relenza
Generic Name: (
zanamivir)
Dosage Type: powder Organization: GlaxoSmithKline
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 C12
H20
N4
O7
and
a molecular weight of 332.3. It has the following structural formula:
Zanamivir
is a white to off-white powder with a solubility of approximately 18 mg/mL
in water at 20°C.
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. In a study of 5 adult and 5 adolescent patients
with obstructive airway diseases, the combined peak inspiratory flow rates
(PIFR) ranged from 66 to 140 L/min. In a separate study of 16 pediatric
patients, PIFR results were more variable; 4 did not achieve measurable flow
rates, and PIFR for measurable inhalations by 12 children ranged from
30.5 to 122.4 L/min. Only 1 of 4 children under age 8 had a measurable flow
rate (see CLINICAL PHARMACOLOGY: Pediatric Patients, INDICATIONS AND USAGE:
Description of Clinical Studies, and PRECAUTIONS: Pediatric Use).
MICROBIOLOGY
Mechanism of Action
The mechanism of action of zanamivir is via inhibition of
influenza virus neuraminidase with the possibility of alteration of virus
particle aggregation and release.
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 (EC50
and EC90
)
of zanamivir were in the range of 0.005 to 16.0 µM and 0.05 to
>100 µM, respectively (1 µM = 0.33 mcg/mL).
The relationship between the in vitro 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 recovered in vitro 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 vitro 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 vitro
which result in neuraminidase amino acid substitutions include E119G/A/D and
R292K.Mutations selected in vitro 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 mutation
(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 vitro.
However, some of the in vitro 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
studies have been performed to assess risk of emergence of cross-resistance
during clinical use.
Influenza Vaccine Interaction Study
An interaction study (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 clear difference in hemagglutination
inhibition antibody titers at 2 weeks and 4 weeks after vaccine
administration between zanamivir and placebo recipients.
Influenza Challenge Studies
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 1 studies 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.
CLINICAL PHARMACOLOGY
Pharmacokinetics
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 (AUC8)
ranged from 111 to 1,364 ng•hr/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/hr. Unabsorbed drug is excreted
in the feces.
Special Populations
Impaired Hepatic Function
The pharmacokinetics of zanamivir have not been studied in
patients with impaired hepatic function.
Impaired Renal Function
Systemic exposure
is limited after inhalation (see Absorption and Bioavailability). 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.
Pediatric Patients
The pharmacokinetics of zanamivir were evaluated in pediatric
patients with signs and symptoms of respiratory illness. Sixteen patients,
6 to 12 years of age, received a single dose of 10-mg zanamivir dry powder
via DISKHALER. Five patients had 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 patients had Cmax
median values of
43 ng/mL (range 15 to 74) and AUC8 median values of 167 ng•hr/mL
(range 58 to 279). Low or undetectable serum concentrations were related to
lack of measurable PIFR in individual patients (see DESCRIPTION, INDICATIONS
AND USAGE: Description of Clinical Studies, and PRECAUTIONS: Pediatric Use).
Geriatric Patients
The pharmacokinetics
of zanamivir have not been studied in patients over 65 years of age (see
PRECAUTIONS: Geriatric Use).
Gender, Race, and Weight
In a population pharmacokinetic analysis in patient studies,
no clinically significant differences in serum concentrations and/or pharmacokinetic
parameters (V/F, CL/F, ka, AUC0-3
, Cmax
, Tmax
,
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.
Drug Interactions
No clinically significant
pharmacokinetic drug interactions are predicted based on data from in vitro
studies.
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.
INDICATIONS AND USAGE
Treatment of Influenza
RELENZA is indicated for treatment of uncomplicated acute
illness due to influenza A and B virus in adults and pediatric patients 7 years
of age and older who have been symptomatic for no more than 2 days (see
Description of Clinical Studies and PRECAUTIONS).
Prophylaxis of Influenza
RELENZA is indicated in adults and pediatric patients 5 years
of age and older for prophylaxis of influenza.
Important Information on Use of RELENZA
- RELENZA is not recommended for treatment or prophylaxis of influenza
in individuals with underlying airways disease (such as asthma or chronic
obstructive pulmonary disease [see WARNINGS]) due to risk of serious bronchospasm.
- RELENZA has not been proven effective for treatment of influenza in
individuals with underlying airways disease.
- RELENZA has not been proven effective for prophylaxis of influenza in
the nursing home setting.
- RELENZA is not a substitute for early vaccination on an annual basis
as recommended by the Centers for Disease Control's Immunization Practices
Advisory Committee.
Description of Clinical Studies
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 studies conducted in North America,
the Southern Hemisphere, and Europe during their respective influenza seasons.
The magnitude of treatment effect varied between studies, with possible relationships
to population-related factors including amount of symptomatic relief medication
used.
Populations Studied
The principal Phase 3
studies enrolled 1,588 patients ages 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 patients with confirmed influenza, 89% had influenza A and 11%
had influenza B. These studies served as the principal basis for efficacy
evaluation, with more limited Phase 2 studies providing supporting information
where necessary. Following randomization to either zanamivir or placebo (inhaled
lactose vehicle), all patients 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 2 and a Phase 3 study conducted in North America
(total of over 600 influenza-positive patients) suggested up to one day
of shortening of median time to this defined improvement in symptoms in patients
receiving zanamivir compared to placebo, although statistical significance
was not reached in either of these studies. In a study conducted in the Southern
Hemisphere (321 influenza-positive patients), a 1.5-day difference in
median time to symptom improvement was observed. Additional evidence of efficacy
was provided by the European study.
Other Findings
There was no
consistent difference in treatment effect in patients with influenza A compared
to influenza B; however, these trials enrolled smaller numbers of patients
with influenza B and thus provided less evidence in support of efficacy in
influenza B.
In general, patients 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 patients with underlying chronic medical
conditions, including respiratory or cardiovascular disease (see WARNINGS
and PRECAUTIONS).
No consistent differences in rate
of development of complications were observed between treatment groups.
Some
fluctuation of symptoms was observed after the primary study 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 study conducted in North America and Europe, enrolling
471 patients, ages 5 to 12 years (55% male, 90% Caucasian), within
36 hours of symptom onset. Of 346 patients 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 one day shorter in patients 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 study endpoint in both treatment
groups.
Although this study was designed to enroll
children ages 5 to 12 years, the product is indicated only for children
7 years of age 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 study population, and evidence of inadequate inhalation through
the DISKHALER in a pharmacokinetic study (see DESCRIPTION, CLINICAL PHARMACOLOGY:
Pediatric Patients, and PRECAUTIONS: Pediatric Use).
Prophylaxis of Influenza
The efficacy
of RELENZA in preventing naturally occurring influenza illness has been demonstrated
in 2 post-exposure prophylaxis studies in households and 2 seasonal
prophylaxis studies during community outbreaks of influenza. The primary efficacy
endpoint in these studies was the incidence of symptomatic, laboratory-confirmed
influenza, defined as the presence of 2 or more of the following symptoms:
oral temperature =100°F/37.8°C or feverishness, cough, headache,
sore throat, and myalgia; and laboratory confirmation of influenza A or B
by culture, PCR, or seroconversion (defined as a 4-fold increase in convalescent
antibody titer from baseline).
Two studies assessed
post-exposure prophylaxis in household contacts of an index case. Within 1.5 days
of onset of symptoms in an index case, each household (including all family
members =5 years of age) was randomized to RELENZA 10 mg
inhaled once daily or placebo inhaled once daily for 10 days. In the
first study only, each index case was randomized to RELENZA 10 mg inhaled
twice daily for 5 days or inhaled placebo twice daily for 5 days.
In this study, the proportion of households with at least 1 new case
of symptomatic laboratory-confirmed influenza was reduced from 19.0% (32 of
168 households) for the placebo group to 4.1% (7 of 169 households)
for the group receiving RELENZA.
In the second study,
index cases were not treated. The incidence of symptomatic laboratory-confirmed
influenza was reduced from 19.0% (46 of 242 households) for the placebo
group to 4.1% (10 of 245 households) for the group receiving RELENZA.
Two
seasonal prophylaxis studies assessed RELENZA 10 mg inhaled once daily
versus placebo inhaled once daily for 28 days during community outbreaks.
The first study enrolled subjects 18 years of age or greater (mean age
29 years) from two university communities. The majority of subjects were
unvaccinated (86%). In this study, the incidence of symptomatic laboratory-confirmed
influenza was reduced from 6.1% (34 of 554) for the placebo group to 2.0%
(11 of 553) for the group receiving RELENZA.
The second
seasonal prophylaxis study enrolled subjects 12 to 94 years of age (mean
age 60 years) with 56% of them older than 65 years of age. Sixty-seven
percent of the subjects were vaccinated. In this study, the incidence of symptomatic
laboratory-confirmed influenza was reduced from 1.4% (23 of 1,685) for the
placebo group to 0.2% (4 of 1,678) for the group receiving RELENZA.
CONTRAINDICATIONS
RELENZA is contraindicated
in patients with a known hypersensitivity to any component of the formulation
(see DESCRIPTION).
WARNINGS
RELENZA IS NOT RECOMMENDED FOR
TREATMENT OR PROPHYLAXIS OF INFLUENZA IN INDIVIDUALS WITH UNDERLYING AIRWAYS
DISEASE (SUCH AS ASTHMA OR CHRONIC OBSTRUCTIVE PULMONARY DISEASE) (see INDICATIONS
AND USAGE).
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.
Bronchospasm
was documented following administration of zanamivir in 1 of 13 patients
with mild or moderate asthma (but without acute influenza-like illness) in
a Phase 1 study. In interim results from an ongoing treatment study in patients
with acute influenza-like illness superimposed on underlying asthma or chronic
obstructive pulmonary disease, more patients on zanamivir than on placebo
experienced greater than 20% decline in FEV1
or peak expiratory
flow rate.
If treatment with 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.
PRECAUTIONS
General
Patients should be instructed
in the use of the delivery system. Instructions should include a demonstration
whenever possible.
Patients should read and follow carefully the
Patient Instructions for Use accompanying the product. Effective and safe
use of RELENZA requires proper use of the DISKHALER to inhale the drug.
There
is no evidence for efficacy of zanamivir in any illness caused by agents other
than influenza virus A and B.
No data are available
to support safety or efficacy in patients who begin treatment after 48 hours
of symptoms.
Safety and efficacy of repeated treatment
courses have not been studied.
Allergic Reactions
Allergic-like reactions, including oropharyngeal edema,
serious skin rashes, and anaphylaxis have been reported in post-marketing
experience with RELENZA. RELENZA should be stopped and appropriate treatment
instituted if an allergic reaction occurs or is suspected.
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.
Prevention of Influenza
Use of zanamivir should not affect the evaluation of individuals
for annual influenza vaccination in accordance with guidelines of the Centers
for Disease Control and Prevention Advisory Committee on Immunization Practices.
Limitations of Populations Studied
Safety and efficacy have not been
demonstrated in patients with high-risk underlying medical conditions (see
INDICATIONS AND USAGE: Description of Clinical Studies, and WARNINGS). 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.
Information for Patients
Patients should be instructed in use of the delivery system.
Instructions should include a demonstration whenever possible.
For
the proper use of RELENZA, the patient should read and follow carefully the
accompanying Patient Instructions for Use.
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.
Patients should be advised of the risk of bronchospasm, especially
in the setting of underlying airways disease, and should stop RELENZA and
contact their physician if they experience increased respiratory symptoms
during treatment such as worsening wheezing, shortness of breath, or other
signs or symptoms of bronchospasm (see WARNINGS). If a decision is made to
prescribe RELENZA for a patient with asthma or chronic obstructive pulmonary
disease, the patient should be made aware of the risks and should have a fast-acting
bronchodilator available.
Patients scheduled to take inhaled bronchodilators
at the same time as RELENZA should be advised to use their bronchodilators
before taking RELENZA.
Drug Interactions
No clinically significant
pharmacokinetic drug interactions are predicted based on data from in vitro
studies.
Carcinogenesis, Mutagenesis, and 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
and 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•hr/mL (>300 times
the human exposure at the proposed clinical dose).
Pregnancy
Pregnancy Category C.
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. Pre- and post-natal developmental studies were performed
in rats (dosed from day 16 of pregnancy until litter day 21 to 23). In all
studies, intravenous (1, 9, and 90 mg/kg/day) instead of the inhalational
route of drug administration was used. No malformations, maternal toxicity,
or embryotoxicity were observed in pregnant rats or rabbits and their fetuses.
Because of insufficient blood sampling timepoints in both rat and rabbit reproductive
toxicity studies, AUC values were not available. However, 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 high
dose in the study produced an exposure greater than 1,000 times the human
exposure at the proposed clinical dose. However, the individual incidence
rate of each skeletal alteration or variant, in most instances, 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.
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.
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.
Pediatric Use
Safety and effectiveness
of RELENZA for treatment of influenza have not been assessed in pediatric
patients less than 7 years of age.
The safety
and effectiveness of RELENZA have been studied in a Phase 3 treatment study
in pediatric patients, where 471 children 5 to 12 years of age received
zanamivir or placebo (see INDICATIONS AND USAGE: Description of Clinical Studies,
ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). In a Phase 1 study of 16 children
ages 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 under 8 years old) 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 DESCRIPTION, CLINICAL PHARMACOLOGY: Pediatric Patients,
and INDICATIONS AND USAGE: Description of Clinical Studies). Prescribers should
carefully evaluate the ability of young children to use the delivery system
if prescription of RELENZA is considered. When RELENZA is prescribed for children,
it should be used only under adult supervision and with attention to proper
use of the delivery system.
Adolescents were included
in the three principal Phase 3 adult treatment studies. In these studies,
67 patients were 12 to 16 years of age. No definite differences
in safety and efficacy were observed between these adolescent patients and
young adults.
In addition, the safety and effectiveness
of RELENZA for prophylaxis of influenza have been studied in four Phase 3
studies where 273 children 5 to 11 years of age and 239 adolescents
12 to 16 years of age received RELENZA. No differences in safety and
effectiveness were observed between pediatric and adult subjects.
Geriatric Use
Of the total number of patients in 6 clinical studies
of RELENZA for treatment of influenza, 59 were 65 and over, while 24 were
75 and over. Of the total number of patients in 4 clinical studies
of RELENZA for prophylaxis of influenza in households and community settings,
954 were 65 and over, while 347 were 75 and over. No overall differences in
safety or effectiveness were observed between these subjects and younger patients,
and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some
older individuals cannot be ruled out.
In 2 additional
studies of RELENZA for prophylaxis of influenza in the nursing home setting,
efficacy was not demonstrated (see INDICATIONS AND USAGE). Elderly subjects
may need assistance with use of the device.
ADVERSE REACTIONS
See WARNINGS and PRECAUTIONS for
information about risk of serious adverse events such as bronchospasm and
allergic-like reactions, and for safety information in patients with underlying
airways disease.
Because the placebo consisted of inhaled lactose powder, which is
also the vehicle for the active drug, 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 studies are listed in Table 1.
This table shows adverse events occurring in patients =12 years
of age 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).
Table
1. Summary of Adverse Events =1.5% Incidence During Treatment in Adults
and Adolescents
|
|
RELENZA
|
|
|
Adverse Event
|
10 mg b.i.d. Inhaled
(n = 1,132)
|
All Dosing Regimens*
(n = 2,289)
|
Placebo
(Lactose
Vehicle)
(n = 1,520)
|
|
Body as a whole
|
|
|
|
|
Headaches
|
2%
|
2%
|
3%
|
|
Digestive
|
|
|
|
|
Diarrhea
|
3%
|
3%
|
4%
|
|
Nausea
|
3%
|
3%
|
3%
|
|
Vomiting
|
1%
|
1%
|
2%
|
|
Respiratory
|
|
|
|
|
Nasal signs and symptoms
|
2%
|
3%
|
3%
|
|
Bronchitis
|
2%
|
2%
|
3%
|
|
Cough
|
2%
|
2%
|
3%
|
|
Sinusitis
|
3%
|
2%
|
2%
|
|
Ear, nose, and throat infections
|
2%
|
1%
|
2%
|
|
Nervous system
|
|
|
|
|
Dizziness
|
2%
|
1%
|
<1%
|
Additional adverse
reactions occurring in less than 1.5% of patients receiving RELENZA included
malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria.
The
most frequent laboratory abnormalities in Phase 3 treatment studies 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 Patients
Adverse events that occurred with an incidence =1.5%
in children receiving treatment doses of RELENZA in two Phase 3 studies are
listed in Table 2. This table shows adverse events occurring in pediatric
patients 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).
|
Adverse Event
|
RELENZA
10 mg
b.i.d. Inhaled
(n = 291)
|
Placebo
(Lactose
Vehicle)
(n = 318)
|
|
Respiratory
|
|
|
|
Ear, nose, and throat infections
|
5%
|
5%
|
|
Ear, nose, and throat hemorrhage
|
<1%
|
2%
|
|
Asthma
|
<1%
|
2%
|
|
Cough
|
<1%
|
2%
|
|
Digestive
|
|
|
|
Vomiting
|
2%
|
3%
|
|
Diarrhea
|
2%
|
2%
|
|
Nausea
|
<1%
|
2%
|
In
1 of the 2 studies described in Table 2, some additional information
is available from children (5 to 12 years old) 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.
Prophylaxis of Influenza
Family/Household Prophylaxis Studies
Adverse events that occurred with an incidence of =1.5%
in the 2 prophylaxis studies are listed in Table 3. This table shows adverse
events occurring in patients =5 years of age receiving RELENZA
10 mg inhaled once daily for 10 days.
Table 3. Summary of Adverse Events =1.5% Incidence During
10-Day Prophylaxis Studies in Adults, Adolescents, and Children*
|
|
Contact Cases
|
|
Adverse Event
|
RELENZA
(n = 1,068)
|
Placebo
(n = 1,059)
|
|
Lower respiratory
|
|
|
|
Viral respiratory infections
|
13%
|
19%
|
|
Cough
|
7%
|
9%
|
|
Neurologic
|
|
|
|
Headaches
|
13%
|
14%
|
|
Ear, nose, and throat
|
|
|
|
Nasal signs and symptoms
|
12%
|
12%
|
|
Throat and tonsil discomfort and pain
|
8%
|
9%
|
|
Nasal inflammation
|
1%
|
2%
|
|
Musculoskeletal
|
|
|
|
Muscle pain
|
3%
|
3%
|
|
Endocrine and metabolic
|
|
|
|
Feeding problems (decreased or increased appetite
and anorexia)
|
2%
|
2%
|
|
Gastrointestinal
|
|
|
|
Nausea and vomiting
|
1%
|
2%
|
|
Non-site specific
|
|
|
|
Malaise and fatigue
|
5%
|
5%
|
|
Temperature regulation disturbances (fever and/or
chills)
|
5%
|
4%
|
Community Prophylaxis Studies
Adverse events that occurred with an incidence of =1.5%
in 2 prophylaxis studies are listed in Table 4. This table shows adverse events
occurring in patients =5 years of age receiving RELENZA 10 mg
inhaled once daily for 28 days.
Table
4. Summary of Adverse Events =1.5% Incidence During 28-Day Prophylaxis
Studies in Adults, Adolescents, and Children*
|
Adverse Event
|
RELENZA
(n = 2,231)
|
Placebo
(n = 2,239)
|
|
Neurologic
|
|
|
|
Headaches
|
24%
|
26%
|
|
Ear, nose, and throat
|
|
|
|
Throat and tonsil discomfort and pain
|
19%
|
20%
|
|
Nasal signs and symptoms
|
12%
|
13%
|
|
Ear, nose, and throat infections
|
2%
|
2%
|
|
Lower respiratory
|
|
|
|
Cough
|
17%
|
18%
|
|
Viral respiratory infections
|
3%
|
4%
|
|
Musculoskeletal
|
|
|
|
Muscle pain
|
8%
|
8%
|
|
Musculoskeletal pain
|
6%
|
6%
|
|
Arthralgia and articular rheumatism
|
2%
|
<1%
|
|
Endocrine and metabolic
|
|
|
|
Feeding problems (decreased or increased appetite
and anorexia)
|
4%
|
4%
|
|
Gastrointestinal
|
|
|
|
Nausea and vomiting
|
2%
|
3%
|
|
Diarrhea
|
2%
|
2%
|
|
Non-site specific
|
|
|
|
Temperature regulation disturbances (fever and/or
chills)
|
9%
|
10%
|
|
Malaise & fatigue
|
8%
|
8%
|
Observed During Clinical Practice
In addition to adverse events reported from clinical trials,
the following events have been identified during post-marketing 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).
General
Allergic or allergic-like reaction, including oropharyngeal
edema (see PRECAUTIONS).
Cardiac
Arrhythmias, syncope.
Neurologic
Seizures.
Respiratory
Bronchospasm, dyspnea (see WARNINGS and PRECAUTIONS).
Skin
Facial edema; rash, including serious cutaneous reactions
(see PRECAUTIONS).
OVERDOSAGE
There have been no reports of overdosage from administration
of RELENZA. Doses of zanamivir up to 64 mg/day have been administeredby nebulizer. Additionally, doses of up to 1,200 mg/day for 5 days
have been administered intravenously. Adverse effects were similar to those
seen in clinical studies at the recommended dose.
DOSAGE AND ADMINISTRATION
RELENZA is for administration to the respiratory tract by
oral inhalation only, using the DISKHALER device provided. 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 PRECAUTIONS).
Patients scheduled to use an inhaled bronchodilator
at the same time as RELENZA should use their bronchodilator before taking
RELENZA (see WARNINGS and PRECAUTIONS regarding patients with underlying airways
disease and other medical conditions).
Treatment
The recommended dose of RELENZA for treatment of influenza
in adults and pediatric patients ages 7 years of age and older is 2 inhalations
(one 5-mg blister per inhalation for a total dose of 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.
There are no data on the effectiveness of treatment with RELENZA when initiated
more than 2 days after the onset of signs or symptoms.
Prophylaxis
Household Setting
The recommended dose of RELENZA for prophylaxis of influenza
in adults and pediatric patients 5 years of age and older in a household
setting is 10 mg once daily for 10 days. The 10-mg dose is provided
by 2 inhalations (one 5-mg blister per inhalation). The dose should be
administered at approximately the same time each day. There are no data on
the effectiveness of prophylaxis with RELENZA in a household setting when
initiated more than 1.5 days after the onset of signs or symptoms in
the index case.
Community Outbreaks
The recommended dose of RELENZA for prophylaxis of influenza
in adults and adolescents in a community setting is 10 mg once daily
for 28 days. The 10-mg dose is provided by 2 inhalations (one 5-mg
blister per inhalation). The dose should be administered at approximately
the same time each day. There are no data on the effectiveness of prophylaxis
with RELENZA in a community outbreak when initiated more than 5 days
after the outbreak was identified in the community. The safety and effectiveness
of prophylaxis with RELENZA have not been evaluated for longer than 28 days
duration.
HOW SUPPLIED
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
at 25°C (77°F); excursions permitted to 15° to 30°C (59°
to 86°F) (see USP Controlled Room Temperature).
Keep out of
reach of children. Do not puncture any RELENZA ROTADISK blister until taking
a dose using the DISKHALER.
GlaxoSmithKline
Research
Triangle Park, NC 27709
©2006, GlaxoSmithKline.
All rights reserved.
March 2006 RL-2270
PATIENT INFORMATION ABOUT
RELENZA®
(zanamivir
for inhalation)
This leaflet contains important
patient information about RELENZA (zanamivir for inhalation), and should be
read completely before beginning treatment. It does not, however, take the
place of discussions with your healthcare provider about your medical condition
or your treatment. This summary does not list all benefits and risks of RELENZA.
The medication described here can only be prescribed and dispensed by a licensed
healthcare provider, who has information about your medical condition and
more information about the drug, including how to take it, what to expect,
and potential side effects. If you have any questions about RELENZA, talk
with your healthcare provider.
What
is RELENZA?
RELENZA (ruh-LENS-uh) is a medicine
for the treatment of influenza (flu, infection caused by influenza virus)
and for reducing the chance of getting the flu in community and household
settings. It belongs to a group of medicines called neuraminidase inhibitors.
These medications attack the influenza virus and prevent it from spreading
inside your body. RELENZA treats the cause of influenza at its source, rather
than simply masking the symptoms.
Important
Safety Information About RELENZA
Some patients
have had bronchospasm (wheezing) or serious breathing problems when they used
RELENZA. Many but not all of these patients had previous asthma or chronic
obstructive pulmonary disease. RELENZA has not been shown to shorten the duration
of influenza in people with these diseases. Because of the risk of side effects
and because it has not been shown to help them, RELENZA is not recommended
for people with chronic respiratory disease such as asthma or chronic obstructive
pulmonary disease.
If you develop worsening respiratory
symptoms such as wheezing or shortness of breath, stop using RELENZA and contact
your healthcare provider right away.
If you have chronic
respiratory disease such as asthma and chronic obstructive pulmonary disease
and your healthcare provider has prescribed RELENZA, you should have a fast-acting,
inhaled bronchodilator available for your use. If you are scheduled to use
an inhaled bronchodilator at the same time as RELENZA, use the inhaled bronchodilator before
using RELENZA.
Read
the rest of this leaflet for more information about side effects and risks.
Other
kinds of infections can appear like influenza or occur along with influenza,
and need different kinds of treatment. Contact your healthcare provider if
you feel worse or develop new symptoms during or after treatment, or if your
influenza symptoms do not start to get better.
Who should not take RELENZA?
RELENZA
is not recommended for people who have chronic lung disease such as asthma
or chronic obstructive pulmonary disease. RELENZA has not been shown to shorten
the duration of influenza in people with these diseases, and some people have
had serious side effects of bronchospasm and worsening lung function. (See
the section of this Patient Information entitled “Important
Safety Information About RELENZA.”)
You
should not take RELENZA if you are allergic to zanamivir or any other ingredient
of RELENZA. Also tell your healthcare provider if you have any type of chronic
condition including lung or heart disease, if you are allergic to any other
medicines or food products, or if you are pregnant.
RELENZA
was not effective in reducing the chance of getting the flu in in 2 studies
in nursing home patients.
RELENZA does not treat flu-like
illness that is not caused by influenza virus.
Who should consider taking RELENZA?
Adult
and pediatric patients at least 7 years of age who have influenza symptoms
that appeared within the previous day or two. Typical symptoms of influenza
include sudden onset of fever, cough, headache, fatigue, muscular weakness,
and sore throat.
RELENZA can also help reduce the chance
of getting the flu in adults and children at least 5 years of age who have
a higher chance of getting the flu because they spend time with someone who
has the flu. RELENZA can also reduce the chance of getting the flu if there
is a flu outbreak in the community.
The use of RELENZA
for the treatment of flu has not been shown to reduce the risk of spreading
the virus to others.
Can I take other medications with RELENZA?
RELENZA
has been shown to have an acceptable safety profile when used as labeled,
with minimal risk of drug interactions. Your healthcare provider may recommend
taking other medications, including over-the-counter medications, to reduce
fever or other symptoms while you are taking RELENZA. Before starting treatment,
make sure that your healthcare provider knows if you are taking other medicines.
If you are scheduled to use an inhaled bronchodilator at the same time as
RELENZA, you should use the inhaled bronchodilator before
using RELENZA.
How
and when should I take RELENZA?
RELENZA is
packaged in medicine disks called ROTADISKS® and is inhaled by mouth
using a delivery device called a DISKHALER®. Each ROTADISK contains 4 blisters.
Each blister contains 5 mg of active drug and 20 mg of lactose powder
(which contains milk proteins).
You should receive
a demonstration on how to use RELENZA in the DISKHALER from a healthcare provider.
Before taking RELENZA, read the “Patient Instructions for Use.”
Make sure that you understand these instructions and talk to your healthcare
provider if you have any questions. Children who use RELENZA should always
be supervised by an adult who understands how to use RELENZA. Proper use of
the DISKHALER to inhale the drug is necessary for safe and effective use of
RELENZA.
If you have the flu the usual dose for treatment
is 2 inhalations of RELENZA (1 blister per inhalation) twice daily
(in the morning and evening) for 5 days. It is important that you begin
your treatment with RELENZA as soon as possible from the first appearance
of your flu symptoms. Take 2 doses on the first day of treatment whenever
possible if there are at least 2 hours between doses.
To
reduce the chance of getting the flu, the usual dose is 2 inhalations
of RELENZA (1 blister per inhalation) once daily for 10 or 28 days
as prescribed by your healthcare provider.
Never share
RELENZA with anyone, even if they have the same symptoms. If you feel worse
or develop new symptoms during treatment with RELENZA, or if your flu symptoms
do not start to get better, stop using the medicine and contact your healthcare
provider.
What if I miss a
dose?
If you forget to take your medicine
at any time, take the missed dose as soon as you remember, except if it is
near the next dose (within 2 hours). Then continue to take RELENZA at
the usual times. You do not need to take a double dose. If you have missed
several doses, inform your healthcare provider and follow the advice given
to you.
What are important
or common possible side effects of taking RELENZA?
Some
patients have had breathing problems while taking RELENZA. This can be very
serious and need treatment right away. Most of the patients who had this problem
had asthma or chronic obstructive pulmonary disease, but some did not. If
you have trouble breathing or have wheezing after your dose of RELENZA, stop
taking RELENZA and get medical attention.
In studies,
the most common side effects with RELENZA have been headaches; diarrhea; nausea;
vomiting; nasal irritation; bronchitis; cough; sinusitis; ear, nose, and throat
infections; and dizziness. Other side effects that have been reported, but
were not as common, include rashes and allergic reactions, some of which were
severe.
This list of side effects is not complete.
Your healthcare provider or pharmacist can discuss with you a more complete
list of possible side effects with RELENZA. Talk to your healthcare provider
promptly about any side effects you have.
Please refer
to the section entitled "Important Safety Information
About RELENZA"
for additional information.
Should I get a flu shot?
RELENZA
is not a substitute for a flu shot. You should receive an annual flu shot
according to guidelines on immunization practices that your healthcare provider
can share with you.
What if
I am pregnant or nursing?
If you are pregnant
or planning to become pregnant while taking RELENZA, talk to your healthcare
provider before taking this medication. RELENZA is normally not recommended
for use during pregnancy or nursing, as the effects on the unborn child or
nursing infant are unknown.
How
and where should I store RELENZA?
RELENZA
should be stored at room temperature below 77°F (25°C). RELENZA
is not in a childproof container. Keep RELENZA out of the reach of children.
Discard the DISKHALER after finishing your treatment.
PATIENT INSTRUCTIONS FOR USE
RELENZA®
(zanamivir
for inhalation)
IMPORTANT:
Read Step-by-Step Instructions
before
using the DISKHALER®.
Be
sure to take the dose your healthcare provider has prescribed.
BEFORE YOU START:
Please read the entire Patient Information for important
information about the effects of RELENZA including the section “Important Safety Information About RELENZA” for information about the risk of breathing difficulties.
If RELENZA is
prescribed for a child, dosing should be supervised by an adult who understands
how to use RELENZA and has been instructed in its use by a healthcare provider.
Step-by-step instructions for
using the DISKHALER®
Step
A: Load the medicine into the DISKHALER
- Start by pulling off the blue cover.
- Always check inside the mouthpiece to make
sure it is clear before each use. If foreign objects are in the mouthpiece,
they could be inhaled and cause serious harm.
- Pull the white mouthpiece by the edges to extend the white tray all
the way.
- Once the white tray is extended all the way, find the raised ridges
on each side of it. Press in these ridges, both sides at the same time, and pull the whole white tray out of theDISKHALER
body
.
- Place one silver medicine disk onto the dark brown wheel, flat side
up. The four silver blisters on the underside of the medicine disk will drop
neatly into the four holes in the wheel.
- Push in the white tray as far as it will go. Now the DISKHALER is loaded
with medicine.
Step B: Puncture the blister
Be sure to keep the DISKHALER level.
The DISKHALER punctures one blister of medicine at a time
so you can inhale the right amount. It does not matter which blister you start
with. Check to make sure that the silver foil is unbroken.
- Be sure to keep the DISKHALER level so the medicine does not spill out.
- Locate the half-circle flap with the name “RELENZA” on
top of the DISKHALER.
- Lift this flap from the outer edge until it cannot go any farther. Flap
must be straight up
for the plastic needle
to puncture both the top
and bottom
of the silver medicine disk inside.
- Keeping the DISKHALER level, click the flap down into place.
Step C: Inhale
- Before putting the white mouthpiece into your mouth, breathe all the
way out (exhale).
- Then put the white mouthpiece into your mouth.
Be sure to keep the DISKHALER level so the medicine does not spill out.
- Close your lips firmly around the mouthpiece. Be sure not to cover the
small holes on either side of it.
- Breathe in through your mouth steadily and as deeply as you can. Your
breath pulls the medicine into your airways and lungs.
- Hold your breath for a few seconds to help RELENZA stay in your lungs
where it can work.
To take another inhalation, move
to the next blister by following Step D below.
Once you’ve inhaled the number of blisters prescribed
by your healthcare provider, replace the cover until your next dose.
Step D: Move the medicine disk to the next blister
- Pull
the mouthpiece to extend the
white tray, without removing it.
- Then push
it back until it clicks.
This pull-push motion rotates the medicine disk to the next blister.
- To take your next inhalation, repeat Steps B and C.
If all four blisters in the medicine
disk have been used, you are ready to start a new medicine disk (see Step
A). Check to make sure that the silver foil is unbroken each time you are
ready to puncture the next blister.
|
IMPORTANT INSTRUCTIONS
|
- Read this entire leaflet before using RELENZA. Even if you have had
a previous prescription for RELENZA, read this leaflet to see if any information
has changed.
- If you have the flu, the usual dose is 2 inhalations twice daily. To
reduce the chance of getting the flu, the usual dose is 2 inhalations once
daily. However, you must take the number of inhalations your healthcare provider
has prescribed.
- If you feel worse or develop new symptoms during or after treatment,
or if your flu symptoms do not start to improve, stop using the medicine and
contact your healthcare provider.
- Keep out of reach of children.
- Always check inside the mouthpiece to make sure it is clear before each
use. If foreign objects are in the mouthpiece, they could be inhaled and cause
serious harm.
- Always replace the cover after each use.
- Throw away the DISKHALER after treatment is completed.
- This DISKHALER is for use only with RELENZA. Do not use the RELENZA
DISKHALER device with FLOVENT® (fluticasone propionate) and do not use
RELENZA with the FLOVENT DISKHALER device.
Store at 25°C (77°F);
excursions permitted to 15° to 30°C (59° to 86°F) (see
USP Controlled Room Temperature).
REMEMBER: This medicine
has been prescribed for you by your healthcare provider.
DO
NOT give this medicine to anyone else.
|
GlaxoSmithKline
Research Triangle Park, NC 27709
©2006, GlaxoSmithKline. All rights reserved.
March 2006 RL-2271
Revised: 03/2006GlaxoSmithKline