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OSMOHALE INHALATION POWDER HARD CAPSULES

Active substance(s): MANNITOL / MANNITOL / MANNITOL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Osmohale inhalation powder, hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 capsule contains 0 mg, 5 mg, 10 mg, 20 mg or 40 mg mannitol
The delivered dose from each of the 5, 10, 20 and 40 mg capsules is
approximately 3.4, 7.7, 16.5 and 34.1 mg, respectively.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Inhalation powder, hard capsules.
The powder is white or almost white.
The empty capsule is clear, printed with two white bands.
The capsule containing 5 mg is half white, half clear, marked 5 mg.
The capsule containing 10 mg is half yellow, half clear, marked 10 mg.
The capsule containing 20 mg is half pink, half clear, marked 20 mg.
Capsules containing 40 mg are half red, half clear, marked 40 mg.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
This medicinal product is for diagnostic use only.
Osmohale is indicated for identifying bronchial hyperresponsiveness in
subjects with a baseline forced expiratory volume in one second (FEV1) of
70% or more of the predicted value.

4.2

Posology and method of administration
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.
Paediatric population
The Osmohale test should not be used in children aged under 6 years because of
their inability to provide reproducible spirometric measurements (see section
5.1).
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. The target FEV1 is calculated by multiplying the baseline
FEV1 by 0.85.
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
#
1
2

Dose
mg
0
5

Cumulative Dose
mg
0
5

Capsules per
dose
1
1

3
4
5
6
7
8
9

10
20
40
80
160
160
160

15
35
75
155
315
475
635

1
1
1
2 x 40 mg
4 x 40 mg
4 x 40 mg
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.

The 80 and 160 mg doses are administered in multiples of 40 mg capsules
(i.e., 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.

4.3

Contraindications
Hypersensitivity to mannitol or to any of the capsule ingredients.
Osmohale should not be given to patients with severe airflow limitation (FEV1
< 50% predicted or< 1.0 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.

4.4

Special warnings and precautions for use
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 smallvolume nebuliser should be readily available for the administration of
bronchodilators.
General precautions when conducting spirometry and bronchial provocation
testing should be observed, including using caution in patients with the
following: ventilatory impairment (baseline FEV1 of less than 70% of predicted
normal values or an absolute value of 1.5 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.

4.5

Interaction with other medicinal products and other forms of interaction
Regular use of inhaled corticosteroids reduces the airway sensitivity to
Osmohale and in many individuals, complete inhibition of the airway response
occurs.
The following medicines should be withheld before conducting an Osmohale
test as they may affect the results:
Recommended periods for withholding medicines before the Osmohale test are
listed below.

Time to
Withhold

Medication

6-8 hours

INHALED NON-STEROIDAL ANTI-INFLAMMATORY AGENTS e.g.
sodium cromoglycate, nedocromil sodium

8 hours

SHORT-ACTING BETA2 AGONISTS e.g. salbutamol, terbutaline

12 hours

INHALED CORTICOSTEROIDS e.g. beclomethasone dipropionate,
budesonide, fluticasone propionate

12 hours

IPRATROPIUM BROMIDE

24 hours

LONG-ACTING BETA2 AGONISTS e.g. salmeterol, formoterol

24 hours

INHALED CORTICOSTEROIDS PLUS LONG-ACTING BETA2
AGONISTS e.g. fluticasone and salmeterol, budesonide and formoterol

24 hours

THEOPHYLLINE

72 hours

TIOTROPIUM BROMIDE

72 hours

ANTIHISTAMINES e.g. cetirizine, fexofenadine and loratadine

4 days

LEUKOTRIENE-RECEPTOR ANTAGONISTS e.g. montelukast sodium

Food: Ingestion of significant quantities of coffee, tea, cola drinks, chocolate or
other food containing caffeine may decrease bronchial responsiveness and
should be totally avoided on the day of the test.

4.6

Fertility, pregnancy and lactation
Pregnancy
There are no data or limited amount of data (less than 300 pregnancy outcomes)
from the use of D-mannitol in pregnant women. Animal studies do not indicate
direct or indirect harmful effects with respect to reproductive toxicity (see
section 5.3).
The effects of a possible hyperresponsiveness reaction on the mother and/or the
foetus is unknown and therefore Osmohale should not be given to pregnant
women.
Breastfeeding
No effects on the breast-fed newborn/infant are anticipated since the systemic
exposure of the breast-feeding woman to inhaled D-mannitol is negligible.
Osmohale may be used during breast-feeding.
Fertility
For mannitol no clinical data on fertility are available. Animal reproduction
studies have not been carried out with inhaled mannitol. However, studies with
orally administered mannitol indicate no fertility effects (see section 5.3).

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed. Osmohale has no or negligible influence on the ability to drive and
use machines.

4.8

Undesirable effects
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. Five adult subjects (0.6%) discontinued from the studies within a day
following administration of Osmohale because of cough, decreased lung
function, feeling jittery, sore throat, and throat irritation. One subject (0.4%)
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*.
4.9

Overdose
Susceptible persons may suffer a hyperresponsiveness reaction from an overdose. The
reaction can be treated with a bronchodilator. There is some experience with
Osmohale in clinical studies where patients experienced a 15% fall in FEV1 and
inhaled a further dose (these studies used 20-25% as the target FEV1 fall). The
maximum fall measured was 50.2%. If excessive bronchoconstriction occurs, a beta2
agonist should be given, and oxygen if necessary.

5
5.1

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Other Diagnostic Agents, ATC code: V04CX
Osmohale is an indirect bronchial provocation test used to measure bronchial
hyperresponsiveness.
Mechanism of action and pharmacodynamic effects
Published data indicate that inhaled mannitol increases the osmolarity in the
airways which results in a release of different bronchoconstriction mediators
from inflammatory cells within the airways. The mediators then act via specific
receptors to cause contraction of the bronchial smooth muscle and the airways to
narrow.
Clinical efficacy and safety
DPM-A-301
The ability of the Osmohale test to identify bronchial hyperresponsiveness was
investigated in a clinical study that enrolled 646 subjects (aged 6 to 83 years) of
whom 466 adult subjects (aged 18 years and over) completed the trial. Subjects
underwent two challenge tests: one with mannitol and one with hypertonic
saline at two separate visits.
Following completion of the study, a respiratory physician assessed the data and
categorised the subjects as being clinically asthmatic or non-asthmatic on the
basis of their medical history, history of respiratory symptoms, medications and
the results of the hypertonic saline challenge. In adults, compared to this clinical

diagnosis, the mannitol challenge had a sensitivity of 55%, and a specificity of
98%. The positive predictive value was 99% and the negative predictive value
was 34%.
The mannitol challenge test was positive (15% fall in FEV1) in 211 adult
subjects at a mean dose of 120.2 mg. The mean maximum FEV1 fall (± SD) for
the two challenges was comparable: 21.0% (± 5.7) for mannitol and 21.3%
(± 5.9) for hypertonic saline.
For the 169 adult subjects classified as asthmatic by the respiratory physician,
but negative to mannitol, 84% were taking either inhaled corticosteroids alone
or in combination with a long acting beta2 agonist. The mean % fall in FEV1 for
this group was 6.3% (± 3.7). It is important to consider current
glucocorticosteroid therapy when interpreting indirect challenge test results. In
195 adults not taking inhaled corticosteroids, compared to the clinical diagnosis,
the mannitol challenge had a sensitivity of 65% and a specificity of 98%. The
positive predictive value was 97% and the negative predictive value was 68%.
DPM- A-305
In the second clinical study, Osmohale was compared with a methacholine
bronchial challenge test in detecting bronchial hyperresponsiveness in subjects
with symptoms suggestive of asthma but without a definite diagnosis of asthma.
The 509 subjects aged 6 to 50 years were screened for enrolment with 419 and
420 subjects receiving at least one dose of Osmohale or methacholine,
respectively. The maximum cumulative dose of Osmohale was 635 mg.
During the course of the study subjects underwent three types of bronchial
challenge tests, exercise, Osmohale, and methacholine. A positive exercise test
was defined as a decrease in FEV1 ≥ 10%, a positive bronchial challenge test
with Osmohale was defined by either a decrease in FEV1 by ≥ 15% from
baseline or a between-dose reduction in FEV1 ≥ 10%, and a positive
methacholine response was defined as a decrease in FEV1 ≥ 20% after breathing
methacholine at a concentration less than or equal to 16 mg/ml. When compared
to the surrogate standards of truth of positive exercise testing and a physicians
diagnosis, the mannitol and methacholine challenge tests were diagnostically
(90% CI within 80-125%) and statistically equivalent using test sensitivity and
specificity as the primary efficacy endpoint.
Comparisons of the sensitivity and specificity for the Osmohale test and
methacholine in Study DPM-A-305

Treatment
Positive Exercise Challenge
Osmohale
Methacholine
Physicians Diagnosis
Osmohale
Methacholine

Sensitivity %
(95% CI)

Specificity %
(95% CI)

59 (51, 66)
56 (48, 63)

65 (59, 71)
69 (64, 75)

56 (49, 62)
51 (45, 57)

73 (66, 80)
75 (66 ,80)

5.2

Pharmacokinetic properties
Absorption and distribution
There are no pharmacokinetic data available for dry powder mannitol following
inhaled administration although limited animal data on mannitol solution
indicates an absorption half-life of approximately 12-60 minutes. Following
absorption, the pharmacokinetic profile of inhaled mannitol can be expected to
follow that of intravenously administered mannitol.
Biotransformation and elimination
When administered intravenously, mannitol is eliminated largely unchanged by
glomerular filtration and 80% of the dose is excreted in the urine within 3 hours. The
elimination half-life in adults is approximately 1-2 hours. In the presence of renal
failure, the half-life is extended, however this is not expected to be of clinical
significance.

5.3

Preclinical safety data
Preclinical data reveal no special hazard for humans based on short- and longterm oral repeat dose toxicity, genotoxicity and local tolerance studies.
Animal reproduction studies have not been carried out with inhaled mannitol.
However, studies conducted with orally administered mannitol indicated no
teratogenic effects in mice or rats, at doses of up to 1.6 g/kg, or in hamsters at
1.2 g/kg.
In addition, safety of the inhalation route was demonstrated by a single dose and
a two week repeat dose toxicity study in rats that revealed no toxicologically
significant findings.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
None.

6.2

Incompatibilities
Not applicable

6.3

Shelf life
36 months

6.4

Special precautions for storage
Do not store above 25°C.

6.5

Nature and contents of container
Capsules are packed in Aluminium/Aluminium blisters.
1 diagnostic kit consists of:

1 empty capsule

6.6



1 capsule containing 5 mg mannitol



1 capsule containing 10 mg mannitol



1 capsule containing 20 mg mannitol



15 capsules containing 40 mg mannitol



1 inhaler made of styrene plastics

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Pharmaxis Pharmaceuticals Limited
25 Moorgate
London
EC2R 6AY
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 27944/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/10/2011

10

DATE OF REVISION OF THE TEXT

14/10/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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