Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pharmaxis Europe Limited, 108 Q House, Furze Road, Sandyford, Dublin 18, D18AY29, Ireland
Pharmacotherapeutic group: Other Diagnostic Agents
ATC code: V04CX
Osmohale is an indirect bronchial provocation test used to measure bronchial hyperresponsiveness.
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.
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%.
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 | Sensitivity % (95% CI) | Specificity (95 CI) |
|---|---|---|
| Positive Exercise Challenge | ||
| Osmohale | 59 (51, 66) | 65 (59, 71) |
| Methacholine | 56 (48, 63) | 69 (64, 75) |
| Physicians Diagnosis | ||
| Osmohale | 56 (49, 62) | 73 (66, 80) |
| Methacholine | 51 (45, 57) | 75 (66, 80) |
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.
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.
Preclinical data reveal no special hazard for humans based on short- and long-term 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.
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