RELENZA Rotadisks
Zanamivir 5mg/blister
Qualitative and Quantitative Composition
Each Relenza Rotadisk consists of four regularly spaced double foil blisters each containing a powder mixture of zanamivir (5mg) and lactose (20mg).
Pharmaceutical Form
Inhalation powder.
Clinical Particulars
Therapeutic Indications
Treatment of Influenza
Relenza is indicated for treatment of both influenza A and B in adults and adolescents ( 12 years of age or older).
Posology and Method of Administration
Relenza is for administration to the respiratory tract by oral inhalation only, using the Diskhaler device provided.
Treatment of Influenza
The recommended dose of Relenza is two inhalations (2 x 5mg) twice daily for five days, providing a total daily inhaled dose of 20mg.
For maximum benefit, treatment should begin as soon as possible (preferably within two days) after onset of symptoms.
Impaired Renal or Hepatic Function
No dose modification is required. (See Pharmacokinetic properties).
Elderly patients
No dose modification is required. (See Pharmacokinetic properties).
Patients on asthma mediction
Inhaled drugs, e.g. fast acting bronchodilators, should be administered prior to administration of Relenza (see Special Warnings & Precautions for Use).
Contraindications
Hypersensitivity to any ingredient of the preparation.
Special Warnings and Special Precautions for Use
Influenza infection can be associated with increased airways hyper-responsiveness. There have been very rare reports of patients being treated for influenza who have experienced bronchospasm and/or decline in respiratory function after the use of zanamivir, some of whom did not have any previous history of respiratory disease. Any such patients should discontinue zanamivir and seek medical evaluation. Patients with underlying respiratory disease should have a fast acting bronchodilator available when taking zanamivir.
Interaction with Other Medicinal Products and Other Forms of Interaction
Zanamivir is not protein bound and not hepatically metabolised or modified. Clinically significant drug interactions are unlikely.
Use During Pregnancy and Lactation
Pregnancy
The safe use of Relenza during pregnancy has not been established.
Reproductive studies performed in rats and rabbits indicated that placental transfer of zanamivir occurs. Studies in rats did not show any evidence of teratogenicity, impairment of fertility or clinically significant impairment of peri or post-natal development of offspring following administration of zanamivir. However, there is no information on placental transfer in humans.
Relenza should not be used in pregnancy, especially during the first trimester, unless the possible benefit to the patient is thought to outweigh any possible risk to the foetus.
Lactation
In rats zanamivir has been shown to be secreted into milk. However, there is no information on secretion into breast milk in humans.
As experience is limited, the use of zanamivir in nursing mothers should be considered only if the possible benefit to the mother is thought to outweigh any possible risk to the infant.
Effects on Ability to Drive and Use Machines
None known
Undesirable Effects
Clinical trial data
Relenza is well tolerated by the oral inhaled route of administration. In clinical studies, the adverse events reported were similar in the Relenza and placebo groups.
General
Very rare: Allergic-type reaction, including facial and oropharyngeal oedema
Respiratory
Very rare: bronchospasm, dyspnea
Skin
Very rare: rash, urticaria
Overdose
Accidental overdose is unlikely due to the physical limitations of the presentation, the route of administration and the poor oral bioavailability (2 to 3%) of zanamivir. Doses of zanamivir up to 64mg/day (approximately 3 times the maximum daily recommended dose) have been administered by oral inhalation (by nebuliser) without adverse effects. Additionally, systemic exposure by intravenous administration of up to 1200mg/day for five days showed no adverse effect.
Pharmacological Properties
Pharmacodynamic Properties
Mechanism of action
Zanamivir is a potent and highly selective inhibitor of neuraminidase, the influenza virus surface enzyme. Viral neuraminidase aids the release of newly formed virus particles from infected cells, and may facilitate access of virus through mucus to epithelial cell surfaces, to allow viral infection of other cells. The inhibition of this enzyme is reflected in both in vitro and in vivo activity against influenza A and B virus replication, and encompasses all of the known neuraminidase subtypes of influenza A viruses.
The activity of zanamivir is extracellular. It reduces the propagation of both influenza A and B viruses by inhibiting the release of infectious influenza virions from the epithelial cells of the respiratory tract. Influenza viral replication is confined to the superficial epithelium of the respiratory tract. The efficacy of topical administration of zanamivir to this site has been confirmed in clinical studies. Clinical trial data have shown that treatment of acute influenza infections with zanamivir produces reductions in virus shedding from the respiratory tract compared to placebo without any detectable emergence of virus with reduced susceptibility to zanamivir.
Clinical experience
Relenza, when taken as recommended for treatment of influenza, alleviates the symptoms and reduces their duration. In some studies, a larger treatment benefit was observed in the 'at risk' patients: the elderly and patients with certain chronic medical conditions (chronic cardiac, pulmonary, renal and metabolic disorders). The efficacy of Relenza has been shown to be optimal if treatment is initiated as soon as possible after the onset of symptoms.
Pharmacokinetic Properties
Absorption
Pharmacokinetic studies in humans have shown that the absolute oral bioavailability of the drug is low (mean 2%). Similar studies of orally inhaled zanamivir indicate that approximately 10-20% of the dose is systemically absorbed, with serum concentrations generally peaking within 1-2 hours. The poor absorption of the drug results in low systemic concentrations and therefore there is no significant systemic exposure to zanamivir after oral inhalation. There is no evidence of modification in the kinetics after repeated dosing with oral inhaled administration.
Distribution
After oral inhalation, zanamivir is widely deposited at high concentrations throughout the respiratory tract, thus delivering the drug to the site of influenza infection. The high concentrations of zanamivir in the respiratory tract will result in the rapid onset of inhibition of the viral neuraminidase. The two major sites of deposition are the oropharynx and the lungs (mean 77.6% and 13.2 %, respectively).
Metabolism
Zanamivir has been shown to be renally excreted as unchanged drug, and does not undergo metabolism.
Elimination
The serum half-life of zanamivir following administration by oral inhalation ranges from 2.6 to 5.05 hours. It is entirely excreted unchanged in the urine. Total clearance ranges from 2.5 to 10.9 L/h as approximated by urinary clearance. Renal elimination is completed within 24 hours.
Patients with renal impairment
At the therapeutic daily dose of 20mg, bioavailabilty is low (10-20%), and as a result there is no significant systemic exposure of patients to zanamivir. Given the wide safety margin of zanamivir the possible increased exposure in patients with severe renal failure is not considered problematic and no dose adjustment is required.
Patients with hepatic impairment
Zanamivir is not metabolised, therefore dose adjustment in patients with hepatic impairment is not required.
Elderly patients
At the therapeutic daily dose of 20mg, bioavailabilty is low (10-20%), and as a result there is no significant systemic exposure of patients to zanamivir. Any alteration of pharmacokinetics that may occur with age is unlikely to be of clinical consequence and no dose modification is recommended.
Paediatric patients:
In an open-label single-dose study the pharmacokinetics of zanamivir have been evaluated in 24 paediatric subjects ages 3 months to 12 years using nebulised (10mg) and dry powder (10mg) inhalation formulations. The systemic exposure in children was similar to 10mg of inhaled powder in adults.
Preclinical Safety Data
Administration of zanamavir in animal toxicity studies was not associated with any clinically relevant effects. Zanamavir was not genotoxic and showed no evidence of carcinogenic potential in long term carcinogenicity studies in rats and mice.
Pharmaceutical particulars
List of Excipients
Relenza is a white to off-white powder blend of micronised zanamivir and lactose.
Incompatibilities
None known
Shelf Life
24 months
Special Precautions for Storage
Relenza Rotadisks should not be stored above 30°C (86°F).
Nature and Contents of Container
Relenza Rotadisks consist of a circular foil disk (a Rotadisk) with four regularly distributed blisters each containing 5mg of zanamivir and 20mg of lactose. A Diskhaler is provided to administer the medication.
Instructions for Use/Handling
The powdered medicine is inhaled through the mouth into the lungs. The Diskhaler device is loaded with a disk which contains the medicine in individual blisters which are opened as the device is manipulated.
Instructions for Use
A Relenza Rotadisk may be kept in the Diskhaler at all times but a blister should only be pierced immediately prior to use. Failure to observe this instruction will affect operation of the Diskhaler.
The Diskhaler is a device which is used together with a Rotadisk for inhaling medication.
The Diskhaler consists of:
- an outer coloured body with a hinged lid and piercing needle
- a dark mouthpiece cover
- a white sliding tray with mouthpiece
- a dark wheel to support the Rotadisk
The Rotadisk consists of 4 blisters. Each blister contains a measured dose of dry powder medication.
WARNING: Do not puncture any Rotadisk blister until loaded into the Diskhaler.
TO LOAD THE ROTADISK INTO THE DISKHALER
- Remove the mouthpiece cover and check inside and outside to ensure that the mouthpiece is clean.
- Hold the corners of the white tray and pull out gently until you can see all the plastic ridges on the sides of the tray.
- Put your finger and thumb on the ridges, squeeze inwards and gently pull the tray out of the Diskhaler body.
- Place the Rotadisk on the dark wheel with the blisters facing down. Then slide the tray back fully into the Diskhaler body.
TO PIERCE THE BLISTER IN THE ROTADISK
- Raise the lid as far as it will go into the fully upright position. Both surfaces of the blister must be pierced. Some resistance will be felt as the upper and especially the lower surfaces of the blister are pierced. Then close the lid.
WARNING: Do not try to lift the lid unless the tray is positioned fully within the body of the Diskhaler or is completely removed.
TO INHALE FROM THE DISKHALER
- Breathe out as far as is comfortable. Keeping the Diskhaler level, raise the Diskhaler to your mouth and gently place the mouthpiece between your teeth and lips but do not bite the mouthpiece. Do not cover the air holes on either side of the mouthpiece. Breathe in through your mouth steadily and as deeply as you can. Hold this breath in for several seconds and remove the Diskhaler from your mouth. Continue to hold your breath for as long as is comfortable.
TO PREPARE FOR THE NEXT INHALATION
- Rotate the Rotadisk to the next blister by gently pulling the tray once out and in. Do not pierce the blister until immediately before inhalation. When you take another inhalation pierce the blister and inhale as shown in steps 5 and 6.
- Always replace the mouthpiece cover after use.
TO REPLACE THE ROTADISK
- Each Rotadisk consists of 4 blisters containing medication. When the Rotadisk is empty, it should be replaced with a new Rotadisk by repeating steps 2 to 4.
WARNING: Do not throw the wheel away with the empty Rotadisk.
| 
