November Horizon Scanning Research & 2016 Intelligence Centre

Zanamivir (Relenza) as an intravenous formulation for the treatment of hospitalised patients with

NIHR HSRIC ID: 6033

Lay summary

Zanamivir is a new drug to treat patients who have been admitted to hospital with influenza. It is for patients who are not responding to other antiviral medicines or who are only able to receive treatment via a drip; it is also an option for patients who are infected with influenza virus which is resistant to other medicines. Zanamivir is administered via a drip directly into the bloodstream.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Patients requiring hospitalisation following influenza infection: patients who are not responding to either oral or inhaled currently authorised antiviral medicinal products; patients for whom drug delivery by a route other than intravenous (IV) infusion is not feasible; or patients infected with documented influenza virus resistant to other antiviral agents and not suitable for therapy with inhaled zanamivir.

TECHNOLOGY

DESCRIPTION

Zanamivir (Relenza; GG167; GR121167) is an inhibitor of the enzyme , a surface glycoprotein essential for the replication of type A and B influenza viruses. In phase III clinical trials, zanamivir is administered by IV at a dose of 600mg twice daily for adults with a treatment duration of 5-10 days1.

Zanamivir IV is available in the EU for compassionate use to treat critically ill adults and children with a life-threatening condition due to suspected or confirmed pandemic influenza virus infection or infection due to seasonal influenza A or B2.

Zanamivir (Relenza) is licensed in the UK as an inhalation powder for the treatment of influenza A and B in adults and children (≥ 5 years) who present with symptoms typical of influenza when influenza is circulating in the community; and for post-exposure prophylaxis of influenza A and B in adults and children (≥ 5 years) following contact with a clinically diagnosed case in a household. In exceptional circumstances, zanamivir may be considered for seasonal prophylaxis of influenza A and B during a community outbreak3.

A common side effect of zanamivir is skin rashes. Less common effects include allergic or vasovagal reactions, respiratory symptoms including breathlessness, and urticarial reactions. Rare adverse events include anaphylactic reactions, and skin problems such as Stevens-Johnson syndrome. There have been reports of convulsions and psychiatric events such as depressed level of consciousness, abnormal behaviour, hallucinations and delirium during zanamivir administration in patients with influenza. The frequency of these effects has not been reported and symptoms were mainly reported in children and adolescents.

INNOVATION and/or ADVANTAGES

If licensed, zanamivir IV will offer an additional treatment option for patients who have been hospitalised with influenza infections. The exact indication has not yet been decideda.

DEVELOPER

GlaxoSmithKline.

AVAILABILITY, LAUNCH OR MARKETING

Zanamivir IV is in phase III clinical trials for hospitalisation following influenza infection.

a Company information. Horizon Scanning Research & Intelligence Centre

PATIENT GROUP

BACKGROUND

Influenza is an acute infection of the respiratory tract usually caused by the influenza A or B virus. Influenza is highly infectious with an incubation period of 1-3 days4. The symptoms of uncomplicated influenza include fever, dry chesty cough, sore throat, tiredness, myalgia and headache5,6. Influenza infection is usually self-limiting and lasts for 3–4 days, with some symptoms persisting for 1–2 weeks4. The severity of the illness however, can vary from asymptomatic infection to life-threatening complications (known as ‘complicated influenza’)6.

Complicated influenza infection is defined as that requiring hospital admission and/or with symptoms of lower respiratory tract infection, central nervous system involvement and/or a significant exacerbation of an underlying medical condition6. The most common complications include secondary bacterial infections such as , and bronchitis4. For certain ‘at risk’ groups, influenza infection can be very serious and require specific antiviral medication to reduce viral replication4. Groups at risk include those over the age of 65; pregnant women; those with long term medical conditions such as diabetes, heart disease, lung disease, kidney disease and/or neurological disease; and those with a weakened immune system5.

CLINICAL NEED and BURDEN OF DISEASE

The impact of influenza infection on the population varies from year to year and is influenced by changes in the virus that, in turn, influence the proportion of the population that may be susceptible to infection and the severity of the illness7.

In 2014-15, there were 4,122 hospital admissions for influenza (ICD-10 J10 and J11), resulting in 41,389 bed days and 7,902 finished consultant episodes8. In 2014, there were 118 deaths from influenza (J09-J11) in England and Wales9. In comparison with in 2013-14, when there were 1,863 hospital admissions for influenza (ICD-10 J10 and J11), resulting in 17,777 bed days and 3,188 finished consultant episodes10. In 2013, there were 161 deaths from influenza (J09-J11) in England and Wales11.The number of registered deaths from influenza is likely to be an underestimate of the impact of influenza virus circulating in the community on mortality; many deaths arising from influenza infections will be from complications e.g. pneumonia or exacerbations of underlying medical conditions.

The population likely to be eligible to receive zanamivir IV could not be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. , and zanamivir for the treatment of influenza (TA168). February 2009. • NICE technology appraisal. Oseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza (TA158). September 2008.

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• NICE public health guidance in development. Flu vaccination-increasing uptake (GID- PHG96). Expected January 2018.

NHS England Policies and Guidance

• NHS England. 2016/17 Enhanced services specification: Seasonal influenza and pneumococcal polysaccharide vaccination programme. NHS England gateway reference: 05076. March 2016. • NHS England. 2016/17 NHS public health functions agreement 2016-17: Service specification no. 13. Seasonal influenza immunisation programme (2016-17 programme). February 2016. • NHS England. 2013/14 NHS Standard Contract for Specialised Services for Infectious Diseases (adult). B07/S/a. • NHS England. Operating framework for managing the response to pandemic influenza. October 2013. • NHS England. Enhanced services specification: Seasonal influenza and pneumococcal immunisation enhanced service. NHS England gateway reference: 01790. 2014. • NHS England. Service specification: Community pharmacy seasonal influenza vaccination advanced service. NHS England gateway reference: 05662. August 2016.

Other Guidance

• Public Health England. PHE guidance on use of antiviral agents for the treatment and prophylaxis of seasonal influenza (PHE publications gateway number: 2016395). 201612. • NICE Clinical Knowledge Summary. Scenario: Treating influenza. 201513. • Public Health England. Infection control precautions to minimise transmission of acute respiratory tract infections in healthcare settings (PHE publications gateway number: 2015247). 201514. • World Health Organization. Pandemic influenza risk management (WHO interim guidance) (WHO/HSE/HEA/HSP/2013.3). 201315. • Public Health England. Influenza: the green book, chapter 19. 20154.

CURRENT TREATMENT OPTIONS

In certain groups and individuals, influenza infection can progress from a mild illness manifesting as fever, cough, sore throat, headache, malaise, and muscle and joint pains to one in which there is shortness of breath, chest pain and/or confusion, which may be indicative of pneumonia. There may also be a significant exacerbation of an underlying medical condition, such as heart, liver, lung or renal insufficiency, or diabetes mellitus. Patients with signs and symptoms of suspected pneumonia are likely to need assessment and treatment in hospital. Treatment options will include antiviral drugs and intravenous antibiotics. Depending on the severity of the disease and any other co-morbidities, some form of ventilation may be required.

Pneumonia that is caused directly by the influenza virus is usually more serious and may require prolonged hospital admission and specialist ventilation techniques including extra- corporeal membrane oxygenation (ECMO). ECMO provides both cardiac and respiratory support and involves removing blood from the patient, adding oxygen and removing carbon dioxide from the blood, and then pumping it back into the patient. ECMO can maintain pulmonary function while the lungs heal.

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EFFICACY and SAFETY

Trial NCT01231620, 114373; NCT01527110, 115215; NCT01014988, 113678; zanamivir vs oseltamivir; zanamivir; phase III. zanamivir; phase II. phase III. Sponsor GlaxoSmithKline. GlaxoSmithKline. GlaxoSmithKline. Status Complete but unpublished. Published. Published. Source of Trial registry16, Publication17, trial Publication19, trial registry1. information manufacturerb. registry18. Location EU (incl UK), USA, Canada Japan. EU (incl UK), USA, and other countries. Canada and other countries. Design Randomised, active- Non-randomised, Non-randomised, controlled. uncontrolled. uncontrolled. Participants n=626 (planned); aged ≥16 n=21; aged ≥16 yrs; n=133; aged ≥6 mnths; yrs; hospitalised; clinical hospitalised; laboratory hospitalised; confirmed symptoms of influenza; confirmed influenza; influenza. laboratory confirmed does not need ECMO at influenza or strong suspicion baseline; potential of influenza; no prior anti- survival ≥ 48 hours. viral agent; does not need ECMO or dialysis at baseline; potential survival ≥ 48 hours. Schedule Randomised to zanamivir IV Pts receive zanamivir IV Pts receive zanamivir IV 300mg plus oral placebo; or 600mg twice daily for 5 600mg twice daily or age- zanamivir IV 600mg plus oral days initially, with an adjusted, weight-based placebo; or oseltamivir 75mg extension of 5 days if dose (not exceeding oral plus IV placebo. clinically warranted. 600mg) for 5 days initially, All administered twice daily with an extension of 5 days for 5 days initially, with an if clinically warranted. extension for 5 more days if clinically warranted. Follow-up Active treatment 24 days Active treatment 5-10 Active treatment 5-10 maximum, follow-up up to 48 days, follow-up up to 33 days, follow-up up to 33 days. days. days. Primary Time to clinical response Adverse events (AEs); AEs; clinical chemistry and outcomes (TTCR). clinical chemistry and haematology data; heart haematology data; rate, blood pressure, treatment emergent oxygen saturation, toxicities; heart rate; respiration rate and blood pressure; oxygen temperature; ECG. saturation; respiration rate; temperature; ECG. Secondary Katz Index of Independence TTCR; time to return to Viral load and time to outcomes in Activities of Daily Living pre-morbid level of undetectable viral RNA; (ADL); mortality; disease activity; ventilation viral susceptibility to progression and status; length of ICU and zanamivir; resistance complications of influenza; hospital stay; viral emergence; mortality; duration of hospitalisation susceptibility to complications; antibiotic and intensive care unit (ICU) zanamivir; resistance use; ventilation status; time stay; time to improvement of emergence; clinical to resolution of all and vital signs; time to symptoms of influenza; individual vital signs; improvement in respiratory complications; antibiotic length of total ICU stay and

b Company information.

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status; time to reduction in use; undetectable viral hospital stay; level of viral load and undetectable RNA. No quality of life physical activity. No quality viral RNA; safety and measurement included in of life measurement tolerability; trial outcomes. included in trial outcomes. electrocardiogram (ECG); . No quality of life measurement included in trial outcomes. Key results No statistically significant Median time to clinical Pts received zanamivir IV difference was observed for response and time to a median of 4.5 days the difference in TTCR virological improvement (range 1-7) after onset of between any trial arms. approximately 4 days influenza; 83% required Results for secondary (range 0.5-22) and 3 intensive care. Most efficacy variables were days (range 2-5), common influenza similar between treatment respectively. type/subtype was groups. A/H1N1pdm09 (71%). Dose adjustments for renal impairment yielded similar zanamivir exposures. 93 pts with PCR confirmed influenza had a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment. Adverse In the zanamivir 300mg IV Overall AEs and SAEs AEs and SAEs reported in effects group 44% pts reported non- reported in 13 (62%) and 85% and 34%, (AEs) serious AEs with the most 4 (19%), respectively. respectively; SAEs frequently reported being There were no reported included bacterial diarrhoea and hypertension. patterns of AEs or SAEs. pulmonary infections (8%), In the zanamivir 600mg IV respiratory failure (7%), group, 45% pts reported sepsis or septic shock non-serious AEs with the (5%), and cardiogenic most frequently reported shock (5%). No drug- being diarrhoea and related trends in safety constipation. In the parameters identified. oseltamivir group 54% Protocol-defined liver AEs subjects reported non- and SAEs were observed serious adverse events with in 13%. The 14- and 28- the most frequently reported day all-cause mortality being diarrhoea, constipation rates were 13% and 17%. and increased aspartate No fatalities were aminotransferase. 8% considered zanamivir IV subjects in the zanamivir related. 300mg IV group reported a serious adverse effect (SAE), the most common being acute respiratory distress syndrome, respiratory failure and acute kidney injury. 6% subjects in the zanamivir 600mg IV group reported an SAE, the most common being acute respiratory distress syndrome and respiratory failure. 7% subjects in the oseltamivir group reported an SAE, the most common being respiratory failure. There were 9 fatalities in the

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zanamivir 300mg IV group, 9 in the zanamivir 600mg IV group, and 5 in the oseltamivir group. Expected Study completion date - - reporting reported as March 2015. date

ESTIMATED COST and IMPACT

COST

Zanamivir powder for inhalation is already marketed as Relenza in the UK; a pack of 20 x 5mg inhalation powder blisters costs £16.3620.

The cost of zanamivir IV is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

 Other  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified

REFERENCES

1 ClinicalTrials.gov. An open-label, multi-center, single arm study to evaluate the safety and tolerability of intravenous zanamivir in the treatment of hospitalized adult, adolescent and pediatric subjects with confirmed influenza infection. www.clinicaltrials.gov/ct2/show/NCT01014988 Accessed 6 October 2016. 2 European Medicines Agency. Conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring addressed to member states for IV Zanamivir available for compassionate use. EMA/671175/2015 Rev. 3. London: EMA; October 2015.

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3 electronic Medicines Compendium (eMC). European Medicines Compendium. www.medicines.org.uk Accessed 6 October 2016. 4 Public Health England. Influenza: the green book, chapter 19. www.gov.uk/government/uploads/system/uploads/attachment_data/file/456568/2904394_Green_ Book_Chapter_19_v10_0.pdf Accessed 6 October 2016. 5 NHS Choices: Flu-Symptoms. www.nhs.uk/Conditions/Flu/Pages/Symptoms.aspx Accessed 1 November 2016. 6 Patient.co.uk. Influenza. www.patient.co.uk/doctor/influenza Accessed 1 November 2016. 7 NHS England. Flu Plan Winter 2016/17. www.gov.uk/government/uploads/system/uploads/attachment_data/file/525967/Annual_flu_plan_ 2016_to_2017.pdf Accessed 6 October 2016. 8 Health & Social Care Information Centre. Hospital Episode Statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk 9 Office for National Statistics. Mortality statistics: Deaths registered in England and Wales, (Series DR), 2014. www.ons.gov.uk 10 Health & Social Care Information Centre. Hospital Episode Statistics for England. Inpatient statistics, 2013-14. www.hscic.gov.uk 11 Office for National Statistics. Mortality statistics: Deaths registered in England and Wales, (Series DR), 2013. www.ons.gov.uk 12 Public Health England. PHE guidance on use of antiviral agents for the treatment and prophylaxis of seasonal influenza PHE publications gateway number: 2016395. London: PHE; October 2016. 13 National Institute for Health and Care Excellence. Influenza – seasonal – management: Scenario: Treating influenza. Clinical Knowledge Summaries. London: NICE; October 2015. 14 Public Health England. Infection control precautions to minimise transmission of acute respiratory tract infections in healthcare settings PHE publications gateway number: 2015247. London: PHE; August 2015. 15 World Health Organization. Pandemic Influenza Risk Management: WHO Interim Guidance WHO/HSE/HEA/HSP/2013.3. Geneva: WHO; June 2013. 16 ClinicalTrials.gov. A phase III international, randomized, double-blind, double-dummy study to evaluate the efficacy and safety of 300 mg or 600 mg of intravenous zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily in the treatment of hospitalized adults and adolescents with influenza. www.clinicaltrials.gov/ct2/show/NCT01231620 Accessed 1 November 2016. 17 Watanabe A, Yates PJ, Murayama M et al. Evaluation of safety and efficacy of intravenous zanamivir in the treatment of hospitalized Japanese patients with influenza: an open-label, single- arm study. Antiviral Therapy 2015;20(4):415-423. 18 ClinicalTrials.gov. An open-label, multi-centre, single arm study to evaluate the safety and efficacy of intravenous zanamivir in the treatment of hospitalized patients with confirmed influenza infection (NAI115215). www.clinicaltrials.gov/ct2/show/NCT01527110 Accessed 1 November 2016. 19 Marty FM, Man CY, Van der Horst C et al. Safety and of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study. The Journal of Infectious Diseases 2014;209(4):542-550. 20 Joint Formulary Committee. British National Formulary. BNF October 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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