.2196

P-value

Inﬂuenza A
Laninamivir Nebulizerc vs. Other drugs groupd
Laninamivir Nebulizerc vs. Laninamivir group
Laninamivir Nebulizerc vs. Oseltamivir groupInﬂuenza B
Laninamivir Nebulizerc vs. Other drugs groupd
Laninamivir Nebulizerc vs. Laninamivir group
Laninamivir Nebulizerc vs. Oseltamivir group

Laninamivir: Laninamivir Octanoate Hydrate
Oseltamivir: Oseltamivir phosphate
Rate of household members with secondary infection: mean ± standard error＊
Statistically signiﬁcantaRate of household members with secondary infection was deﬁned as the number of infected household members divided by the number of residual uninfected household
members.
b
Hazard ratios were adjusted for sex, age, and subtype of inﬂuenza (A vs. B) in any inﬂuenza.
Hazard ratios were adjusted for sex and age in both inﬂuenza A and B.
c
Laninamivir Nebulizer: Laninamivir octanoate hydrate inhalation using a nebulizerdOther drugs include laninamivir octanoate hydrate, oseltamivir phosphate, zanamivir hydrate, peramivir hydrate, and baloxavir marboxil.

group vs. Laninamivir group ＝ 5.6±2.3 vs. 13.3±10.2, p ＝ 0.7227) group. However, the rate ofhousehold members with secondary infection household transmission in the Laninamivir Nebulizer group was not signiﬁcantly lower than that in the Oseltamivir group (Laninamivir Nebulizer
group vs. Oseltamivir groups ＝ 5.6±2.3 vs. 30.0±13.3, p ＝ 0.0165) in the inﬂuenza B cohort(Table 2).
The hazard ratios of the rate of household members with secondary infection in the Laninamivir Nebulizer group did not signiﬁcantly diﬀer from those in the Other drugs group [Laninamivir Nebulizer group ＝ 1.40 (95% CI: 0.75–2.60), p ＝ 0.2877], Laninamivir group [Laninamivir
Nebulizer group ＝ 1.14 (95% CI: 0.51–2.51), p ＝ 0.7543], and Oseltamivir group [Laninamivir
Nebulizer group ＝ 2.15 (95% CI: 0.63–7.28), p ＝ 0.2196] in the inﬂuenza B cohort (Table 2).
Adverse events
The prevalence of adverse events in the Laninamivir Nebulizer group did not signiﬁcantly
diﬀer from that in the Other drugs group [Laninamivir Nebulizer group vs. Other drugs
groups ＝ 9.8% (5/51) vs. 14.7% (11/75), p ＝ 0.5872], Laninamivir group [Laninamivir Nebulizer
group vs. Laninamivir groups ＝ 9.8% (5/51) vs. 18.2% (6/33), p ＝ 0.3278], and Oseltamivirgroup [Laninamivir Nebulizer group vs. Oseltamivir groups ＝ 9.8% (5/51) vs. 7.1% (2/28),
p ＝ 1.0000] (Table 3-1)).
In the logistic regression analysis, the odds ratio of adverse events in the Laninamivir Nebu-

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Table 3. Adverse events
1) Prevalence and odds ratio
Prevalence of adverse events (%)a (%)
n

Odds ratio of adverse eventsb

Mean ± standard error

P-value

Odds ratio(95% conﬁdence interval)

P-value

Laninamivir Nebulizerc vs. Other drugs groupd

51 vs. 75

9.8 (5/51) vs. 14.7 (11/75)

0.58720.71 (0.20–2.56)

0.6028Laninamivir Nebulizerc vs. Laninamivir group

51 vs. 33

9.8 (5/51) vs. 18.2 (6/33)

0.32780.46 (0.07–2.95)

0.4154

Laninamivir Nebulizerc vs. Oseltamivir group

51 vs. 28

9.8 (5/51) vs. 7.1 (2/28)

1.00002.15 (0.34–13.82)

0.41862) Details of adverse eventse
Adverse events (outcome)
Spontaneous remission

Improved by medication

Admission

Laninamivir Nebulizera

2: Delirium
2: Diarrhea
1: Anorexia
1: Eyelid function disorder

None

None

Laninamivir

2: Diarrhea
2: Delirium
1: Confusion

1: Diarrhea
1: Vomiting
1: Chest pain

None

Oseltamivir

1: DeliriumNone

1: Rash maculopapular

Zanamivir

1: Diarrhea

None

None

Peramivir

1: Delirium

None

None

Baloxavir

1: Hallucinations

None

None

3) Details of adverse eventse
Adverse events (outcome)
Spontaneous remissionaImproved by medication

Admission

Laninamivir Nebulizer

2: Delirium
2: Diarrhea
1: Anorexia
1: Eyelid function disorder

None

None

Laninamivir

2: Diarrhea
2: Delirium
1: Confusion

1: Diarrhea
1: Vomiting
1: Chest pain

None

Oseltamivir

1: DeliriumNone

1: Rash maculopapular

Zanamivir

1: Diarrhea

None

None

Peramivir

1: Delirium

None

None

Baloxavir

1: Hallucinations

None

None

Laninamivir: Laninamivir octanoate hydrate
Oseltamivir: Oseltamivir phosphate* Statistically signiﬁcantaPrevalence of adverse events was deﬁned as the number of cases with adverse events divided by the total number of cases.
b
Laninamivir Nebulizer: Laninamivir octanoate hydrate inhalation using a nebulizerc
Other drugs include laninamivir octanoate hydrate, oseltamivir phosphate, zanamivir hydrate, peramivir hydrate, and baloxavir
marboxil.
dOdds ratios of adverse events were adjusted for sex and age.
eOverlapping, yes (i.e., one case may show multiple adverse events).

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Table 4. Eﬀectiveness and adverse events in the Laninamivir Nebulizer group during nebulizermediated inhalation depending on the patientsʼ status
1) EﬀectivenessTime to resolution of feveranMean ± standard error

P-value

Hazard ratio(95% conﬁdence interval)b

P-value

Crying during Nebulizer
treatmentc vs. No crying
during Nebulizer treatmentd

6 vs. 4564.0 ± 16.0 vs. 50.5 ± 4.7

0.49900.78 (0.28–2.14)

0.6246Rate of household memberswith secondary infectionfnMean ± standard error

P-value

Hazard ratio(95% conﬁdence interval)b

P-value

Crying during Nebulizer
treatmentc vs. No crying
during Nebulizer treatmentd

4 vs. 390.0 ± 0.0 vs. 7.7 ± 2.6

0.32111.77 (0.49–6.45)

0.3870Adverse eventsn

Prevalence of adverse
events (%)hP-value

Odds ratio(95% conﬁdence interval)i

P-value

Crying during Nebulizer
treatmentc vs. No crying
during Nebulizer treatmentd

6 vs. 45

16.7 (1/6) vs. 8.9 (4/45)

0.47991.16 (0.06–23.46)

0.92272) Household transmission3) Adverse events

Time to resolution of fever, Time to resolution of the symptom: mean ± standard error
Laninamivir: Laninamivir octanoate hydrate＊
Statistically signiﬁcantaTime to resolution of fever was deﬁned as the time in which the body temperature of the patient returned to less than 37.5℃
and stabilized for at least 24 hours or the time in which the body temperature of each patient returned to the normal range anddid not re-elevate.
b
Hazard ratios were adjusted for sex, age, and subtype of inﬂuenza (A vs. B).
c
Crying during Nebulizer treatment: Patients who cried during nebulizer-mediated inhalationd
No crying during Nebulizer treatment: Patients who did not cry during nebulizer-mediated inhalationeTime to resolution of symptoms was deﬁned as the time in which all symptoms of a patient disappeared except prolonged
cough.
fRate of household members with secondary infection was deﬁned as the number of infected household members divided by
the number of residual uninfected household members.
gHazard ratios were adjusted for sex, age, and subtype of inﬂuenza (A vs. B).
hPrevalence of adverse events was deﬁned as the number of cases with adverse events divided by the total number of cases.
i
Odds ratios of adverse events were adjusted for sex and age.

lizer group did not signiﬁcantly diﬀer from that in the Other drugs group [Laninamivir Nebulizer
group ＝ 0.71 (95% CI: 0.20–2.56), p ＝ 0.6028], Laninamivir group [Laninamivir Nebulizer
group ＝ 0.46 (95% CI: 0.07–2.95), p ＝ 0.4154], and Oseltamivir group [Laninamivir Nebulizer
group ＝ 2.15 (95% CI: 0.34–13.82), p ＝ 0.4186] (Table 3-1)). The details of adverse events areshown in Table 3-2.
Although six adverse events (2: delirium, 2: diarrhea, 1: anorexia, and 1: eyelid function disorder) occurred in the Laninamivir Nebulizer group, all patients recovered spontaneously without
any medication. In the Other drugs group, there were no severe adverse events. However, threecases (1: diarrhea, 1: vomiting, and 1: chest pain) in the group treated with Laninamivir requiredDec. 2022

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79（ 17 ）medication, and one case was admitted to a secondary hospital due to maculopapular rash in thegroup treated with Oseltamivir (Table 3-3).
In the Laninamivir Nebulizer group, 11.8% (6/51) of patients cried during nebulization(Table 4). However, no diﬀerences in eﬀectiveness, household transmission rate, and adverse
events were observed between patients who cried and patients who did not cry during nebulization (Table 4).

Discussion
Although the treatment by inhaling laninamivir and zanamivir in dry powder form is eﬀective and well-tolerated, some patients, such as small children, cannot inhale this drug eﬀectively.
Moreover, the safety of baloxavir in children under 1 year of age has not been established, and ahigh prevalence of baloxavir-resistant strains has been reported in patients younger than 12 years,
particularly for inﬂuenza A20). Since peramivir is used as an intravenous drip injection, some patients, such as small children, have to suﬀer pain. Additionally, ﬁxation of the drip may be needed
to prevent the children from removing the device. Oseltamivir is an orally administered drug andcannot be readily consumed by small children such as those under 1 year of age. Since Laninamivir Nebulizer does not present any of the abovementioned shortcomings, it is viable for use inyounger patients such as small children younger than 1 year. The eﬀectiveness and adverse eventsof Laninamivir Nebulizer were studied and compared with those of other anti-inﬂuenza drugs anddiﬀerent therapeutic statuses of patients, as no study has performed such an evaluation so far.
The mean time to resolution of fever in patients treated with Laninamivir Nebulizer was
52.1, 53.9, and 51.1 h in both inﬂuenza types, inﬂuenza A and inﬂuenza B, respectively. There
were no signiﬁcant diﬀerences in the time to resolution of fever between Laninamivir Nebulizer
and the Other drugs, Laninamivir, and Oseltamivir groups for both inﬂuenza A and B subtypes
and in the inﬂuenza A cohort. Although the hazard ratio of time to resolution of fever in the
Laninamivir Nebulizer group did not signiﬁcantly diﬀer from that of the Other drugs, Laninamivir, and Oseltamivir groups for both inﬂuenza A and B subtypes and in the inﬂuenza A cohort,that of the Laninamivir Nebulizer group was signiﬁcantly lower than that of the Other drugs andOseltamivir groups for the inﬂuenza B cohort. These results suggest that Laninamivir Nebulizer
may be more eﬀective than other drugs (particularly oseltamivir) against inﬂuenza B. Furthermore, the mean time to resolution of fever of patients treated with Laninamivir Nebulizer was
slightly longer than that reported previously8). The reasons for this diﬀerence remain unclear. The
rate of household members with secondary infection in the Laninamivir Nebulizer group was
7.0%, 10.3%, and 5.6% for any inﬂuenza type, inﬂuenza A and inﬂuenza B, respectively. The effectiveness of Laninamivir Nebulizer did not signiﬁcantly diﬀer from that of other drugs in any
inﬂuenza, inﬂuenza A and inﬂuenza B.

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Although adverse events occurred in 9.8% of the cases in the Laninamivir Nebulizer group,
all patients recovered spontaneously without any medication, and there was no signiﬁcant diﬀerence in the prevalence of adverse events between the Laninamivir Nebulizer and Other drugs
groups.
Although the rate of adverse events was greater than that reported previously, there were noserious adverse events8). This may be due to the small sample size of this study.
In addition, in the Laninamivir Nebulizer group, 11.8% of patients cried during nebulization.
However, no diﬀerences in eﬀectiveness, household transmission rate, and adverse events wereobserved between patients who cried and patients who did not cry during nebulization (Table 4).
In this study, two patients in the Laninamivir Nebulizer group were under 1 year of age (one patient was 6 months old and another one was 9 months old). Therefore, laninamivir nebulization
may be better suited for children below 1 year of age who cannot inhale the powder or consume
oral dosage forms.
There are some limitations to the study that must be considered while interpreting the results. First, a relatively small number of patients were enrolled. Since the number of patients was
small, it was not possible to compare the eﬃcacy of Laninamivir Nebulizer with that of each antiinﬂuenza drug. The duration of the inﬂuenza endemic in the 2019–2020 season was shorter thanthat in previous seasons. This may be because of the inﬂuence of the SARS-CoV-2 infection outbreak. A similar trend for inﬂuenza outbreaks was observed worldwide. Second, this study was
conducted at a single center. Discordances in study results have been suggested between single
and multiple centers21). However, this bias was inevitable. Third, data analysis using other statistical methods such as the Reed–Frost model may be more desirable for analyzing household transmission. However, the statistical software used in this study did not include this method. Fourth,
the methods for collecting data were follow-up examination or telephonic interviews. The symptoms and features reported by the patientsʼ parents could be subjective. However, this is an unavoidable limitation of such observational studies.
In conclusion, Laninamivir Nebulizer is safe and eﬀective for both inﬂuenza A and B. Boththe eﬀectiveness and safety of the Laninamivir Nebulizer were found to be equivalent to those ofother anti-inﬂuenza drugs. In addition, the Laninamivir Nebulizer showed comparable eﬀectiveness, even in crying children. Novel drug identiﬁcation for diseases aﬀecting small children, suchas inﬂuenza, should also consider individuals who cannot inhale powders or consume oral formsof medicine. Therefore, the Laninamivir Nebulizer can be a good therapeutic option for infants
with inﬂuenza.
Acknowledgments
None.

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81（ 19 ）Conﬂicts of interest
The author declares no potential conﬂict of interest.

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