RELENZA

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The format of this leaflet was determined by the Ministry of Health and its content was checked and approved in March

2017

Relenza

TM

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-dispensed quantity of inhalation powder (one blister) contains 5 mg zanamivir. Each

delivered inhalation (the amount that leaves the mouthpiece of the Diskhaler) contains 4.0 mg

zanamivir.

Excipients with known effect:

Lactose monohydrate (approximately 20 mg which contains milk protein).

For the full list of excipients, see section 11.

1

INDICATIONS AND USAGE

1.1

Treatment of Influenza

RELENZA is indicated for treatment of both uncomplicated acute illness due to

influenza A and B virus in adults and adolescents (> or = 12 years) who have been symptomatic

for no more than 48 hours and pediatric patients 7 years and older who have been symptomatic

for no more than 36 hours.

1.2

Important Limitations on Use of RELENZA

RELENZA is not recommended for treatment of influenza in individuals with underlying

airways disease (such as asthma or chronic obstructive pulmonary disease) due to risk of

serious bronchospasm

[see Warnings and Precautions (5.1)]

RELENZA has not been proven effective for treatment of influenza in individuals with

underlying airways disease.

Influenza viruses change over time. Emergence of resistance mutations could decrease drug

effectiveness. Other factors (for example, changes in viral virulence) might also diminish

clinical benefit of antiviral drugs. Prescribers should consider available information on

influenza drug susceptibility patterns and treatment effects when deciding whether to use

RELENZA.

There is no evidence for efficacy of zanamivir in any illness caused by agents other than

influenza virus A and B.

Patients should be advised that the use of RELENZA for treatment of influenza has not been

shown to reduce the risk of transmission of influenza to others.

2

DOSAGE AND ADMINISTRATION

2.1

Dosing Considerations

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RELENZA is for administration to the respiratory tract by

oral inhalation only,

using the

DISKHALER device provided

[see Warnings and Precautions (5.6)]

The 10-mg dose is provided by 2 inhalations (one 5-mg blister per inhalation).

Patients should be instructed in the use of the delivery system. Instructions should include a

demonstration whenever possible. If RELENZA is prescribed for children, it should be used

only under adult supervision and instruction, and the supervising adult should first be

instructed by a healthcare professional

[see Patient Counseling Information (17)].

Patients

scheduled to use an inhaled bronchodilator at the same time as RELENZA should use their

bronchodilator before taking RELENZA

[see Patient Counseling Information (17)]

2.2

Treatment of Influenza

The recommended dose of RELENZA for treatment of influenza in adults and pediatric

patients aged 7 years and older is 10 mg twice daily (approximately 12 hours apart) for

5 days.

Two doses should be taken on the first day of treatment whenever possible provided there is

at least 2 hours between doses.

On subsequent days, doses should be about 12 hours apart (e.g., morning and evening) at

approximately the same time each day.

The safety and efficacy of repeated treatment courses have not been studied.

3

DOSAGE FORMS AND STRENGTHS

Blister for oral inhalation: 5 mg. Four 5-mg blisters of powder on a ROTADISK for oral

inhalation via DISKHALER. Packaged in carton containing 5 ROTADISKs (total of 10 doses)

and 1 DISKHALER inhalation device

[see How Supplied/Storage and Handling (16)]

4

CONTRAINDICATIONS

Do not use in patients with history of allergic reaction to any ingredient of RELENZA

including milk proteins

[see Warnings and Precautions (5.2), Description (11

]

5

WARNINGS AND PRECAUTIONS

5.1

Bronchospasm

RELENZA is not recommended for treatment of influenza in individuals with underlying

airways disease (such as asthma or chronic obstructive pulmonary disease).

Serious cases of bronchospasm, including fatalities, have been reported during treatment

with RELENZA in patients with and without underlying airways disease. Many of these cases

were reported during postmarketing and causality was difficult to assess.

RELENZA should be discontinued in any patient who develops bronchospasm or decline

in respiratory function; immediate treatment and hospitalization may be required.

Some patients without prior pulmonary disease may also have respiratory abnormalities

from acute respiratory infection that could resemble adverse drug reactions or increase patient

vulnerability to adverse drug reactions.

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Bronchospasm was documented following administration of zanamivir in 1 of 13 subjects

with mild or moderate asthma (but without acute influenza-like illness) in a Phase I trial. In a

Phase III trial in subjects with acute influenza-like illness superimposed on underlying asthma or

chronic obstructive pulmonary disease, 10% (24 of 244) of subjects on zanamivir and 9% (22 of

237) on placebo experienced a greater than 20% decline in FEV

following treatment for 5 days.

If use of RELENZA is considered for a patient with underlying airways disease, the

potential risks and benefits should be carefully weighed. If a decision is made to prescribe

RELENZA for such a patient, this should be done only under conditions of careful monitoring of

respiratory function, close observation, and appropriate supportive care including availability of

fast-acting bronchodilators.

5.2

Allergic Reactions

Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and

anaphylaxis have been reported in postmarketing experience with RELENZA. RELENZA

should be stopped and appropriate treatment instituted if an allergic reaction occurs or is

suspected.

5.3

Neuropsychiatric Events

Influenza can be associated with a variety of neurologic and behavioral symptoms which

can include events such as seizures, hallucinations, delirium, and abnormal behavior, in some

cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or

encephalopathy but can occur without obvious severe disease.

There have been postmarketing reports (mostly from Japan) of delirium and abnormal

behavior leading to injury in patients with influenza who were receiving neuraminidase

inhibitors, including RELENZA. Because these events were reported voluntarily during clinical

practice, estimates of frequency cannot be made, but they appear to be uncommon based on

usage data for RELENZA. These events were reported primarily among pediatric patients and

often had an abrupt onset and rapid resolution. The contribution of RELENZA to these events

has not been established. Patients with influenza should be closely monitored for signs of

abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing

treatment should be evaluated for each patient.

5.4

Limitations of Populations Studied

Safety and efficacy have not been demonstrated in patients with high-risk underlying

medical conditions. No information is available regarding treatment of influenza in patients with

any medical condition sufficiently severe or unstable to be considered at imminent risk of

requiring inpatient management.

5.5

Bacterial Infections

Serious bacterial infections may begin with influenza-like symptoms or may coexist with

or occur as complications during the course of influenza. RELENZA has not been shown to

prevent such complications.

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Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

5.6

Importance of Proper Route of Administration

RELENZA Inhalation Powder must not be made into an extemporaneous solution for

administration by nebulization or mechanical ventilation. There have been reports of hospitalized

patients with influenza who received a solution made with RELENZA Inhalation Powder

administered by nebulization or mechanical ventilation, including a fatal case where it was

reported that the lactose in this formulation obstructed the proper functioning of the equipment.

RELENZA Inhalation Powder must only be administered using the device provided

[see Dosage

and Administration (2.1)]

5.7

Importance of Proper Use of DISKHALER

Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale

the drug. Prescribers should carefully evaluate the ability of young children to use the delivery

system if use of RELENZA is considered

[see Use in Specific Populations (8.4)].

6

ADVERSE REACTIONS

See Warnings and Precautions for information about risk of serious adverse events such

as bronchospasm

(5.1)

and allergic-like reactions

(5.2),

and for safety information in patients

with underlying airways disease

(5.1)

6.1

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction

rates observed in the clinical trials of a drug cannot be directly compared with rates in the

clinical trials of another drug and may not reflect the rates observed in practice.

The placebo used in clinical trials consisted of inhaled lactose powder, which is also the

vehicle for the active drug; therefore, some adverse events occurring at similar frequencies in

different treatment groups could be related to lactose vehicle inhalation.

Treatment of Influenza:

Clinical Trials in Adults and Adolescents:

Adverse events that

occurred with an incidence

1.5% in treatment trials are listed in Table 1. This table shows

adverse events occurring in subjects aged 12 years and older receiving RELENZA 10 mg inhaled

twice daily, RELENZA in all inhalation regimens, and placebo inhaled twice daily (where

placebo consisted of the same lactose vehicle used in RELENZA).

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Table 1. Summary of Adverse Events

1.5% Incidence During Treatment in Adults and

Adolescents

Adverse Event

RELENZA

Placebo

(Lactose Vehicle)

(n = 1,520)

10 mg b.i.d.

Inhaled

(n = 1,132)

All Dosing

Regimens

a

(n = 2,289)

Body as a whole

Headaches

Digestive

Diarrhea

Nausea

Vomiting

Respiratory

Nasal signs and symptoms

Bronchitis

Cough

Sinusitis

Ear, nose, and throat infections

Nervous system

Dizziness

<1%

Includes trials where RELENZA was administered intranasally (6.4 mg 2 to 4 times per day in

addition to inhaled preparation) and/or inhaled more frequently (q.i.d.) than the currently

recommended dose.

Additional adverse reactions occurring in less than 1.5% of subjects receiving RELENZA

included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria.

The most frequent laboratory abnormalities in Phase III treatment trials included elevations

of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar

proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness.

Clinical Trials in Pediatric Subjects:

Adverse events that occurred with an incidence

1.5% in children receiving treatment doses of RELENZA in 2 Phase III trials are listed in

Table 2. This table shows adverse events occurring in pediatric

Subjects

aged 5 to 12 years old

receiving RELENZA 10 mg inhaled twice daily and placebo inhaled twice daily (where placebo

consisted of the same lactose vehicle used in RELENZA).

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Table 2. Summary of Adverse Events

1.5% Incidence During Treatment in Pediatric

Subjects

a

Adverse Event

RELENZA

10 mg b.i.d. Inhaled

(n = 291)

Placebo

(Lactose Vehicle)

(n = 318)

Respiratory

Ear, nose, and throat infections

Ear, nose, and throat hemorrhage

<1%

Asthma

<1%

Cough

<1%

Digestive

Vomiting

Diarrhea

Nausea

<1%

Includes a subset of subjects receiving RELENZA for treatment of influenza in a prophylaxis

trial.

In 1 of the 2 trials described in Table 2, some additional information is available from

children (aged 5 to 12 years) without acute influenza-like illness who received an investigational

prophylaxis regimen of RELENZA; 132 children received RELENZA and 145 children received

placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough

(zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo

6%) were reported more frequently with RELENZA than placebo. In a subset with chronic

pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral

respiratory infections which could include influenza-like symptoms) were reported in 7 of 7

zanamivir recipients and 5 of 12 placebo recipients.

6.2

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been

identified during postmarketing use of zanamivir (RELENZA). Because they are reported

voluntarily from a population of unknown size, estimates of frequency cannot be made. These

events have been chosen for inclusion due to a combination of their seriousness, frequency of

reporting, or potential causal connection to zanamivir (RELENZA).

Allergic Reactions: Allergic or allergic-like reaction, including oropharyngeal edema

[see

Warnings and Precautions (5.2)]

Psychiatric: Delirium, including symptoms such as altered level of consciousness,

confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares

[see

Warnings and Precautions (5.3)]

Cardiac: Arrhythmias, syncope.

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Neurologic: Seizures. Vasovagal-like episodes have been reported shortly following

inhalation of zanamivir.

Respiratory: Bronchospasm, dyspnea

[see Warnings and Precautions (5.1)].

Skin: Facial edema; rash, including serious cutaneous reactions (e.g., erythema

multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis); urticaria

[see Warnings and

Precautions (5.2)]

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@m

oh.gov.il

7

DRUG INTERACTIONS

Zanamivir is not a substrate nor does it affect cytochrome P450 (CYP) isoenzymes

(CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes. No clinically

significant pharmacokinetic drug interactions are predicted based on data from in vitro studies.

The concurrent use of RELENZA with live attenuated influenza vaccine (LAIV)

intranasal has not been evaluated. However, because of potential interference between these

products, LAIV should not be administered within 2 weeks before or 48 hours after

administration of RELENZA, unless medically indicated. The concern about possible

interference arises from the potential for antiviral drugs to inhibit replication of live vaccine

virus.

Trivalent inactivated influenza vaccine can be administered at any time relative to use of

RELENZA

[see Clinical Pharmacology (12.4)]

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies of zanamivir in

pregnant women. Zanamivir should be used during pregnancy only if the potential benefit

justifies the potential risk to the fetus.

Embryo/fetal development studies were conducted in rats (dosed from days 6 to 15 of

pregnancy) and rabbits (dosed from days 7 to 19 of pregnancy) using the same IV doses (1, 9,

and 90 mg/kg/day). Pre- and post-natal developmental studies were performed in rats (dosed

from day 16 of pregnancy until litter day 21 to 23). No malformations, maternal toxicity, or

embryotoxicity were observed in pregnant rats or rabbits and their fetuses. Because of

insufficient blood sampling timepoints in rat and rabbit reproductive toxicity studies, AUC

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values were not available. In a subchronic study in rats at the 90 mg/kg/day IV dose, the AUC

values were greater than 300 times the human exposure at the proposed clinical dose.

An additional embryo/fetal study, in a different strain of rat, was conducted using

subcutaneous administration of zanamivir, 3 times daily, at doses of 1, 9, or 80 mg/kg during

days 7 to 17 of pregnancy. There was an increase in the incidence rates of a variety of minor

skeleton alterations and variants in the exposed offspring in this study. Based on AUC

measurements, the 80-mg/kg dose produced an exposure greater than 1,000 times the human

exposure at the proposed clinical dose. However, in most instances, the individual incidence rate

of each skeletal alteration or variant remained within the background rates of the historical

occurrence in the strain studied.

Zanamivir has been shown to cross the placenta in rats and rabbits. In these animals, fetal

blood concentrations of zanamivir were significantly lower than zanamivir concentrations in the

maternal blood.

8.3

Nursing Mothers

Studies in rats have demonstrated that zanamivir is excreted in milk. However, nursing

mothers should be instructed that it is not known whether zanamivir is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when RELENZA

is administered to a nursing mother.

8.4

Pediatric Use

Treatment of Influenza:

Safety and effectiveness of RELENZA for treatment of influenza

have not been assessed in pediatric patients younger than 7 years, but were studied in a Phase III

treatment trial in pediatric subjects, where 471 children aged 5 to 12 years received zanamivir or

placebo

[see Clinical Studies (14.1)]

. Adolescents were included in the 3 principal Phase III

adult treatment trials. In these trials, 67 patients were aged 12 to 16 years. No definite differences

in safety and efficacy were observed between these adolescent patients and young adults.

In a Phase I trial of 16 children aged 6 to 12 years with signs and symptoms of respiratory

disease, 4 did not produce a measurable peak inspiratory flow rate (PIFR) through the

DISKHALER (3 with no adequate inhalation on request, 1 with missing data), 9 had measurable

PIFR on each of 2 inhalations, and 3 achieved measurable PIFR on only 1 of 2 inhalations.

Neither of two 6-year-olds and one of two 7-year-olds produced measurable PIFR. Overall, 8 of

the 16 children (including all those younger than 8 years) either did not produce measurable

inspiratory flow through the DISKHALER or produced peak inspiratory flow rates below the

60 L/min considered optimal for the device under standardized in vitro testing; lack of

measurable flow rate was related to low or undetectable serum concentrations

[see Clinical

Pharmacology (12.3), Clinical Studies (14.1) ]

. Prescribers should carefully evaluate the ability

of young children to use the delivery system if prescription of RELENZA is considered.

8.5

Geriatric Use

Of the total number of subjects in 6 clinical trials of RELENZA for treatment of

influenza, 59 subjects were aged 65 years and older, while 24 subjects were aged 75 years and

older. Of the total number of subjects in 4 clinical trials of RELENZA for prophylaxis of

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influenza in households and community settings, 954 subjects were aged 65 years and older,

while 347 subjects were aged 75 years and older. No overall differences in safety or

effectiveness were observed between these subjects and younger subjects, and other reported

clinical experience has not identified differences in responses between the elderly and younger

subjects, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients

may need assistance with use of the device.

10

OVERDOSAGE

There have been no reports of overdosage from administration of RELENZA.

11

DESCRIPTION

The active component of RELENZA is zanamivir. The chemical name of zanamivir is 5-

(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-

non-2-enonic acid. It has a molecular formula of C

and a molecular weight of 332.3. It

has the following structural formula:

Zanamivir is a white to off-white powder for oral inhalation with a solubility of

approximately 18 mg/mL in water at 20

RELENZA is for administration to the respiratory tract by oral inhalation only. Each

RELENZA ROTADISK contains 4 regularly spaced double-foil blisters with each blister

containing a powder mixture of 5 mg of zanamivir and 20 mg of lactose (which contains milk

proteins). The contents of each blister are inhaled using a specially designed breath-activated

plastic device for inhaling powder called the DISKHALER. After a RELENZA ROTADISK is

loaded into the DISKHALER, a blister that contains medication is pierced and the zanamivir is

dispersed into the air stream created when the patient inhales through the mouthpiece. The

amount of drug delivered to the respiratory tract will depend on patient factors such as

inspiratory flow. Under standardized in vitro testing, RELENZA ROTADISK delivers 4 mg of

zanamivir from the DISKHALER device when tested at a pressure drop of 3 kPa (corresponding

to a flow rate of about 62 to 65 L/min) for 3 seconds.

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Zanamivir is an antiviral drug

[see Clinical Pharmacology (12.4)]

12.3

Pharmacokinetics

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Absorption and Bioavailability: Pharmacokinetic studies of orally inhaled zanamivir

indicate that approximately 4% to 17% of the inhaled dose is systemically absorbed. The peak

serum concentrations ranged from 17 to 142 ng/mL within 1 to 2 hours following a 10-mg dose.

The area under the serum concentration versus time curve (AUC

) ranged from 111 to

1,364 ng

h/mL.

Distribution: Zanamivir has limited plasma protein binding (<10%).

Metabolism: Zanamivir is renally excreted as unchanged drug. No metabolites have been

detected in humans.

Elimination: The serum half-life of zanamivir following administration by oral inhalation

ranges from 2.5 to 5.1 hours. It is excreted unchanged in the urine with excretion of a single dose

completed within 24 hours. Total clearance ranges from 2.5 to 10.9 L/h. Unabsorbed drug is

excreted in the feces.

Impaired Hepatic Function: The pharmacokinetics of zanamivir have not been studied in

patients with impaired hepatic function.

Impaired Renal Function: After a single intravenous dose of 4 mg or 2 mg of zanamivir

in volunteers with mild/moderate or severe renal impairment, respectively, significant decreases

in renal clearance (and hence total clearance: normals 5.3 L/hr, mild/moderate 2.7 L/hr, and

severe 0.8 L/hr; median values) and significant increases in half-life (normals 3.1 hr,

mild/moderate 4.7 hr, and severe 18.5 hr; median values) and systemic exposure were observed.

Safety and efficacy have not been documented in the presence of severe renal insufficiency. Due

to the low systemic bioavailability of zanamivir following oral inhalation, no dosage adjustments

are necessary in patients with renal impairment. However, the potential for drug accumulation

should be considered.

Pediatric Patients: The pharmacokinetics of zanamivir were evaluated in pediatric

subjects with signs and symptoms of respiratory illness. Sixteen subjects, aged 6 to 12 years,

received a single dose of 10 mg zanamivir dry powder via DISKHALER. Five subjectshad either

undetectable zanamivir serum concentrations or had low drug concentrations (8.32 to

10.38 ng/mL) that were not detectable after 1.5 hours. Eleven subjects had C

median values of

43 ng/mL (range: 15 to 74) and AUC

median values of 167 ng

h/mL (range: 58 to 279). Low

or undetectable serum concentrations were related to lack of measurable PIFR in individual

subjects

[see Use in Specific Populations (8.4), Clinical Studies (14.1)]

Geriatric Patients:

The pharmacokinetics of zanamivir have not been studied in subjects

older than 65 years

[see Use in Specific Populations (8.5)]

Gender, Race, and Weight: In a population pharmacokinetic analysis in patient trials, no

clinically significant differences in serum concentrations and/or pharmacokinetic parameters

(V/F, CL/F, ka, AUC

, CLr, and % excreted in urine) were observed when

demographic variables (gender, age, race, and weight) and indices of infection (laboratory

evidence of infection, overall symptoms, symptoms of upper respiratory illness, and viral titers)

were considered. There were no significant correlations between measures of systemic exposure

and safety parameters.

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12.4

Microbiology

Mechanism of Action: Zanamivir is an inhibitor of influenza virus neuraminidase

affecting release of viral particles.

Antiviral Activity: The antiviral activity of zanamivir against laboratory and clinical

isolates of influenza virus was determined in cell culture assays. The concentrations of zanamivir

required for inhibition of influenza virus were highly variable depending on the assay method

used and virus isolate tested. The 50% and 90% effective concentrations (EC

and EC

) of

zanamivir were in the range of 0.005 to 16.0

M and 0.05 to >100

M, respectively

M = 0.33 mcg/mL). The relationship between the cell culture inhibition of influenza virus by

zanamivir and the inhibition of influenza virus replication in humans has not been established.

Resistance: Influenza viruses with reduced susceptibility to zanamivir have been selected

in cell culture by multiple passages of the virus in the presence of increasing concentrations of

the drug. Genetic analysis of these viruses showed that the reduced susceptibility in cell culture

to zanamivir is associated with mutations that result in amino acid changes in the viral

neuraminidase or viral hemagglutinin or both. Resistance mutations selected in cell cultures

which result in neuraminidase amino acid substitutions include E119G/A/D and R292K.

Mutations selected in cell culture in hemagglutinin include: K68R, G75E, E114K, N145S,

S165N, S186F, N199S, and K222T.

In an immunocompromised patient infected with influenza B virus, a variant virus

emerged after treatment with an investigational nebulized solution of zanamivir for 2 weeks.

Analysis of this variant showed a hemagglutinin substitution (T198I) which resulted in a reduced

affinity for human cell receptors, and a substitution in the neuraminidase active site (R152K)

which reduced the enzyme’s activity to zanamivir by 1,000-fold. Insufficient information is

available to characterize the risk of emergence of zanamivir resistance in clinical use.

Cross-Resistance: Cross-resistance has been observed between some zanamivir-resistant

and some oseltamivir-resistant influenza virus mutants generated in cell culture. However, some

of the in cell culture zanamivir-induced resistance mutations, E119G/A/D and R292K, occurred

at the same neuraminidase amino acid positions as in the clinical isolates resistant to oseltamivir,

E119V and R292K. No trials have been performed to assess risk of emergence of

cross-resistance during clinical use.

Influenza Vaccine Interaction Trial: An interaction trial (n = 138) was conducted to

evaluate the effects of zanamivir (10 mg once daily) on the serological response to a single dose

of trivalent inactivated influenza vaccine, as measured by hemagglutination inhibition titers.

There was no difference in hemagglutination inhibition antibody titers at 2 weeks and 4 weeks

after vaccine administration between zanamivir and placebo recipients.

Influenza Challenge Trial: Antiviral activity of zanamivir was supported for infection

with influenza A virus, and to a more limited extent for infection with influenza B virus, by

Phase I trials in volunteers who received intranasal inoculations of challenge strains of influenza

virus, and received an intranasal formulation of zanamivir or placebo starting before or shortly

after viral inoculation.

Page 13 of 14

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: In 2-year carcinogenicity studies conducted in rats and mice using a

powder formulation administered through inhalation, zanamivir induced no statistically

significant increases in tumors over controls. The maximum daily exposures in rats and mice

were approximately 23 to 25 and 20 to 22 times, respectively, greater than those in humans at the

proposed clinical dose based on AUC comparisons.

Mutagenesis: Zanamivir was not mutagenic in in vitro and in vivo genotoxicity assays

which included bacterial mutation assays in

S. typhimurium

E. coli

, mammalian mutation

assays in mouse lymphoma, chromosomal aberration assays in human peripheral blood

lymphocytes, and the in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility: The effects of zanamivir on fertility and general reproductive

performance were investigated in male (dosed for 10 weeks prior to mating, and throughout

mating, gestation/lactation, and shortly after weaning) and female rats (dosed for 3 weeks prior

to mating through Day 19 of pregnancy, or Day 21 post partum) at IV doses 1, 9, and

90 mg/kg/day. Zanamivir did not impair mating or fertility of male or female rats, and did not

affect the sperm of treated male rats. The reproductive performance of the F1 generation born to

female rats given zanamivir was not affected. Based on a subchronic study in rats at a

90 mg/kg/day IV dose, AUC values ranged between 142 and 199 mcg

h/mL (>300 times the

human exposure at the proposed clinical dose).

14

CLINICAL STUDIES

14.1

Treatment of Influenza

Adults and Adolescents: The efficacy of RELENZA 10 mg inhaled twice daily for 5 days

in the treatment of influenza has been evaluated in placebo-controlled trials conducted in North

America, the Southern Hemisphere, and Europe during their respective influenza seasons. The

magnitude of treatment effect varied between trials, with possible relationships to

population-related factors including amount of symptomatic relief medication used.

Populations Studied:

The principal Phase III trials enrolled 1,588 subjects aged

12 years and older (median age 34 years, 49% male, 91% Caucasian), with uncomplicated

influenza-like illness within 2 days of symptom onset. Influenza was confirmed by culture,

hemagglutination inhibition antibodies, or investigational direct tests. Of 1,164 subjects with

confirmed influenza, 89% had influenza A and 11% had influenza B. These trials served as the

principal basis for efficacy evaluation, with more limited Phase II studies providing supporting

information where necessary. Following randomization to either zanamivir or placebo (inhaled

lactose vehicle), all subjects received instruction and supervision by a healthcare professional for

the initial dose.

Principal Results:

The definition of time to improvement in major symptoms of

influenza included no fever and self-assessment of “none” or “mild” for headache, myalgia,

cough, and sore throat. A Phase II and a Phase III trial conducted in North America (total of over

Page 14 of 14

600 influenza-positive subjects) suggested up to 1 day of shortening of median time to this

defined improvement in symptoms in subjects receiving zanamivir compared with placebo,

although statistical significance was not reached in either of these trials. In a trial conducted in

the Southern Hemisphere (321 influenza-positive subjects), a 1.5-day difference in median time

to symptom improvement was observed. Additional evidence of efficacy was provided by the

European trial.

Other Findings:

There was no consistent difference in treatment effect in subjects with

influenza A compared with influenza B; however, these trials enrolled smaller numbers of

subjects with influenza B and thus provided less evidence in support of efficacy in influenza B.

In general, subjects with lower temperature (e.g., 38.2

C or less) or investigator-rated as

having less severe symptoms at entry derived less benefit from therapy.

No consistent treatment effect was demonstrated in subjectswith underlying chronic

medical conditions, including respiratory or cardiovascular disease

[see Warnings and

Precautions (5.4)]

No consistent differences in rate of development of complications were observed

between treatment groups.

Some fluctuation of symptoms was observed after the primary trial endpoint in both

treatment groups.

Pediatric Patients: The efficacy of RELENZA 10 mg inhaled twice daily for 5 days in the

treatment of influenza in pediatric patients has been evaluated in a placebo-controlled trial

conducted in North America and Europe, enrolling 471 subjects, aged 5 to 12 years (55% male,

90% Caucasian), within 36 hours of symptom onset. Of 346 subjects with confirmed influenza,

65% had influenza A and 35% had influenza B. The definition of time to improvement included

no fever and parental assessment of no or mild cough and absent/minimal muscle and joint aches

or pains, sore throat, chills/feverishness, and headache. Median time to symptom improvement

was 1 day shorter in subjects receiving zanamivir compared with placebo. No consistent

differences in rate of development of complications were observed between treatment groups.

Some fluctuation of symptoms was observed after the primary trial endpoint in both treatment

groups.

Although this trial was designed to enroll children aged 5 to 12 years, the product is indicated

only for children aged 7 years and older. This evaluation is based on the combination of lower

estimates of treatment effect in 5- and 6-year-olds compared with the overall trial population,

and evidence of inadequate inhalation through the DISKHALER in a pharmacokinetic trial

[see

Use in Specific Populations (8.4), Clinical Pharmacology (12.3)]

6

HOW SUPPLIED/STORAGE AND HANDLING

RELENZA is supplied in a circular double-foil pack (a ROTADISK) containing 4 blisters

of the drug. Five ROTADISKs are packaged in a white polypropylene tube. The tube is

packaged in a carton with 1 blue and gray DISKHALER inhalation device (NDC 0173-0681-01).

Store below 30

Keep out of reach of children. Do not puncture any RELENZA

ROTADISK blister until taking a dose using the DISKHALER.

Page 15 of 14

Shelf life

The expiry date of the product is indicated on the label and packaging.

Manufacturer

Glaxo Wellcome Production, Marly-Le-Roi, France.

GlaxoSmithKline Australia PTY Ltd., Boronia, Australia.

Licence Holder

GlaxoSmithKline (Israel) Ltd., 25 Bazel St., Petach Tikva.

Licence Number

116-29-29741

Relz DR v2