DOCSLIB.ORG

Review Laninamivir and Its Prodrug, CS-8958: Long-Acting Neuraminidase Inhibitors for the Treatment of Influenza

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Review Laninamivir and Its Prodrug, CS-8958: Long-Acting Neuraminidase Inhibitors for the Treatment of Influenza Antiviral Chemistry & Chemotherapy 2010; 21:71–84 (doi: 10.3851/IMP1688) Review Laninamivir and its prodrug, CS-8958: long-acting neuraminidase inhibitors for the treatment of influenza Makoto Yamashita1* 1Biological Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan *Corresponding author e-mail: [email protected] Oseltamivir and zanamivir are currently licensed worldwide after an intranasal administration of CS-8958, therapeutic for influenza treatment and chemoprophylaxis. Both drugs administration of a single dose of CS-8958 showed supe- require twice-daily administration for 5 days for treatment. rior efficacy to repeated administrations of zanamivir or A new influenza drug,laninamivir (code name R-125489), oseltamivir in animal infection models for influenza A and and its prodrug form, CS-8958 (laninamivir octanoate or B viruses. These include pandemic (2009) H1N1 virus and laninamivir prodrug), which are long-acting neuramini- HPAI H5N1 virus. Prophylactic single administration of dase inhibitors, are introduced in this review. Laninamivir CS-8958, as early as 7 days prior to infection, also showed potently inhibited the neuraminidase activities of various superior efficacy. Finally, the potential of a single inhala- influenza A and B viruses, including subtypes N1–N9, pan- tion of CS-8958 for influenza patients was demonstrated demic (2009) H1N1 virus, highly pathogenic avian influ- by clinical studies, and CS-8958 has been approved and is enza (HPAI) H5N1 viruses and oseltamivir-resistant viruses. commercially available as Inavir® (Daiichi Sankyo Co., Ltd, Because of the long retention of laninamivir in mouse lungs Tokyo) in Japan. Introduction Influenza is a serious respiratory illness, which can be disorder, the pathogenicity of this virus is clearly higher debilitating, and could cause complications that lead to than that of seasonal influenza viruses in animal mod- hospitalization and death, especially in elderly individu- els [4–6] and humans, including those who do not have als. This respiratory disease is caused by influenza A and underlying illnesses [7]. The World Health Organization B viruses, which are pathogens that are highly contagious (WHO) [8] has reported >18,000 deaths worldwide as of among humans. Influenza A viruses are classified into 2 July 2010 and the US Centers for Disease Control and subtypes on the basis of the antigenicities of haemagglu- Prevention [9] estimated a 0.02% mortality rate of mid- tinin (HA) and neuraminidase (NA) molecules. To date, level range depending on age. Another possible concern 16 HA subtypes (H1–H16) and 9 NA subtypes (N1–N9) is a pandemic caused by highly pathogenic avian influ- have been reported. Seasonal influenza or influenza epi- enza (HPAI) H5N1 viruses. In 1997, human infections demics are caused by influenza A viruses H1N1 and with HPAI H5N1 viruses were first documented in Hong H3N2 and influenza B virus [1]. The global burden of Kong [10–12]. Since 2003, these viruses have spread influenza epidemics is believed to be 3.5 million cases of throughout Asia, Europe and Africa with high morbidity severe illness and 300,000–500,000 deaths annually [2]; and mortality among avian species and with occasional these numbers were calculated before the new pandemic transmission to humans, resulting in high mortality. A in 2009. In the past 100 years, humans have experienced total of 507 cases infected with the HPAI H5N1 virus three influenza pandemics: the first in 1918 (H1N1), the and as many as 302 deaths were reported as of 18 Octo- second in 1957 (H2N2) and the third in 1968 (H3N2) ber 2010 [13]. Although human-to-human transmission [1]. Since its emergence in the early spring of 2009, is rare, once the H5N1 viruses acquire this ability, a dev- pandemic (2009) H1N1 influenza A viruses have been astating pandemic might be inevitable. circulating worldwide [3]. Although most infected indi- Two countermeasures, vaccination and treatment viduals have exhibited an uncomplicated mild respiratory with antivirals, are available to control human influenza. ©2010 International Medical Press 1359-6535 (print) 2040-2066 (online) 71 M Yamashita Although vaccination plays a crucial role in influenza virus is already adamantane-resistant [3]. Moreover, the prophylaxis, it is insufficient both for prophylaxis and emergence of adamantane-resistant HPAI H5N1 viruses treatment against a pandemic virus; therefore, antivirals in Vietnam, Cambodia and Thailand [18] has prompted are an important tool that might be used to mitigate the WHO to recommend oseltamivir for the treatment influenza pandemics. Currently, two types of anti-influ- and prophylaxis of human H5N1 influenza virus infec- enza virus drugs are available: M2 ion channel blockers tions [19]. Accordingly, many countries have stockpiled (adamantanes) [14] and NA inhibitors. In Figure 1, a life oseltamivir in anticipation of an H5N1 pandemic. The cycle of influenza virus and action points of the inhibi- second and most recently developed class of drugs with tors are explained; however, in terms of adamantanes, activities against influenza A and B viruses are the NA adamantane-resistant viruses readily emerge and are inhibitors, which bind to the NA of newly formed virus already prevalent worldwide among the seasonal influ- particles and prevent their efficient release from the host enza viruses (both the H1N1 and the H3N2 subtypes) cell [20]. Two NA inhibitors, zanamivir (inhaled drug, [15,16]. The adamantane drugs have not been recom- 10 mg/dose; Relenza) and oseltamivir (oral drug, 75 mg/ mended for use for the treatment or chemoprophylaxis dose; Tamiflu), are currently licensed worldwide. Both of influenza in the US since the 2005 influenza season drugs require twice-daily administration for treatment. [15,17]. The recently emerged pandemic (2009) H1N1 Another NA inhibitor, peramivir (single intravenous Figure 1. Life cycle of the influenza virus and the inhibition step of neuraminidase inhibitors I J H G A E F H+ B vRNA mRNA D +RNA C A. The haemagglutinin (HA) of influenza virus recognizes neuraminic acid linked to glycoproteins or glycolipids on the cell surface, and viruses thus bind to target cells. B. The viruses bound to cells penetrate into the cell via endocytosis. C. Protons in the endosome enter the virion via the M2 ion channel protein, and the HA structure altered by acidification triggers membrane fusion, followed by the release of viral RNAs (vRNAs) into the cytoplasm. Adamantane drugs block the M2 ion channel. D. From vRNAs, messenger RNAs (mRNAs) for protein synthesis and positive-strand RNA (+RNA) for replication of vRNAs are synthesized in the nucleus. E. vRNAs for progeny viruses are transported close to the cell membrane. F. Viral proteins are synthesized. G. vRNAs and viral proteins are assembled and generate progeny viruses on the cell surface. H. Progeny viruses form aggregates of each other or with cells through the binding of HA to neuraminic acid on viruses and/or cells. I and J. Viral neuraminidase (NA) cleaves the neuraminic acid linkage, releasing progeny viruses from the virus aggregates and expanding infection. NA inhibitors inhibit this step to stop the release of progeny viruses from virus aggregates. The inset shows virus aggregates (arrow) when cultured cells were infected with influenza viruses in the presence of laninamivir. 72 ©2010 International Medical Press Laninamivir and its prodrug CS-8958 for treating influenza drip infusion, 300 mg/dose; Rapiacta), was licensed in Figure 2. Chemical structures of laninamivir and CS-8958 2010 in Japan. Oseltamivir is predominant and is used worldwide for the treatment of influenza, and the gen- eration and circulation of oseltamivir-resistant seasonal OH OCH3 influenza viruses have become major concerns [21–25]. H In particular, the worldwide prevalence of oseltamivir- O CO2H resistant mutants of seasonal H1N1 virus with the OH H274Y substitution (histidine to tyrosine at position H3C NH 274, numbering based on the N2 subtype) in NA has HN O been reported. In addition, 95% of H1N1 isolates tested NH from the fourth quarter of 2008 to January 2009 [26] H2N and almost all the H1N1 isolates of the 2008–2009 sea- son in the US [27] were reported to be oseltamivir-resist- Laninamivir (R-125489) ant. Additionally, a number of oseltamivir-resistant pan- demic 2009 H1N1 viruses [28] and HPAI H5N1 viruses [25] have already appeared, although their appearance is still sporadic. These epidemics of oseltamivir-resistant influenza viruses therefore necessitate the development O of alternative antiviral agents. H3C O OCH3 Yamashita et al. [29] and Kubo et al. [30] found a new H potent NA inhibitor, laninamivir (code name R-125489), O CO2H and reported that CS-8958 (laninamivir octanoate or lan- inamivir prodrug) acts as a long-acting NA inhibitor. The OH H3C HN results of in vitro and in vivo experiments of laninamivir HN and CS-8958 [4,29–34] and the clinical studies of CS-8958 O NH [35,36] are introduced in this review. The potential of the H N single administration of CS-8958 for influenza patients 2 was confirmed by the clinical studies conducted for the Laninamivir prodrug (CS-8958) 2008–2009 influenza season [36–38]. CS-8958 has been approved and is commercially available as Inavir® (Dai- ichi Sankyo Co., Ltd, Tokyo) in Japan. Reproduced with permission from the American Society for Microbiology [29]. Compound H1N1 [29], pandemic (2009) H1N1 [4], H3N2 [29], Laninamivir (R-125489) is a potent NA inhibitor HPAI H5N1 viruses [33] and influenza B viruses [29]. of various influenza viruses. Its chemical structure is Laninamivir showed a 50% inhibitory concentra- (2R,3R,4S)-3-acetamido-2-[(1R,2R)-2,3-dihydroxy- tion (IC50) of 0.41 nM to pandemic (2009) H1N1, A/ 1-methoxypropyl]-4-guanidino-3,4-dihydro-2H- California/4/2009, and exhibited a median IC50 of pyran-6-carboxylic acid, as shown in Figure 2 [29]. It 1.55 nM to nine pandemic (2009) H1N1 strains isolated demonstrated a prolonged survival effect in a mouse in Japan.
Load more

Recommended publications
  • Drug Name Peramivir Brand Name(S)
    Antimicrobial Stewardship Program Drug Name Peramivir Brand Name(s) Rapivab Drug Class Neuraminidase inhibitor Restriction level Restricted to Infectious Diseases and Pulmonology/Critical Care Accepted Indications Management of Influenza A or B in patients with the following: Strict NPO (no NGT/OGT/G-tube/J-tube) Concerns about poor gut absorption (i.e. ileus) Unacceptable Uses Management of Influenza A or B in a patient who can tolerate oral therapy whether by mouth, G-tube, or J-tube Side Effects Insomnia (3%), Diarrhea (8%), Hyperglycemia (serum glucose >160 mg/dL, 5%), Neutropenia (8%), Increased serum ALT/AST (3%), Increased CPK, 4% Pregnancy Class C Dosing Adult: 600 mg IV once* Renal dosing: - CrCl 30-50 mL/min: 200 mg dose IV once* - CrCl 15-29 mL/min: 100 mg dose IV once* - CrCl <10 mL/min or ESRD on HD: 100 mg dose once after HD‡ Pediatrics: - Children: 2-12 years: 12 mg/kg as a single dose; maximum 600mg - Adolescents ≥13 years: Refer to adult dosing Renal dosing: Infants, Children, and Adolescents <18 years: Note: Dosage adjustment based on renal function estimated using the Schwartz equation. CrCl ≥50 mL/minute/1.73 m2: No adjustment necessary CrCl 31 to 49 mL/minute/1.73 m2: 29 to 30 days of life: 1.5 mg/kg/dose once daily for 5 to 10 days 31 to 90 days of life: 2 mg/kg/dose once daily for 5 to 10 days 91 to 180 days of life: 2.5 mg/kg/dose once daily for 5 to 10 days 181 days of life through 5 years: 3 mg/kg/dose once daily for 5 to 10 days; maximum dose: 150 mg/dose 6 to 17 years: 2.5 mg/kg/dose once daily for 5 to 10
    [Show full text]
  • Dectova, INN-Zanamivir
    28 February 2019 EMA/CHMP/851480/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report DECTOVA International non-proprietary name: zanamivir Procedure No. EMEA/H/C/004102/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 9 2. Scientific discussion .............................................................................. 12 2.1. Problem statement ............................................................................................. 12 2.1.1. Disease or condition ......................................................................................... 12 2.1.2. Epidemiology .................................................................................................. 12 2.1.3. Biologic features .............................................................................................
    [Show full text]
  • Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza
    Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza Aeron Hurt WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, Australia www.influenzacentre.org NA inhibitor antiviral drugs Top view of NA NA inhibitor NA enzyme active site The NA inhibitors Oseltamivir Zanamivir - Oral, IV(?) - Inhaled, IV(?) - Global - Global Peramivir Laninamivir -IV - Inhaled (single) - Japan, - Japan S.Korea, China, US The NA inhibitors Oseltamivir Zanamivir - Oral, IV(?) - Inhaled, IV(?) - Global - Global • Came on the market in many countries in 2000 after clinical studies had been conducted among influenza virus–infected patients with uncomplicated illness. • Oseltamivir is market leader ……due to ease of oral administration • Use for seasonal influenza mainly in Japan and US • With human infections of highly pathogenic influenza A(H5N1) virus from 2003 with a high case‐fatality risks of >50%, governments began to consider antiviral drug administration as a key component of their pandemic response • suitable vaccines would not be available Stockpiling for a pandemic • Oseltamivir was simpler (oral) administration than zanamivir (inhalation) and because of systemic effect of oseltamivir was expected to be appropriate for treatment of highly pathogenic viruses • Oseltamivir was suddenly in high demand! • Roche had warned that need to stockpile to guarantee availability • Since 2005, governments of middle‐income and high‐income countries around the world have spent billions of dollars (estimated) stockpiling oseltamivir (US Gov. Accounting Office). 2009 A(H1N1)pdm09 pandemic • The first pandemic of the 21st century occurred unexpectedly in 2009 after the global spread of a novel virus—influenza A(H1N1)pdm09—of swine (rather than avian) origin.
    [Show full text]
  • Influenza: Diagnosis and Treatment
    Influenza: Diagnosis and Treatment David Y. Gaitonde, MD; Cpt. Faith C. Moore, USA, MC; and Maj. Mackenzie K. Morgan, USA, MC Dwight D. Eisenhower Army Medical Center, Fort Gordon, Georgia Influenza is an acute viral respiratory infection that causes significant morbidity and mortality worldwide. Three types of influ- enza cause disease in humans. Influenza A is the type most responsible for causing pandemics because of its high susceptibility to antigenic variation. Influenza is highly contagious, and the hallmark of infection is abrupt onset of fever, cough, chills or sweats, myalgias, and malaise. For most patients in the outpatient setting, the diagnosis is made clinically, and laboratory con- firmation is not necessary. Laboratory testing may be useful in hospitalized patients with suspected influenza and in patients for whom a confirmed diagnosis will change treatment decisions. Rapid molecular assays are the preferred diagnostic tests because they can be done at the point of care, are highly accurate, and have fast results. Treatment with one of four approved anti-influenza drugs may be considered if the patient presents within 48 hours of symptom onset. The benefit of treatment is greatest when antiviral therapy is started within 24 hours of symptom onset. These drugs decrease the duration of illness by about 24 hours in otherwise healthy patients and may decrease the risk of serious complications. No anti-influenza drug has been proven superior. Annual influenza vaccination is recommended for all people six months and older who do not have contraindications. (Am Fam Physician. 2019; 100:online. Copyright © 2019 American Academy of Family Physicians.) Published online November 11, 2019 BEST PRACTICES IN INFECTIOUS DISEASE Influenza is an acute respiratory infection caused by a negative-strand RNA virus of the Orthomyxoviridae fam- Recommendations from the Choosing ily.
    [Show full text]
  • Case Report Prolonged Shedding of Amantadine- and Oseltamivir- Resistant Influenza A(H3N2) Virus with Dual Mutations in an Immunocompromised Infant
    Antiviral Therapy 2010 15:1059–1063 (doi: 10.3851/IMP1657) Case report Prolonged shedding of amantadine- and oseltamivir- resistant influenza A(H3N2) virus with dual mutations in an immunocompromised infant Guillermo Ruiz-Carrascoso1*, Inmaculada Casas1, Francisco Pozo1, Marta González-Vincent2, Pilar Pérez-Breña1 1Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain 2Hospital Infantil Universitario Niño Jesús, Madrid, Spain *Corresponding author e-mail: [email protected] In this study, we report a case of multidrug-resistant contained the substitutions E119V in neuraminidase and influenza A(H3N2) virus isolated from an immunosup- V27A in M2, which produce resistance to oseltamivir and pressed patient with prolonged viral shedding. We also adamantanes, respectively. This is the first report of this describe the genetic characterization of the haemagglu- dual mutation pattern in multidrug-resistant influenza tinin, neuraminidase and M2 influenza genes. The virus A(H3N2) virus. Introduction Influenza, which causes significant morbidity and daily because of neurological toxicity). After receiving mortality in immunocompromised patients, is often fludarabine and melphalan as conditioning therapy, he associated with prolonged viral shedding [1,2] underwent allogenic non-identical peripheral blood regardless of vaccination and antiviral therapy. The transplantation from his mother in May 2005 (day 0). multidrug-resistant influenza viruses, including pan- Total lymphocyte cell (TLC) count prior to transplan- demic A(H1N1) and seasonal A(H1N1) and A(H3N2), tation was 1,340 cells/mm3 (25%). On day 10, fever as reported to date in treated immunocompromised was observed and oxygen therapy was required because patients [1,3–6], have presented the E119V, R292K or of respiratory insufficiency.
    [Show full text]
  • Alpivab, INN-Peramivir
    22 February 2018 EMA/CHMP/148367/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Alpivab International non-proprietary name: peramivir Procedure No. EMEA/H/C/004299/0000 authorised Note longer Assessment report as adopted by the CHMP with allno information of a commercially confidential nature deleted. Product Medicinal 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier ...................................................................................... 6 1.2. Steps taken for the assessment of the product ......................................................... 7 2. Scientific discussion ................................................................................ 8 2.1. Problem statement ............................................................................................... 8 2.1.1. Disease or condition ........................................................................................... 8 2.1.2. Epidemiology and risk factors, screening tools/prevention ...................................... 8 2.1.3. Aetiology and pathogenesis ...............................................................................
    [Show full text]
  • Efficacy of Baloxavir Marboxil on Household Transmission Of
    Umemura et al. Journal of Pharmaceutical Health Care and Sciences (2020) 6:21 https://doi.org/10.1186/s40780-020-00178-4 RESEARCH ARTICLE Open Access Efficacy of baloxavir marboxil on household transmission of influenza infection Takumi Umemura1,2* , Yoshikazu Mutoh2, Takato Kawamura1, Masayuki Saito1, Takahito Mizuno1, Aiko Ota1, Koji Kozaki1, Tetsuya Yamada1, Yoshiaki Ikeda3 and Toshihiko Ichihara2 Abstract Background: Baloxavir marboxil (baloxavir) is a new anti-influenza virus agent that is comparable to oseltamivir phosphate (oseltamivir). Since the efficacy of baloxavir in preventing household transmission of influenza is not well established, we compared the secondary household influenza virus transmission rates between patients on baloxavir vs oseltamivir. Methods: Between October 2018 and March 2019, we enrolled index patients (diagnosed with influenza and treated with baloxavir or oseltamivir) and household members. The secondary attack rate of household members was compared between index patients treated with baloxavir vs oseltamivir. Risk factors of household transmission were determined using multivariate logistic analyses. Results: In total, 169 index patients with influenza type A were enrolled. The median age was 27.0 (interquartile range; 11–57) years. The number of index patients treated with baloxavir and oseltamivir was 49 and 120, respectively. The secondary attack rate was 9.0% (95% confidence interval [CI]: 4.6–15.6) in the baloxavir group and 13.5% (95% CI: 9.8–17.9) in the oseltamivir group. In the multivariate analysis, independent risk factors were 0–6 years of age (odds ratio [OR] 2.78, 95% CI: 1.33–5.82, p < 0.01) and not being on baloxavir treatment.
    [Show full text]
  • Summary of Neuraminidase Amino Acid Substitutions Associated with Reduced Inhibition by Neuraminidase Inhibitors
    Summary of neuraminidase amino acid substitutions associated with reduced inhibition by neuraminidase inhibitors. Susceptibility assessed by NA inhibition assays Source of Type/subtype Amino acid N2 b (IC50 fold change vs wild type [NAI susceptible virus]) viruses/ References Comments substitutiona numberinga Oseltamivir Zanamivir Peramivir Laninamivir selection withc A(H1N1)pdm09 I117R 117 NI (1) RI (10) ? ?d Sur (1) E119A 119 NI/RI (8-17) RI (58-90) NI/RI (7-12) RI (82) RG (2, 3) E119D 119 RI (25-23) HRI (583-827) HRI (104-286) HRI (702) Clin/Zan; RG (3, 4) E119G 119 NI (1-7) HRI (113-1306) RI/HRI (51-167) HRI (327) RG; Clin/Zan (3, 5, 6) E119V 119 RI (60) HRI (571) RI (25) ? RG (5) Q136K/Q 136 NI (1) RI (20) ? ? Sur (1) Q136K 136 NI (1) HRI (86-749) HRI (143) RI (42-45) Sur; RG; in vitro (2, 7, 8) Q136R was host Q136R 136 NI (1) HRI (200) HRI (234) RI (33) Sur (9) cell selected D151D/E 151 NI (3) RI (19) RI (14) NI (5) Sur (9) D151N/D 151 RI (22) RI (21) NI (3) NI (3) Sur (1) R152K 152 RI(18) NI(4) NI(4) ? RG (3, 6) D199E 198 RI (16) NI (7) ? ? Sur (10) D199G 198 RI (17) NI (6) NI (2) NI (2) Sur; in vitro; RG (2, 5) I223K 222 RI (12–39) NI (5–6) NI (1–4) NI (4) Sur; RG (10-12) Clin/No; I223R 222 RI (13–45) NI/RI (8–12) NI (5) NI (2) (10, 12-15) Clin/Ose/Zan; RG I223V 222 NI (6) NI (2) NI (2) NI (1) RG (2, 5) I223T 222 NI/RI(9-15) NI(3) NI(2) NI(2) Clin/Sur (2) S247N 246 NI (4–8) NI (2–5) NI (1) ? Sur (16) S247G 246 RI (15) NI (1) NI (1) NI (1) Clin/Sur (10) S247R 246 RI (36-37) RI (51-54) RI/HRI (94-115) RI/HRI (90-122) Clin/No (1)
    [Show full text]
  • RAPIVAB (Peramivir) Injection, for Intravenous Use  See the Full Prescribing Information for Drug Compatibility Information Initial U.S
    HIGHLIGHTS OF PRESCRIBING INFORMATION No recommendation for dosage adjustment can be made for pediatric These highlights do not include all the information needed to use patients 6 months to less than 2 years of age with creatinine clearance RAPIVAB safely and effectively. See full prescribing information for less than 50 mL/min (2.2) RAPIVAB. Hemodialysis: Administer after dialysis (2.2) RAPIVAB must be diluted prior to administration (2.3) ® RAPIVAB (peramivir) injection, for intravenous use See the Full Prescribing Information for drug compatibility information Initial U.S. Approval: 2014 (2.4) --------------------------RECENT MAJOR CHANGES-------------------------- ------------------------DOSAGE FORMS AND STRENGTHS------------------- Indications and Usage (1) 01/2021 Injection: 200 mg in 20 mL (10 mg/mL) in a single-use vial (3) Dosage and Administration Dosage in Acute Uncomplicated Influenza (2.1) 01/2021 --------------------------------CONTRAINDICATIONS------------------------------ Dosing in Patients with Renal Impairment (2.2) 01/2021 Patients with known serious hypersensitivity or anaphylaxis to peramivir or Preparation of RAPIVAB for Intravenous Infusion (2.3) 01/2021 any component of RAPIVAB (4) ---------------------------INDICATIONS AND USAGE--------------------------- --------------------------WARNINGS AND PRECAUTIONS---------------------- RAPIVAB is an influenza virus neuraminidase inhibitor indicated for the Cases of anaphylaxis and serious skin/hypersensitivity reactions such treatment of acute uncomplicated influenza
    [Show full text]
  • Official Title: a Phase III, Randomized, Double-Blind Placebo-Controlled
    Official Title: A Phase III, Randomized, Double-Blind Placebo-Controlled, Multicenter Study To Evaluate the Efficacy and Safety of Baloxavir Marboxil in Combination With Standard-of-Care Neuraminidase Inhibitor in Hospitalized Participants With Severe Influenza NCT Number: NCT03684044 Document Date: Protocol Version 2: 30-May-2019 PROTOCOL TITLE: A PHASE III, RANDOMIZED, DOUBLE-BLIND PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF BALOXAVIR MARBOXIL IN COMBINATION WITH STANDARD-OF-CARE NEURAMINIDASE INHIBITOR IN HOSPITALIZED PATIENTS WITH SEVERE INFLUENZA PROTOCOL NUMBER: CP40617 VERSION NUMBER: 2 EUDRACT NUMBER: 2018-001416-30 IND NUMBER: 126653 TEST PRODUCT: Baloxavir marboxil (RO7191686) MEDICAL MONITOR: M.D. SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: Version 1: 17 July 2018 DATES AMENDED: Version 1 (VHP only): 27 November 2018 Version 2: See electronic date stamp below. FINAL PROTOCOL APPROVAL Approver's Name Title Date and Time (UTC) Company Signatory 30-May-2019 16:10:33 CONFIDENTIAL This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States. The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without written authorization from Roche except to the extent necessary to obtain informed consent from persons to whom the drug may be administered.
    [Show full text]
  • Development of Effective Anti-Influenza Drugs: Congeners and Conjugates – a Review Jiun-Jie Shie1 and Jim-Min Fang2,3*
    Shie and Fang Journal of Biomedical Science (2019) 26:84 https://doi.org/10.1186/s12929-019-0567-0 REVIEW Open Access Development of effective anti-influenza drugs: congeners and conjugates – a review Jiun-Jie Shie1 and Jim-Min Fang2,3* Abstract Influenza is a long-standing health problem. For treatment of seasonal flu and possible pandemic infections, there is a need to develop new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses, including the resistant strains. Relenza™ (zanamivir), Tamiflu™ (the phosphate salt of oseltamivir), Inavir™ (laninamivir octanoate) and Rapivab™ (peramivir) are four anti-influenza drugs targeting the viral neuraminidases (NAs). However, some problems of these drugs should be resolved, such as oral availability, drug resistance and the induced cytokine storm. Two possible strategies have been applied to tackle these problems by devising congeners and conjugates. In this review, congeners are the related compounds having comparable chemical structures and biological functions, whereas conjugate refers to a compound having two bioactive entities joined by a covalent bond. The rational design of NA inhibitors is based on the mechanism of the enzymatic hydrolysis of the sialic acid (Neu5Ac)-terminated glycoprotein. To improve binding affinity and lipophilicity of the existing NA inhibitors, several methods are utilized, including conversion of carboxylic acid to ester prodrug, conversion of guanidine to acylguanidine, substitution of carboxylic acid with bioisostere, and modification of glycerol side chain. Alternatively, conjugating NA inhibitors with other therapeutic entity provides a synergistic anti-influenza activity; for example, to kill the existing viruses and suppress the cytokines caused by cross-species infection.
    [Show full text]
  • Oseltamivir, Zanamivir and Amantadine in the Prevention of Influenza: a Systematic Review
    Journal of Infection (2011) 62,14e25 www.elsevierhealth.com/journals/jinf Oseltamivir, zanamivir and amantadine in the prevention of influenza: A systematic review Rachel J. Jackson a,*, Katy L. Cooper a, Paul Tappenden a, Angie Rees b, Emma L. Simpson a, Robert C. Read c, Karl G. Nicholson d a Health Economics and Decision Science, School of Health and Related Research, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA, UK b School of Health and Related Research, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA, UK c Department of Infection & Immunity, School of Medicine, University of Sheffield, Beech Hill Rd, Sheffield, S10 2RX, UK d Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, LE2 7LX, UK Accepted 5 October 2010 Available online 13 October 2010 KEYWORDS Summary Objective: To systematically review evidence relating to the clinical efficacy of Influenza; oseltamivir, zanamivir and amantadine in the prevention of influenza. Prophylaxis; Methods: RCTs evaluating these interventions in seasonal prophylaxis and post-exposure pro- Prevention; phylaxis were identified using electronic bibliographic databases and handsearching of Amantadine; retrieved articles. Oseltamivir; Results: Oseltamivir was effective in preventing symptomatic laboratory-confirmed influenza Zanamivir; (SLCI) in seasonal prophylaxis in healthy adults and at-risk elderly subjects and in post-expo- Neuraminidase sure prophylaxis within households of mixed composition. Post-exposure prophylaxis using inhibitor; oseltamivir for paediatric contacts was observed to prevent SLCI. Zanamivir prevented M2 inhibitor; SLCI in seasonal prophylaxis in healthy adults, at-risk adults and adolescents and in post-expo- Systematic review sure prophylaxis within mixed households, with a trend for seasonal and post-exposure preven- tative effects in elderly subjects.
    [Show full text]