Relenza

Zanamivir treats flu (influenza) by preventing the viruses causing the infection from spreading once they are inside your body. This reduces the symptoms of the influenza infection. It also reduces the risk of other problems which can sometimes occur alongside flu, such as pneumonia. It is most effective when it is started within an hour or two of the first symptoms of infection, but it can still be effective after this time, as long as it is started within 48 hours of the first symptoms for adults, or within 36 hours for children.

Zanamivir is also used to prevent flu when there is a flu outbreak in the community, such as in epidemics and pandemics. It is used for those who have been in close contact with people with flu and for those who would be at particular risk if they developed flu (such as children, people with long-term medical conditions, and the elderly). It is most effective when treatment begins as soon as possible after the contact, but it can still be effective when started up to 36 hours afterwards.

Another antiviral medicine called oseltamivir is often prescribed in preference to zanamivir, so you will have been prescribed zanamivir because oseltamivir is not suitable for you for some reason. Zanamivir is not a substitute for seasonal flu vaccination.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Some people using zanamivir have had rare side effects of confusion, delirium and self-injury. These symptoms have occurred most often in children. It is not known whether zanamivir was the exact cause of these symptoms. However, anyone using zanamivir should be watched closely for signs of confusion or unusual behavior. Call a doctor at once if you or the child using zanamivir has any of these symptoms.

Stop using zanamivir and call your doctor at once if you have wheezing or severe breathing problems, or if you feel like you might pass out.

Less serious side effects may include:

• headache;
• dizziness;
• nausea, vomiting, diarrhea;
• fever, chills, joint pain;
• ear pain; or
• cold symptoms such as stuffy nose, sneezing, sore throat;

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Treatment with zanamivir should start as soon as possible when flu symptoms appear, such as fever, chills, muscle aches, sore throat, and runny or stuffy nose.

Zanamivir is packaged in disk-shaped foil packs that contain 4 blisters of medicine. These disks are placed into a device called a DISKHALER that you will use to inhale the medicine. The device opens and loads a blister of zanamivir each time you use the inhaler. The disk device is not to be used with a spacer. Follow the patient instructions provided with the DISKHALER.

Do not use a nebulizer or ventilator to give zanamivir. Zanamivir inhalation powder should never be mixed with a liquid.

Do not use any other medicines in the DISKHALER. Always put the cover back on the device when not in use.

To treat flu symptoms: Use 2 inhalations every 12 hours for 5 days. Your doctor may tell you to use two doses on the first day of treatment, spaced at least 2 hours apart. On the following days, the doses should be spaced 12 hours apart. Follow your doctor's instructions.

To prevent flu symptoms: Use 2 inhalations every 24 hours for 10 to 28 days. Follow your doctor's instructions.

If you have a chronic respiratory disease such as asthma or COPD and you are scheduled to use an inhaled bronchodilator at the same time as zanamivir, use the inhaled bronchodilator before using zanamivir.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Tell your doctor if your symptoms do not improve, or if they get worse.

Store at room temperature away from moisture and heat. Throw away the DISKHALER after your treatment ends.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Use the missed dose as soon as you remember. Skip the missed dose if it is within 2 hours of your next scheduled dose. Do not use extra medicine to make up the missed dose.

Call your doctor if you miss several doses.

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

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.

Distributed by: GlaxoSmithKline.,Research Triangle Park, NC 27709. Revised: Aug 2016

Mechanism Of Action

Zanamivir is an antiviral drug [see Microbiology].

Pharmacokinetics

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 per 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•hour per mL.

Zanamivir has limited plasma protein binding (less than 10%).

Zanamivir is renally excreted as unchanged drug. No metabolites have been detected in humans.

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 per hour. Unabsorbed drug is excreted in the feces.

The pharmacokinetics of zanamivir have not been studied in patients with impaired hepatic 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 per hour, mild/moderate 2.7 L per hour, and severe 0.8 L per hour; median values) and significant increases in half-life (normals 3.1 hours, mild/moderate 4.7 hours, and severe 18.5 hours; 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.

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 subjects had either undetectable zanamivir serum concentrations or had low drug concentrations (8.32 to 10.38 ng per mL) that were not detectable after 1.5 hours. Eleven subjects had Cmax median values of 43 ng per mL (range: 15 to 74) and AUC∞ median values of 167 ng•hour per 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 , Clinical Studies].

The pharmacokinetics of zanamivir have not been studied in subjects older than 65 years [see Use In Specific Populations].

In a population pharmacokinetic analysis in patient trials, 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.

Microbiology

Zanamivir is an inhibitor of influenza virus neuraminidase affecting release of viral particles.

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 microM and 0.05 to greater than 100 microM, respectively (1 microM = 0.33 mcg per 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.

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 culture 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 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 zanamivirinduced 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.

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.

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.

Clinical Studies

Treatment Of Influenza

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 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 subjects 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 trial endpoint in both treatment groups.

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 , CLINICAL PHARMACOLOGY].

Prophylaxis Of Influenza

The efficacy of RELENZA in preventing naturally occurring influenza illness has been demonstrated in 2 post-exposure prophylaxis trials in households and 2 seasonal prophylaxis trials during community outbreaks of influenza. The primary efficacy endpoint in these trials was the incidence of symptomatic, laboratory-confirmed influenza, defined as the presence of 2 or more of the following symptoms: oral temperature greater than or equal to 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 trials 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 aged 5 years and older) was randomized to RELENZA 10 mg inhaled once daily or placebo inhaled once daily for 10 days. In the first trial 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 trial, 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 trial, 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 trials assssed RELENZA 10 mg inhaled once daily versus placebo inhaled once daily for 28 days during community outbreaks. The first trial enrolled subjects aged 18 years or older (mean age: 29 years) from 2 university communities. The majority of subjects were unvaccinated (86%). In this trial, 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 trial enrolled subjects aged 12 to 94 years (mean age 60 years) with 56% of them older than 65 years. Sixty-seven percent of the subjects were vaccinated. In this trial, 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.

Tell your doctor if you are allergic to Relenza or any other medicines.

Tell your doctor if you:

• are pregnant or breastfeeding.
• have asthma or other breathing problems
• have heart, kidney, or liver disease

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if Relenza excreted in human breast milk or if it will harm your nursing baby.

Zanamivir is an antiviral medication. It blocks the actions of viruses in your body.

Zanamivir is used to treat flu symptoms caused by influenza virus in patients who have had symptoms for less than 2 days. Zanamivir may also be given to prevent influenza in people who may be exposed but do not yet have symptoms. Zanamivir will not treat the common cold.

Zanamivir should not be used in place of getting a yearly flu shot. The Centers for Disease Control recommends an annual flu shot to help protect you each year from new strains of influenza virus.

Zanamivir may also be used for purposes not listed in this medication guide.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Some people using zanamivir have had rare side effects of confusion, delirium and self-injury. These symptoms have occurred most often in children. It is not known whether zanamivir was the exact cause of these symptoms. However, anyone using zanamivir should be watched closely for signs of confusion or unusual behavior. Call a doctor at once if you or the child using zanamivir has any of these symptoms.

Stop using zanamivir and call your doctor at once if you have wheezing or severe breathing problems, or if you feel like you might pass out.

Less serious side effects may include:

• headache;

• dizziness;

• nausea, vomiting, diarrhea;

• fever, chills, joint pain;

• ear pain; or

• cold symptoms such as stuffy nose, sneezing, sore throat;

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Antiviral; neuraminidase inhibitor; sialic acid analog.1 144

Absorption

Bioavailability

Following oral inhalation of zanamivir, approximately 4–17% of the inhaled dose is absorbed systemically.1

Absolute bioavailability averages 2% following oral inhalation;3 peak serum concentrations attained within 1–2 hours.1 3

Special Populations

In pediatric patients <12 years of age with signs and symptoms of respiratory illness, zanamivir serum concentrations may be low or undetectable following oral inhalation because of inadequate or absent inspiratory flow rates.1 (See Pediatric Use under Cautions.)

Distribution

Extent

Delivered to epithelial lining of the respiratory tract following oral inhalation.22 Amount of drug in respiratory tract depends on patient factors such as inspiratory flow rate.1 May be present in sputum and nasal washings for at least 12 hours after a dose.22

Crosses the placenta in animals.1

Distributed into milk in animals;1 not known whether distributed into human milk.1

Plasma Protein Binding

<10% bound to plasma proteins.1

Elimination

Metabolism

Not metabolized.1

Not a substrate for and does not affect CYP isoenzymes.1

Elimination Route

Following oral inhalation, absorbed drug is excreted unchanged in urine within 24 hours;1 unabsorbed drug excreted in feces.1

Half-life

Serum half-life following oral inhalation is 2.5–5.1 hours.1 23

Special Populations

Half-life prolonged in those with renal impairment;1 studies using IV zanamivir indicate half-life is 4.7 hours if mild to moderate impairment and 18.5 hours if severe impairment.1

In the U.S.

• Relenza

Available Dosage Forms:

• Disk

Therapeutic Class: Antiviral

Pharmacologic Class: Neuraminidase Inhibitor, Influenza A&B Virus

Talk to your doctor about the possibility of getting a flu shot if you have not had one yet. This medicine works best if used as soon as possible after exposure to people who have the flu. If you already have the flu, continue using this medicine for the full time of treatment even if you begin to feel better after a few days. This will help to clear up your infection completely. If you stop using this medicine too soon, your symptoms may return. This medicine should be taken for 5 days.

Inhaled zanamivir is to be used only with a special inhaler (Diskhaler®). Do not mix this medicine with other solutions. Do not use this medicine in any nebulizer or mechanical ventilator.

This medicine usually comes with patient instructions. Read them carefully before using the medicine. If you do not understand the directions or you are not sure how to use the inhaler, ask your doctor to show you how to use it.

To load the inhaler:

• Pull off the blue cover. Make sure the mouthpiece is clean and free of foreign objects.
• Pull the white mouthpiece until the tray is extended.
• Hold the corners of the white tray and pull out gently until you can see all the raised ridges on the sides of the tray.
• Put your finger and thumb on the ridges, squeeze inward, and gently pull the tray out of the body of the inhaler.
• Place a disk on the wheel and then slide the tray back into the inhaler.
• To replace the empty disk with a full disk, follow the same steps you used to load the inhaler.

To use the inhaler:

• Hold the inhaler flat in your hand.
• A plastic needle will break the blister containing one inhalation of medicine. When the flap is raised as far as it will go, the blister will be pierced. Do not lift the flap if the cartridge is not in the inhaler. Doing this will break the needle and you will need a new inhaler.
• After the blister is broken open, close the lid. Keeping the inhaler flat and well away from your mouth, breathe out to the end of a normal breath.
• Raise the inhaler to your mouth, and place the mouthpiece in your mouth.
• Close your lips around the mouthpiece and tilt your head slightly back. Do not bite down on the mouthpiece. Do not block the mouthpiece with your teeth or tongue. Do not cover the air holes on the side of the mouthpiece.
• Breathe in through your mouth as steadily and as deeply as you can until you have taken a full deep breath.
• Hold your breath and remove the mouthpiece from your mouth. Continue holding your breath as long as you can up to 10 seconds before breathing out. This gives the medicine time to settle in your airways and lungs.
• Hold the inhaler well away from your mouth and breathe out to the end of a normal breath.
• Prepare the cartridge for your next inhalation. Pull the mouthpiece to extend the tray then push it in until it clicks. The disk will turn to the next dose. Do not pierce the blister until just before the inhalation.
• Take the second puff following exactly the same steps you used for the first puff.
• When you are finished, wipe off the mouthpiece and replace the cover to keep the mouthpiece clean and free of foreign objects.

If you are also using another inhaled bronchodilator (e.g., albuterol, Atrovent®, Combivent®, or Serevent®), use it before you use zanamivir.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For inhalation dosage form (powder):
  • For prevention of flu in a household:
    • Adults, teenagers, and children 5 years of age and older—Two puffs once a day for 10 days. Doses should be taken at the same time each day. Zanamivir must be started within 36 hours after the onset of signs and symptoms of the flu in a household.
    • Children younger than 5 years of age—Use and dose must be determined by your doctor.
  • For prevention of flu during community outbreaks:
    • Adults, teenagers, and children 5 years of age and older—Two puffs once a day for 28 days. Doses should be taken at the same time each day. Zanamivir must be started within 5 days after the outbreak was identified in the community.
    • Children younger than 5 years of age—Use and dose must be determined by your doctor.
  • For treatment of the flu:
    • Adults, teenagers, and children 7 years of age and older—Two puffs two times a day (about 12 hours apart in the morning and evening) for 5 days. Doses should be taken at the same time each day. Two doses should be taken on the first day of treatment whenever possible provided there are at least 2 hours between doses. Zanamivir must be started within 48 hours after the onset of signs and symptoms of the flu.
    • Children younger than 7 years of age—Use and dose must be determined by your doctor.
  • Canada: For treatment of flu:
    • Adults, teenagers, and children 12 years of age and older—Two puffs two times a day (about 12 hours apart in the morning and evening) for 5 days. Two doses should be taken on the first day of treatment whenever possible provided there are at least 2 hours between doses. Zanamivir must be started within 48 hours after the onset of signs and symptoms of the flu.
    • Children younger than 12 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose or forget to use it, use it as soon as you can, except if it is less than 2 hours before your next dose. Use your next dose at the normal time. Do not use extra medicine to make up for a missed dose.

Storage

Keep the medicine in the foil pouch until you are ready to use it. Store at room temperature, away from heat and direct light. Do not freeze.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is very important that your doctor check your or your child's progress after treatment. This is to make sure that the infection is cleared up completely, and to allow your doctor to check for any unwanted effects.

This medicine is not a substitute for an annual flu shot. It also will not keep you or your child from getting a bacterial infection that starts with flu-like symptoms.

Zanamivir may cause people with lung disease (e.g., chronic obstructive lung disease or asthma) to have shortness of breath, trouble breathing, or wheezing. If you have these symptoms after using this medicine, stop using this medicine and call your doctor right away.

Bronchospasm (wheezing) is a risk for patients with asthma or chronic respiratory disease. Always have a fast-acting inhaled bronchodilator available for your use.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Stop using this medicine and call your doctor right away if you or your child have itching, hives, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Zanamivir may cause some people, especially children and teenagers, to be agitated, irritable, or display other abnormal behaviors, which may result in injury. If you, your child, or your caregiver notice any of these side effects, tell your doctor or your child's doctor right away.

Make sure your doctor knows if you or your child plan to get the live nasal flu vaccine (FluMist®) before you start using this medicine. You should not receive the vaccine within two weeks before or 48 hours after using this medicine.

If your or your child's symptoms do not improve after you or your child finish taking the medicine, or if they become worse, check with your doctor.

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

Relenza (zanamivir) is an antiviral medication. It blocks the actions of viruses in your body.

Relenza is used to treat flu symptoms caused by influenza virus in patients who have had symptoms for less than 2 days. Relenza may also be given to prevent influenza in people who may be exposed but do not yet have symptoms. Zanamivir will not treat the common cold.

Relenza should not be used in place of getting a yearly flu shot. The Centers for Disease Control recommends an annual flu shot to help protect you each year from new strains of influenza virus.

You should not use Relenza if you are allergic to zanamivir or to lactose (milk protein). Before using this medicine, tell your doctor if you have asthma, chronic obstructive pulmonary disease (COPD), or any other chronic lung condition. Serious or life-threatening bronchospasm (difficulty breathing) and other effects on the lungs can occur while using Relenza.

If you have asthma, COPD, or other chronic lung disease, make sure you have a fast-acting inhaled bronchodilator available to treat any serious breathing problems that may occur while using Relenza. Fast-acting bronchodilators include albuterol (Ventolin, Proventil), bitolterol (Tornalate), metaproterenol (Alupent), and pirbuterol (Maxair). Talk with your doctor about which medicine is best for you.

If you are scheduled to use a bronchodilator at the same time as Relenza, use the bronchodilator first.

FDA pregnancy category C. It is not known whether Relenza will harm an unborn baby. Tell your doctor if you are pregnant. Your doctor will decide whether you should receive Relenza, especially if you have a high risk of infection with influenza. It is not known whether zanamivir passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not use this medication to treat flu symptoms in a child younger than 7 years old. Children as young as 5 years old may use the medication to prevent flu symptoms.

Get emergency medical help if you have any of these signs of an allergic reaction to Relenza: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Some people using zanamivir have had rare side effects of confusion, delirium and self-injury. These symptoms have occurred most often in children. It is not known whether Relenza was the exact cause of these symptoms. However, anyone using this medicine should be watched closely for signs of confusion or unusual behavior. Call a doctor at once if you or the child using Relenza has any of these symptoms.

Stop using Relenza and call your doctor at once if you have wheezing or severe breathing problems, or if you feel like you might pass out.

Less serious Relenza side effects may include:

• headache;

• dizziness;

• nausea, vomiting, diarrhea;

• fever, chills, joint pain;

• ear pain; or

• cold symptoms such as stuffy nose, sneezing, sore throat;

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Zanamivir has been assigned to pregnancy category C by the FDA. High-dose animal studies have failed to reveal evidence of embryotoxicity, teratogenicity, or maternal toxicity. Another high-dose study (1000 times the human exposure) found minor skeletal changes and variants; however, the incidence was not significantly different than the background incidence for the strain. Although zanamivir has been shown to cross the placenta in animal studies, drug concentrations in fetal blood have been significantly lower than those in maternal blood. There are no controlled data in human pregnancy. Zanamivir should only be given during pregnancy when benefit outweighs risk.