relenza

DESCRIPTION
The active component of RELENZA is zanamivir relenza. The chemical name of zanamiviris 5-(acetylamino)-4-[(aminoimino-methyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonicacid relenza. It has a molecular formula of C 12 H 20 N 4 O 7 and a molecular weightof 332.3 relenza.

Zanamivir is a white to off-white powder with a solubility of approximately18 mg/mL in water at 20°C relenza.

RELENZA is for administration to the respiratory tract by oral inhalation only relenza. Each RELENZA ROTADISK® contains 4 regularly spaced double-foil blisterswith each blister containing a powder mixture of 5 mg of zanamivir and 20 mgof lactose (which contains milk proteins) relenza. The contents of each blister areinhaled using a specially designed breath-activated plastic device for inhalingpowder called the DISKHALER relenza. After a RELENZA ROTADISK is loaded into the DISKHALER,a blister that contains medication is pierced and the zanamivir is dispersedinto the air stream created when the patient inhales through the mouthpiece relenza. The amount of drug delivered to the respiratory tract will depend on patientfactors such as inspiratory flow relenza. Under standardized in vitro testing, RELENZAROTADISK delivers 4 mg of zanamivir from the DISKHALER device when tested ata pressure drop of 3 kPa (corresponding to a flow rate of about 62 to 65 L/min)for 3 seconds relenza. In a study of 5 adult and 5 adolescent patients with obstructiveairway diseases, the combined peak inspiratory flow rates (PIFR) ranged from66 to 140 L/min relenza. In a separate study of 16 pediatric patients, PIFR resultswere more variable; 4 did not achieve measurable flow rates, and PIFR for measurableinhalations by 12 children ranged from 30.5 to 122.4 L/min relenza. Only 1 of 4 childrenunder age 8 had a measurable flow rate (see CLINICAL PHARMACOLOGY : PediatricPatients, INDICATIONS AND USAGE : Description of Clinical Studies , and PRECAUTIONS: Pediatric Use ) relenza.

MICROBIOLOGY
Mechanism of Action: The proposed mechanism of action of zanamivir is via inhibitionof influenza virus neuraminidase with the possibility of alteration of virusparticle aggregation and release relenza.

Antiviral Activity In Vitro: The antiviral activity of za-namivir against laboratoryand clinical isolates of influenza virus was determined in cell culture assays relenza. The concentrations of zanamivir required for inhibition of influenza virus werehighly variable depending on the assay method used and virus isolate tested relenza. The 50% and 90% inhibitory concentrations (IC 50 and IC 90 ) of zanamivir werein the range of 0.005 to 16.0 µM and 0.05 to >100 µM, respectively(1 µM = 0.33 mcg/mL) relenza. The relationship between the in vitro inhibitionof influenza virus by zanamivir and the inhibition of influenza virus replicationin humans has not been established relenza.

Drug Resistance: Influenza viruses with reduced susceptibility to zanamivirhave been recovered in vitro by passage of the virus in the presence of increasingconcentrations of the drug relenza. Genetic analysis of these viruses showed that thereduced susceptibility in vitro to zanamivir is associated with mutations thatresult in amino acid changes in the viral neuraminidase or viral hemagglutininor both relenza.

In an immunocompromised patient infected with influenza B virus, a variantvirus emerged after treatment with an investigational nebulized solution ofzanamivir for 2 weeks relenza. Analysis of this variant showed a hemagglutinin mutation(Thr 198 Ile) which resulted in a reduced affinity for human cell receptors,and a mutation in the neuraminidase active site (Arg 152 Lys) which reducedthe enzyme's activity to zanamivir by 1000-fold relenza.

Insufficient information is available to characterize the risk of emergenceof zanamivir resistance in clinical use relenza.

Cross-Resistance: Cross-resistance has been observed between zanamivir-resistantand oseltamivir-resistant influenza virus mutants generated in vitro relenza. No studieshave been performed to assess risk of emergence of cross-resistance during clinicaluse relenza.

Influenza Vaccine Interaction Study: An interaction study (n = 138) was conductedto evaluate the effects of zanamivir (10 mg once daily) on the serological responseto a single dose of trivalent inactivated influenza vaccine, as measured byhemagglutination inhibition titers relenza. There was no clear difference in hemagglutinationinhibition antibody titers at 2 weeks and 4 weeks after vaccine administrationbetween zanamivir and placebo recipients relenza.

Influenza Challenge Studies: Antiviral activity of za-namivir was supportedfor influenza A, and to a more limited extent for influenza B, by Phase 1 studiesin volunteers who received intranasal inoculations of challenge strains of influenzavirus, and received an intranasal formulation of zanamivir or placebo startingbefore or shortly after viral inoculation relenza.

CLINICAL PHARMACOLOGY
Pharmacokinetics: Absorption and Bioavailability: Pharmacokinetic studies oforally inhaled zanamivir indicate that approximately 4% to 17% of the inhaleddose is systemically absorbed relenza. The peak serum concentrations ranged from 17to 142 ng/mL within 1 to 2 hours following a 10-mg dose relenza. The area under theserum concentration versus time curve (AUC (infinity) ) ranged from 111 to 1,364ng·hr/mL relenza.

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

Metabolism: Zanamivir is renally excreted as unchanged drug relenza. No metaboliteshave been detected in humans relenza.

Elimination: The serum half-life of zanamivir following administration by oralinhalation ranges from 2.5 to 5.1 hours relenza. It is excreted unchanged in the urinewith excretion of a single dose completed within 24 hours relenza. Total clearance rangesfrom 2.5 to 10.9 L/hr relenza. Unabsorbed drug is excreted in the feces relenza.

Special Populations: Impaired Hepatic Function: The pharmacokinetics of zanamivirhave not been studied in patients with impaired hepatic function relenza.

Impaired Renal Function: Systemic exposure is limited after inhalation (seeAbsorption and Bioavailability) relenza. After a single intravenous dose of 4 mg or2 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 relenza. Safetyand efficacy have not been documented in the presence of severe renal insufficiency relenza.

Pediatric Patients: The pharmacokinetics of zanamivir were evaluated in pediatricpatients with signs and symptoms of respiratory illness relenza. Sixteen patients, 6to 12 years of age, received a single dose of 10-mg zanamivir dry powder viaDISKHALER relenza. Five patients had either undetectable zanamivir serum concentrationsor had low drug concentrations (8.32 to 10.38 ng/mL) that were not detectableafter 1.5 hours relenza. Eleven patients had C max median values of 43 ng/mL (range15 to 74) and AUC (infinity) median values of 167 ng·hr/mL (range 58to 279) relenza. Low or undetectable serum concentrations were related to lack of measurablePIFR in individual patients (see DESCRIPTION , INDICATIONS AND USAGE: Descriptionof Clinical Studies , and PRECAUTIONS: Pediatric Use ) relenza.

Geriatric Patients: The pharmacokinetics of zanamivir have not been studiedin patients over 65 years of age (see PRECAUTIONS : Geriatric Use ) relenza.

Gender, Race, and Weight: In a population pharmacokinetic analysis in patientstudies, no clinically significant differences in serum concentrations and/orpharmacokinetic parameters (V/F, CL/F, ka, AUC 0-3 , C max , T max , 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) wereconsidered relenza. There were no significant correlations between measures of systemicexposure and safety parameters relenza.

Drug Interactions: No clinically significant pharmacokinetic drug interactionsare predicted based on data from in vitro studies relenza.

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 relenza.

INDICATIONS AND USAGE
RELENZA is indicated for treatment of uncomplicated acute illness due to influenzaA and B virus in adults and pediatric patients 7 years and older who have beensymptomatic for no more than 2 days (see Description of Clinical Studies andPRECAUTIONS ) relenza.

RELENZA is not recommended for treatment of patients with underlying airwaysdisease (such as asthma or chronic obstructive pulmonary disease) (see WARNINGSand PRECAUTIONS ) relenza.

Description of Clinical Studies: Adults and Adolescents: The efficacy of RELENZA10 mg inhaled twice daily for 5 days in the treatment of influenza has beenevaluated in placebo-controlled studies conducted in North America, the SouthernHemisphere, and Europe during their respective influenza seasons relenza. The magnitudeof treatment effect varied between studies, with possible relationships to population-relatedfactors including amount of symptomatic relief medication used relenza.

Populations Studied: The principal Phase 3 studies enrolled 1,588 patientsages 12 years and older (median age 34 years, 49% male, 91% Caucasian), withuncomplicated influenza-like illness within 2 days of symptom onset relenza. Influenzawas confirmed by culture, hemagglutination inhibition antibodies, or investigationaldirect tests relenza. Of 1,164 patients with confirmed influenza, 89% had influenzaA and 11% had influenza B relenza. These studies served as the principal basis for efficacyevaluation, with more limited Phase 2 studies providing supporting informationwhere necessary relenza. Following randomization to either zanamivir or placebo (inhaledlactose vehicle), all patients received instruction and supervision by a healthcareprofessional for the initial dose relenza.

Principal Results: The definition of time to improvement in major symptomsof influenza included no fever and self-assessment of "none" or "mild"for headache, myalgia, cough, and sore throat relenza. A Phase 2 and a Phase 3 studyconducted in North America (total of over 600 influenza-positive patients) suggestedup to one day of shortening of median time to this defined improvement in symptomsin patients receiving zanamivir compared to placebo, although statistical significancewas not reached in either of these studies relenza. In a study conducted in the SouthernHemisphere (321 influenza-positive patients), a 1.5-day difference in mediantime to symptom improvement was observed relenza. Additional evidence of efficacy wasprovided by the European study relenza.

Other Findings: There was no consistent difference in treatment effect in patientswith influenza A compared to influenza B; however, these trials enrolled smallernumbers of patients with influenza B and thus provided less evidence in supportof efficacy in influenza B relenza.

In general, patients with lower temperature (e.g., 38.2°C or less) or investigator-ratedas having less severe symptoms at entry derived less benefit from therapy relenza.

No consistent treatment effect was demonstrated in patients with underlyingchronic medical conditions, including respiratory or cardiovascular disease(see WARNINGS and PRECAUTIONS ) relenza.

No consistent differences in rate of development of complications were observedbetween treatment groups relenza.

Some fluctuation of symptoms was observed after the primary study endpointin both treatment groups relenza.

Pediatric Patients: The efficacy of RELENZA 10 mg inhaled twice daily for 5days in the treatment of influenza in pediatric patients has been evaluatedin a placebo-controlled study conducted in North America and Europe, enrolling471 patients, ages 5 to 12 years (55% male, 90% Caucasian), within 36 hoursof symptom onset relenza. Of 346 patients with confirmed influenza, 65% had influenzaA and 35% had influenza B relenza. The definition of time to improvement included nofever and parental assessment of no or mild cough and absent/minimal muscleand joint aches or pains, sore throat, chills/feverishness, and headache relenza. Mediantime to symptom improvement was one day shorter in patients receiving zanamivircompared with placebo relenza. No consistent differences in rate of development of complicationswere observed between treatment groups relenza. Some fluctuation of symptoms was observedafter the primary study endpoint in both treatment groups relenza.

Although this study was designed to enroll children ages 5 to 12 years, theproduct is indicated only for children 7 years of age and older relenza. This evaluationis based on the combination of lower estimates of treatment effect in 5- and6-year-olds compared with the overall study population, and evidence of inadequateinhalation through the DISKHALER in a pharmacokinetic study (see DESCRIPTION, CLINICAL PHARMACOLOGY : Pediatric Patients , and PRECAUTIONS: Pediatric Use) relenza.

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