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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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Diss Factsheets

Administrative data

Endpoint:
health surveillance data
Type of information:
other: clinical data from therapeutic use of human insulin
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Drug information data from European Medicines Agency and data form clinical investigations by Novo Nordisk A/S on inhalation treatment with human insulin
Justification for type of information:
Data from medical inhalation treatment with human insulin

Data source

Materials and methods

Results and discussion

Results:
Extraction of relevant data on inhalation therapy with human insulin

EXUBERA (Pfizer)
Data extracted from EMEA website:
ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS; 09/07/2008 Exubera -EMEA/H/C/000588 -II/0015
and
Drug information sheet by Pfizer; (Revised April 2008)
(Withdrawn from the market in 2008 for commercial reasons)

Extracted data:

Administration and kinetics:
Inhaled human insulin is delivered by the pulmonary route. Inhaled human insulin is absorbed as rapidly as fast-acting insulin analogues and more rapidly than subcutaneously administered fast-acting human insulin, both in healthy subjects and in subjects with type 1 or type 2 diabetes. When human insulin is inhaled, the onset of glucose lowering activity is within 10-20 minutes, and the maximum effect is obtained approximately 2 hours after inhalation. The duration of action lasts approximately 6 hours. The relative bioavailability of EXUBERA compared to subcutaneous fast-acting human insulin is approximately 10%.
Only approximately 70% of the dose is inhaled as 30% of the powder formulation is retained in the blister and inhalation equipment.
Recommended dose level of a 70 kg diabetic person is 3 x 3 mg/ d (before meals).
The intra-subject variability of glucose lowering activity of inhaled human insulin was generally comparable to that of subcutaneously administered fast-acting human insulin in subjects with type 1and 2 diabetes mellitus.
Smoking greatly increases the rate and extent of absorption of inhaled human insulin (Cmax about 3 to 5 times and AUC about 2 to 3 times higher) and therefore could increase the risk of hypoglycemia.

Side effects from treatment:
Very Common (> 1/10): Hypoglycaemia; cough
Common (> 1/100, < 1/10): Dyspnoea; productive cough; throat irritation; dry throat
Uncommon (> 1/1000, < 1/100): Pharyngitis; Epistaxis; Bronchospasm; Wheezing; Dysphonia; Pharyngolaryngeal Pain; Tonsillar Disorder; Dry Mouth; Chest pain.
Hypoglycaemia is the most commonly reported adverse event of insulin therapy, including EXUBERA. Further, in clinical trials small but consistent decline of pulmonary function (particularly Forced Expiratory Volume in one second (FEV1)) in treated subjects have been observed). In clinical studies of up to two years duration, there was no accelerated decline beyond 3-6 months. These small treatment group differences resolved within 6 weeks upon discontinuation after 2 years of treatment. Use of inhaled human insulin is associated with an increase in frequency, and levels of insulin antibodies. In a prospective exploratory 6 month study in subjects with type 1 diabetes, alterations in the glucose pharmacodynamics with inhaled human insulin were not observed.

Former Smokers and cancer:
In clinical trials of Exubera, there have been 6 newly diagnosed cases of primary lung malignancies among Exubera-treated patients, and 1 newly diagnosed case among comparator treated patients.
There has also been one post-marketing report of a primary lung malignancy in an Exubera-treated patient. In controlled clinical trials with Exubera, the incidence of new primary lung cancer per 100 patient-years of study drug exposure was 0.130 (5 cases over 3800 patient-years) for Exubera-treated patients and 0.03 (1 case over 3900 patient-years) for comparator-treated patients. There were too few cases to determine whether the emergence of these events is related to Exubera. All patients who were diagnosed with lung cancer had a prior history of cigarette smoking.

Data from Novo Nordisk 2006: Clinical Risk Management Plan for
Pulmonary Delivery of Insulin Human via AERx® insulin Diabetes Management System)
Also data from Novo Nordisk indicate hypoglycaemic espisodes as rather frequent in a clinical study with diabetic persons :
“Overall, in the clinical trials with AERx, the number of hypoglycaemic episodes was similar between treatment groups. In the 12-month data from the NN1998-1496 trial, the proportion of subjects who experienced hypoglycaemia over 24 hours during the 0-12 month treatment period was similar for subjects treated with inhaled human insulin (96%) and s.c. insulin aspart (98%)”

Applicant's summary and conclusion

Conclusions:
Repeated dose toxicity, identification of human LOAEL:

As indicated from the experience from inhalation therapy with human insulin very common side-effects are hypoglycaemia and a slight reduction in lung function. This has been reported in relation to the therapeutic dose level of 3 mg inhaled three times a day.
Of this dose daily dose, about 70% or 6.3 mg/d of the dose will reach the respiratory tract as approximately 30% of the dose is retained in the blister and inhaler.
Thus, a dose level of 6.3 mg/day can be used as LOAEL for inhalation of human insulin.
It is generally recognised that diabetic persons are much more susceptible to hypoglycaemic episodes than the normal population as their homeostatic mechanisms for blood sugar regulation is impaired. E.g. they are more susceptible to changes in blood suger levels caused by changes in food composition and meal pattern or physical activity which can make them more susceptible towards hypoglycaemic episodes from exposure to insulin.

So when using a LOAEL of 6.3 mg/d it should be recognised that this LOAEL pertain to an especially vulnerable subpopulation.
Such a LOAEL is considered relevant for the REACH registration of “Human insulin methyl ester”; “ Insulin DesB30” and “Insulin aspart ethyl ester” due to the close structural relationship to human insulin and as these intermediate substances for the active pharmaceutical ingredients API bind to the human insulin receptor as well.

Cancer:
The above data regarding observation of few cases of lung cancer among smokers and the lack of causal association is not considered sufficient for a carc. cat 2 classification. As the effects only have been observed in smokers it most probably points towards a co-carcinogenic effect and not as a carcinogenic effect of insulin as such.