OSMOHALE INHALATION

Posology Adults The capsules are supplied in kit form containing sufficient number of capsules to complete one maximum dose challenge, and an inhaler. The airway response to Osmohale is measured using the FEV1. 1). There is limited information on the use of Osmohale in patients 6-18 years of age therefore Osmohale is not recommended in this population.

Method of administration Prior to the challenge, spirometry should be performed and the reproducibility of the baseline FEV1 established. The patient should be seated comfortably and encouraged to maintain good posture to assist the effective delivery of Osmohale to the lungs.

The test should proceed as follows: 1. Apply a nose clip. The patient should be directed to breathe through the mouth. 2. Insert the 0 mg capsule into the inhalation device. Puncture the capsule by depressing the buttons on the sides of the device carefully, and once only (a second puncture may shatter the capsules).

3. The patient should exhale completely, before inhaling from the device in a controlled rapid deep inhalation. 4. At the end of the deep inspiration, start a 60 second timer. The patient should hold his/her breath for 5 seconds and exhale through the mouth before removal of the nose clip.

5. At the end of the 60 seconds, measure the FEV1 at least in duplicate to obtain two reproducible measurements. The highest reading becomes baseline FEV1. 85. 6. Insert the 5 mg capsule into the inhalation device, and proceed as above.

7. Repeat steps 1 – 5 following the dose steps in the table below until the patient has a positive response or 635 mg have been administered. DOSE STEPS FOR OSMOHALE CHALLENGE Dose # Dose mg Cumulative Dose mg Capsule s per dose 1 0 0 1 2 5 5 1 3 10 15 1 4 20 35 1 5 40 75 1 6 80 155 2 x 40 mg 7 160 315 4 x 40 mg 8 160 475 4 x 40 mg 9 160 635 4 x 40 mg A positive response is achieved when the patient experiences either of the following: 15% fall in FEV1 from baseline (0 mg dose) or 10% incremental fall in FEV1 between doses Examples of positive tests: 1.

FEV1 fall following dose step 2: 3% FEV1 fall following dose step 3: 8% FEV1 fall following dose step 4: 16% - as the total fall is 16% (≥ 15%), the test is positive. 2. FEV1 fall following dose step 2: 3%FEV1 fall following dose step 3: 14% - although the total fall is < 15%, the incremental fall is 11% (≥ 10%) and the test is positive.

Points to remember: 1. There should be minimal delay between FEV1 measurement and the next dose so that the osmotic effect in the airway is cumulative. 2. At least 2 acceptable FEV1 measures should be obtained after each dose. More than 2 measurements may be required, for example in the case of variability between readings or improper manoeuvres during measurement (such as the occurrence of cough).

3. , 2 x 40 mg and 4 x 40 mg, respectively). There is no interval between administering multiple capsules for these doses. One capsule should be followed immediately by the next until the total dose has been inhaled. 4. After inhalation of each dose, the capsule should be checked to ensure it is empty.

A second inhalation from the same capsule may be required if the dose has not been entirely dispersed from the capsule. Most patients recover spontaneously after the challenge test, however those with a positive challenge or who experience aggravation of asthma should receive a standard dose of a beta2 agonist to expedite recovery.

Those with a negative challenge may also receive a standard dose of a beta2 agonist to expedite recovery. Following administration of a beta2 agonist, FEV1 usually returns to baseline within 10 - 20 minutes. Patients should be monitored until their FEV1 has returned to within 5% of baseline levels.

Summary of the safety profile A positive result with Osmohale may produce symptoms of bronchospasm such as chest tightness, cough or wheezing. The safety population consisted of 1,046 subjects including patients with asthma, symptoms suggestive of asthma, and healthy individuals from 6 to 83 years of age who participated in the two clinical trials.

The racial distribution of subjects was 84% Caucasian, 5% Asian, 4% Black, and 7% Other. In study DPM-A-301, adverse events were monitored from the beginning of the challenge to a week following the challenge day. In study DPM-A-305, adverse reactions were reported at the time of the testing procedure and for one day thereafter.

No serious adverse reactions were reported following bronchial challenge testing with Osmohale in either trial. Due to the short half- life of mannitol, the causal link would be expected to diminish over this period of time. No serious adverse events were reported during the study.

Most adverse events were reported to be mild and transient. Most patients experienced cough during the challenge; however, it was only occasional in the majority of these patients (87%). In the remainder, it was frequent enough to cause some delay in continuation of the challenge (13%) or discontinuation (1%).

Pharyngolaryngeal pain was also a commonly reported adverse event; its occurrence may be reduced if the mouth is rinsed after the test. 6%) discontinued from the studies within a day following administration of Osmohale because of cough, decreased lung function, feeling jittery, sore throat, and throat irritation.

4%) discontinued from the studies within a day following administration of Osmohale because of retching. Tabulated list of adverse reactions The adverse reactions reported in the two studies are listed below by organ class and absolute frequency: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) Infections and infestations: Common: Nasopharyngitis Nervous system disorders: Common: Headache Uncommon: Dizziness Eye disorders: Uncommon: Eye irritation Vascular disorders: Uncommon: Flushing, Peripheral coldness Respiratory, thoracic and mediastinal disorders: Common: Cough*, Dyspnoea, Pharyngolaryngeal pain, Rhinorrhoea, Throat irritation, Aggravated Asthma Uncommon: Hoarseness, Epistaxis, Oxygen saturation decreased Gastrointestinal disorders: Common: Nausea, Vomiting Uncommon: Upper abdominal pain, Diarrhoea, Mouth ulceration Skin and subcutaneous tissue disorders: Uncommon: Pruritus, Hyperhidrosis Musculoskeletal and connective tissue disorders: Uncommon: Musculoskeletal pain General disorders: Common: Chest tightness Uncommon: Fatigue, Feeling jittery, Thirst * Cough was only defined as an adverse event during the challenge test if it led to discontinuation of the challenge.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.

Osmohale is to be administered by inhalation only. Inhaled mannitol causes bronchoconstriction. The Osmohale inhalation test should only be conducted in suitable laboratories/clinics under the supervision of an experienced physician and by a physician or another health professional appropriately trained to perform bronchial provocation tests and to manage acute bronchospasm.

The responsible physician, appropriately trained to treat acute bronchospasm, including appropriate use of resuscitation equipment, must be close enough to respond quickly to an emergency. A stethoscope, sphygmomanometer, and pulse oximeter should be available.

Patients should not be left unattended during the procedure once the administration of Osmohale has begun. Medications to treat severe bronchospasm must be present in the testing area. They include adrenaline for subcutaneous injection, and salbutamol or other beta agonists in metered-dose inhalers.

Oxygen must be available. A small- volume nebuliser should be readily available for the administration of bronchodilators. 5 l or less in adults), spirometry induced bronchoconstriction, haemoptysis of unknown origin, pneumothorax, recent abdominal or thoracic surgery, recent intraocular surgery, unstable angina, inability to perform spirometry of acceptable quality or upper or lower respiratory tract infection in the previous 2 weeks.

If a patient has spirometry induced asthma or the FEV1 fall is greater than 10% at continued administration after the 0 mg capsule, a standard dose of bronchodilator should be given and the Osmohale challenge discontinued.

Exercise:

Vigorous exercise should be fully avoided on the day of the test, as this may affect test results.

Smoking:

Since smoking may affect test results it is recommended that patients refrain from smoking for at least 6 hours prior to testing. The effects of repeat Osmohale testing within a short period of time have not been investigated therefore careful consideration should be given to repeat use of Osmohale.

Paediatric population The Osmohale test should not be used in patients below 6 years of age due to their inability to provide reproducible spirometric measurements. There is limited information on the use of Osmohale in patients 6-18 years of age therefore Osmohale is not recommended in this population.

Hypersensitivity to mannitol or to any of the capsule ingredients. 0 l) or conditions that may be compromised by induced bronchospasm or repeated blowing manoeuvres. These include: aortic or cerebral aneurysm, uncontrolled hypertension, myocardial infarction or a cerebral vascular accident in the previous six months.