Exubera - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

EXUBERA 1 mg inhalation powder pre-dispensed.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each unit dose blister contains 1 mg insulin human.

The exposure of human insulin following administration of three 1 mg blisters is significantly greater than that following a single 3 mg blister. Therefore, the 3 mg blister is not interchangeable with three 1 mg blisters (see sections 4.2, 4.4 and 5.2).

Produced by recombinant DNA technology

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Inhalation powder, pre-dispensed.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

EXUBERA is indicated for the treatment of adult patients with type 2 diabetes mellitus not adequately controlled with oral antidiabetic agents and requiring insulin therapy.

ent of adult patients with type 1 diabetes mellitus, in addition to long or intermediate acting subcutaneous insulin, for whom the potential benefits of adding inhaled insulin outweigh the potential safety concerns (see section 4.4).

4.2 Posology and method of administration

EXUBERA (inhaled human insulin) is a fast-acting human insulin for use in type 1 or type 2 diabetes. Inhaled human insulin may be used alone or in combination with oral antidiabetic agents and/or long or intermediate acting subcutaneously administered insulins to optimise glycaemic control.

EXUBERA is available in 1 mg and 3 mg unit dose blisters which are for administration via the lungs by oral inhalation only with the insulin inhaler.

Consecutive inhalation of three 1 mg unit dose blisters causes a significantly higher insulin exposure than inhalation of one 3 mg unit dose blister. Therefore three 1 mg unit dose blisters should not be substituted for one 3 mg unit dose blister (see sections 2, 4.4 and 5.2).

Inhaled human insulin has a faster onset of activity than subcutaneously administered fast-acting human insulin. Due to the rapid onset of activity, inhaled human insulin should be given within 10 minutes before the start of a meal.

The starting and subsequent dosage (dose and timings) should be determined individually by the physician and adjusted according to the patient’s indi­vidual response and requirements (e.g. diet, physical activity and life-style).

Daily doses and timing of administration

There are no fixed rules for insulin dosage. However, a recommended starting daily dose is based on the following formula:

Body weight (kg) X 0.15 mg/kg = Total Daily Dose (mg). The total daily dose should be divided into three pre-meal doses.

Approximate guidelines for initial, pre-meal EXUBERA doses, based on patient body weight, are indicated in Table 1:

Patient Weight	Initial Dose per Meal	Approximate IU Dose	Number of 1 mg Blisters per Dose	Number of 3 mg Blisters per Dose
30 to 39.9 kg	1 mg per meal	3 IU	1	w –
40 to 59.9 kg	2 mg per meal	6 IU	2       (	–
60 to 79.9 kg	3 mg per meal	8 IU	–      a!	1
80 to 99.9 kg	4 mg per meal	11 IU	1	1
100 to 119.9 kg	5 mg per meal	14 IU	2	1
120 to 139.9 kg	6 mg per meal	16 IU	A-WJ	2

Table 1: Approximate Guidelines for Initial, Pre-Meal EXUBERA Dose (based on patient body weight).

A 1 mg blister of inhaled insulin is approximately equivalent to 3 IU of subcutaneously injected fastacting human insulin. A 3 mg blister of inhaled insulin is approximately equivalent to 8 IU of subcutaneously injected fast-acting human insulin. Table 1 above presents the approximate IU dose of fast-acting human insulin for initial, pre-meal EXUBERA doses in mg.

Therefore, EXUBERA should be used with caution in patients of low body weight. The use of EXUBERA in patients requiring dose titrations of less than 1 mg is not recommended (see section 4.4).

Dose adjustment may be required based on the meal size and nutrient composition, time of day (higher insulin requirements in the morning), pre-meal blood glucose concentration, recent or anticipated exercise.

During intercurrent respiratory illness (e.g. bronchitis, upper respiratory tract infections) close monitoring of blood glucose concentrations and dose adjustment may be required on an individual basis (see section 4.4).

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For further details on how to use the insulin inhaler refer to the instructions for use (IFU).

Hepatic and renal impairment

In patients with hepatic or renal impairment insulin requirements may be diminished.

Children and adolescents

Long-term safety of inhaled human insulin has not been established in paediatric patients with diabetes and its use is therefore not recommended in patients under 18 years of age (see section 5.2).

Elderly

Experience with inhaled insulin in patients > 75 years of age is limited.

Congestive heart failure

Experience with inhaled insulin in patients with congestive heart failure is very limited and its use is therefore not recommended in such patients where lung function is significantly compromised.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Hypoglycaemia.

Patients must not smoke during therapy with EXUBERA and must have stopped s months prior to starting EXUBERA therapy. If a patient starts or resumes smokin be discontinued immediately due to the increased risk of hypoglycaemia and a utilised (see section 5.2).

Poorly controlled, unstable, or severe asthma.

Severe (GOLD stage III or IV) Chronic obstructive pulmonary disease (COPD).

4.4 Special warnings and precautions for use

Patients started on EXUBERA must receive comprehensive instructions in the use of the inhaler (see IFU). Patients should inhale the insulin powder from the mouthpiece in one slow and steady inhalation. Patients should then hold their breath for 5 seconds and exhale normally. A consistent and standard inhalation technique should be employed to ensure both optimal and consistent drug delivery.

Patients should avoid exposing the product to high moisture or relative humidity conditions e.g. a steamy bathroom, when taking their dose.

If the insulin inhaler is inadvertently exposed to extremely moist conditions during use this usually leads to a subsequent decreased insulin dose delivered from the inhaler. In this case, the Insulin Release Unit (IRU) must be changed prior to the next inhalation (see section 6.6).

Dosing

Transferring a patient to another type or brand of insulin should be done under strict medical supervision as this may result in a change in dosage.

Consecutive inhalation of three 1 mg unit dose blisters causes a significantly higher insulin exposure than inhalation of one 3 mg unit dose blister. Therefore three 1 mg unit dose blisters should not be substituted for one 3 mg unit dose blister (see sections 2, 4.2 and 5.2).

If the 3 mg blister is temporarily unavailable, two 1 mg blisters should be substituted and blood glucose monitored closely.

A 1 mg blister of inhaled insulin is approximately equivalent to 3 IU of subcutaneously injected fastacting human insulin. Therefore, EXUBERA should be used with caution in patients of low body weight. The use of EXUBERA in patients requiring dose titrations of less than 1 mg is not recommended (see section 4.2).

Hypoglycaemia

Hypoglycaemia, in general the most frequent undesirable effect of insulin therapy including EXUBERA and many oral antidiabetic agents, may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life threatening.

Symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

Hypoglycaemia can generally be corrected by immediate carbohydrate intake. In order to be able to take action immediately, patients should carry glucose with them at all times.

Omission of a meal or unplanned, strenuous physical exercise may lead to hypog mia.

Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia an accordingly.

Usual warning symptoms may disappear in patients with longstandi

A few patients who have experienced hypoglycaemic reactio         nsfer from animal source

insulin to human insulin have reported that early warning symptoms of hypoglycaemia were less pronounced or different from those experienced with their previous insulin.

Before travelling between different time zones, the patient should be advised to consult the doctor, since this may mean that the patient has to take insulin and meals at different times.

Inadequate dosage or discontinuation of treatment especially in insulin-dependant diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

When used with other antidiabetic agents, the dose of each agent should be carefully adjusted to determine the optimal dose required to achieve the desired pharmacological effect.

Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances, or stress.

Pulmonary Safety

• •espiratory disorders

EXUBERA should not be used in patients with lung disease such as asthma and COPD, as there are insufficient data to support the safe use in these patients.

The concomitant use of bronchodilators such as salbutamol may increase the absorption of EXUBERA and may therefore increase the risk of hypoglycaemia when used to relieve acute respiratory symptoms (see section 4.5).

Respiratory

Bronchospasm may rarely occur. Any patients experiencing such a reaction should discontinue EXUBERA and seek medical evaluation immediately. Re-administration of EXUBERA requires a careful risk evaluation, and may only be done under close medical monitoring with appropriate clinical facilities.

Decline in pulmonary function

In clinical trials small but consistent treatment group differences in decline of pulmonary function (particularly Forced Expiratory Volume in one second (FEV1)) favouring comparator 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 (see sections 4.8 and 5.1).

All patients initiated on EXUBERA should have a baseline lung function examination (e.g. spirometry to measure FEV1). The efficacy and safety of inhaled human insulin in patients with baseline FEV1 < 70% predicted have not been established and the use of inhaled human insulin in t population is not recommended. A follow-up lung function measurement is recommended after the first 6 months of therapy. If at 6 months a decline of < 15% FEV1 is observed, spirometry should b repeated at one year and then annually. If at 6 months a decline of 15–20% or > lung function is observed, spirometry should be repeated after 3 months.

In patients with a confirmed (i.e. at least two consecutive tests, 3 to 4 weeks apar > 20% from baseline, EXUBERA therapy should be discontinued and the patient clinically indicated. There is no experience with the reinstitution of EXUB whose lung function recovers.

Patients developing dyspnoea while treated with EXUBERA should be examined for pulmonary or cardiac causes. Where pulmonary oedema is present, or there is a clinically relevant reduction in pulmonary function, EXUBERA should be discontinued and the patient switched to injectable insulin.

Intercurrent Respiratory Illness

EXUBERA has been administered to patients with intercurrent respiratory illness (e.g. bronchitis, upper respiratory tract infections) during clinical trials. Increased risk of hypoglycaemia or poor glycaemic control has not been observed in these trials. During intercurrent respiratory illness close monitoring of blood glucose concentrations and dose adjustment may be required on an individual basis (see section 4.2). There is no experience with EXUBERA in patients with pneumonia.

Former Smokers

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 1 post-marketing report of a primary lung malignancy in an Exubera-treated patient. In controlled clinical trials of 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.

Interaction with other medicinal products and other forms of interaction

number of substances affect glucose metabolism and may require dose adjustment of insulin.

Substances that may enhance the blood-glucose lowering effect and increase susceptibility to hypoglycaemia include oral antidiabetic agents, angiotensin converting enzyme (ACE) inhibitors, monoamino oxidase (MAO) inhibitors, non-selective beta-blocking agents, salicylates and sulphonamide antibiotics.

Administration of salbutamol prior to EXUBERA may result in increased insulin absorption (see section 5.2).

Administration of fluticasone prior to EXUBERA does not appear to affect insulin absorption (see section 5.2).

Active smoking greatly enhances whereas passive exposure to tobacco smoke in non-smokers decreases the rate and extent of absorption of EXUBERA (see sections 4.3 and 5.2).

Substances that may reduce the blood-glucose lowering effect include corticosteroids, danazol, oral contraceptives, thyroid hormones, growth hormone, sympathomimetic agents and thiazides.

Octreotide/lan­reotide may both decrease or increase insulin requirements.

Beta-blocking agents may mask the symptoms of hypoglycaemia. Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

Administration of EXUBERA 10 minutes prior to administration of salbutamol did not affect the bronchodilatory response to salbutamol in non-diabetic subjects with mild-moderate asthma.

Other drugs that may alter pulmonary absorption or lung permeability have not been studied. Close monitoring of blood glucose concentrations and dose titration as appropriate are recommended when inhaled human insulin is used in these patients. Caution should be exercised with concomitant use of EXUBERA and such drugs.

• 4.6 Pregnancy and lactation

There is no clinical experience with EXUBERA use in pregnancy. Inhaled insulin frequently induces insulin antibodies, the risk of which to the foetus is not known. Therefore, EXUBERA should not be used during pregnancy. When an EXUBERA treated patient becomes pregnant appropriate subcutaneous insulin should be substituted for inhaled insulin.

Breast-feeding women may require adjustments in insulin dose and diet.

4.7 Effects on ability to drive and use machines

As with other insulins, the patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

4.8 Undesirable effects

The safety of EXUBERA alone, or in combination with subcutaneous insulin or oral agents has been evaluated in clinical studies of more than 2700 patients with type 1 or type 2 diabetes, including more than 1975 adults exposed for greater than 6 months and more than 745 adults for greater than 2 years.

The table below contains adverse reactions seen in controlled clinical studies including more than 1970 patients exposed to EXUBERA.

Body System	Very Common (> 1/10)	Common (> 1/100, < 1/10)	Uncommon (> 1/1000, < 1/100)
Infections and Infestations			Pharyngitis
Metabolism and Nutritional Disorders	Hypoglycaemia
Respiratory, Thoracic and Mediastinal Disorders	Cough	Dyspnoea Productive Cough Throat Irritation Dry Throat	Epistaxis Bronchospasm Wheezing Dysphonia Pharyngolaryngeal Pain Tonsillar Disorder
Gastrointestinal Disorders			Dry Mouth
General Disorders and Administration Site Conditions			Chest Pain

Note: In the overall clinical program, including uncontrolled extension studies, there were two reports of pleural effusion in which a treatment-related effect could not be excluded.

Hypoglycaemia

As with other insulins, hypoglycaemia was the most frequently observed undesirable effect in patients treated with EXUBERA.

Cough

The cough tended to occur within seconds to minutes after insulin inhalation and was predominantly mild in severity. This cough decreased over time. One percent of patients discontinued EXUBERA treatment due to cough.

The majority (> 95%) of dyspnoea was reported as mild to moderate. In EXUBERA treated subjects 0.4% discontinued treatment due to dyspnoea.

Chest pain

A range of different chest symptoms were reported as treatment-related adverse reactions and were referred to as non-specific chest pain. The majority (> 95%) of these events was reported as mild to moderate. One subject in the EXUBERA and one in the comparator group discontinued treatment due to chest pain. Importantly, the incidence of all-causality adverse events related to coronary artery disease, such as angina pectoris or myocardial infarction was not increased with the use of EXUBERA.

Other reactions

FEV 1 decline

Small treatment group differences in decline of FEV1 were observed in the EXUBERA group relative to comparator therapy. In clinical studies of up to two years duration, there was no accelerated decline beyond 3–6 months. Discontinuation of EXUBERA therapy after 2 years resulted in resolution of treatment group differences within 6 weeks (see sections 4.4 and 5.1).

A decline from baseline in FEV1 of > 15% occurred in 1.3% of EXUBERA-treated type 1 subjects and in 5.0% of EXUBERA-treated type 2 subjects.

Insulin antibodies

Insulin antibodies may develop during treatment with all insulins including EXUBERA. In clinical trials, insulin antibodies developed more frequently and mean levels of insulin antibodies were higher in patients who switched their subcutaneous human insulin to EXUBERA compared to subjects who remained on subcutaneous human insulin. Insulin antibody levels were higher in patients with type 1 diabetes compared to type 2 diabetes and plateaued within 6–12 months of exposure in both groups. No clinical significance of these antibodies has been identified.

Hypersensitivity reactions

As with other insulins, generalised allergic reactions may occur very rarely. Such reactions to insulin or the excipients may, for example, be associated with generalised skin reactions, angio-oedema, bronchospasm, hypotension and shock and may be life-threatening (see section 4.4 Respiratory).

Oedema and refraction abnormalities of the eye

Insulin therapy may cause sodium retention and oedema. Refraction abnormalities of the eye may occur upon initiation of insulin therapy. These effects are usually transitory.

4.9 Overdose

Hypoglycaemia may occur as expenditure or both.

Mild episodes of hypoglycaemia usually can be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed.

More severe episodes, with coma, seizure, or neurological impairment may be treated with intramuscular/sub­cutaneous glucagon (0.5 to 1 mg) or concentrated intravenous glucose. Glucose must also be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes.

Upon regaining consciousness, administration of oral carbohydrate is recommended for the patient in order to prevent relapse.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Medicinal products used in diabetes, ATC code: A10AF01

Mode of Action

Human insulin lowers blood glucose and promotes anabolic effects as well as decreasing catabolic effects, increases the transport of glucose into cells as well as the formation of glycogen in the muscles and the liver, and improves pyruvate utilisation. It inhibits glycogenolysis and gluconeogenesis, increases lipogenesis in the liver and adipose tissue and inhibits lipolysis. It also promotes the uptake of amino acids into cells and promotes protein synthesis and enhances the uptake of potassium into cells.

Inhaled human insulin, like fast-acting insulin analogues, has a more rapid onset of glucose lowering activity compared to subcutaneously administered soluble human insulin. Inhaled human insulin has a duration of glucose lowering activity comparable to subcutaneously administered fast-acting human insulin and longer than fast-acting insulin analogues (see Figure 1).

o tn             ico             tao imo

Time (min)

Figure 1. Mean Glucose Infusion Rate (GIR) Normalised to GIRmax for Each Subject Treatment Versus Time in Healthy Volunteers.

When human insulin is inhaled, the onset of glucose lowering activity is within 10–20 minutes, the maximum effect is exerted approximately 2 hours after inhalation. The duration of action lasts approximately 6 hours.

In subjects with type 1 or type 2 diabetes, inhaled human insulin has a faster onset of glucose lowering effect in the early hours after dosing when compared with subcutaneously administered fastacting human insulin.

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 1 and 2 diabetes mellitus.

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.

Information on Clinical Trials

Controlled clinical trials in type 1 or type 2 diabetes have shown that EXUBERA achieves and maintains effective glycaemic control comparable to subcutaneously administered fast-acting human insulin.

Type 1 Diabetes

In clinical trials in type 1 diabetes, patients using a regimen of EXUBERA in combination with long-or intermediate-acting insulin had similar reductions in HbA1c compared with patients taking subcutaneous insulin alone. The percentage of patients who achieved a goal of HbA1c < 7.0% was comparable between the treatment groups.

Fasting plasma glucose levels were significantly lower in patients treated with regimens including EXUBERA compared with those treated with subcutaneously administered fast-acting human insulin only regimens.

Type 2 Diabetes

Patients in a clinical trial for type 2 diabetes, who used a regimen of EXUBERA in combination with long- or intermediate-acting insulin, had similar changes in HbA1c compared with patients treated with subcutaneous insulin alone.

Fasting plasma glucose levels were significantly lower in patients treated with EXUBERA regimens compared with those treated with subcutaneous insulin.

In clinical trials involving patients with type 2 diabetes not sufficiently controlled with oral agents alone, patients using a regimen of EXUBERA alone or in combination with oral agents, had greater improvements in HbA1c compared with patients treated with oral agents alone. In most of these studies the percentages of patients achieving HbA1c < 7.0% were higher for patients using a regimen including EXUBERA compared to patients on oral agents alone. Fasting plasma glucose was similar to or lower in patients using a regimen including EXUBERA compared to patients treated with oral agents alone. In patients with type 2 diabetes sufficiently controlled with oral agents the glycaemic control was not further improved by inhaled insulin.

FEV i decline              Q

Randomised, open label parallel group studies were conducted to examine FEV1 changes following initiation of EXUBERA therapy in type 1 and 2 subjects. Both EXUBERA and comparator treated subjects experienced declines in lung function over time during these trials (Figures 2 and 3). Small treatment group differences (favouring comparator) in change from baseline of 0.034L in type 1 and 0.039L in type 2 occurred after 2 years of therapy.

A decline from baseline in FEVi of > 15% occurred in 1.3% of EXUBERA-treated and 1.0% of comparator-treated type 1 subjects and in 5.0% of EXUBERA-treated and 3.4% of comparator-treated type 2 subjects.

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FEV 1 reversibility

In type 1 subjects, resolution of small treatment group differences (0.010L favouring comparator) occurred within 2 weeks of EXUBERA cessation following 12 weeks of therapy. In type 2 subjects, resolution of small treatment group differences (0.039L favouring comparator) occurred within 6 weeks of EXUBERA cessation following 2 years of therapy (Figure 3). In a smaller group (n=36) of mixed type 1 and 2 subjects treated with EXUBERA for > 36 months, cessation of therapy resulted in a mean FEV1 increase of 0.036L over the subsequent 6 months.

5.2 Pharmacokinetic properties

Absorption

The time to peak insulin concentration (Tmax) is generally half of that for subcutaneously administered fast-acting human insulin. Peak insulin concentration is reached generally by 45 minutes for inhaled human insulin. Intrasubject variability of time to peak insulin concentrations was less for inhaled human insulin than for subcutaneous fast-acting human insulin in subjects with type 1 or 2 diabetes.

In subjects with type 1 diabetes mellitus, inhaled human insulin had a comparable intrasubject variability of AUC to subcutaneously administered fast-acting human insulin. For Cmax, the intrasubject variability of inhaled insulin is greater than that of subcutaneously administered fastacting human insulin. In obese subjects with type 2 diabetes, intrasubject variability was comparable to or less than that of subcutaneously administered fast-acting human insulin for Cmax and AUC.

The relative bioavailability of EXUBERA compared to subcutaneous fast-acting human insulin is approximately 10%. Unlike subcutaneous insulin preparations, the bioavailability of EXUBERA is not influenced by Body Mass Index.

In a study in healthy subjects, systemic exposure (AUC and Cmax) of inhaled human insulin increased in an approximately dose proportional fashion from 1 mg to 6 mg when a maximum of two blisters from either strength or their combination was administered. In a study where the dosage form of three 1 mg blisters was compared with one 3 mg blister, Cmax and AUC of inhaling three 1 mg blisters were approximately 30% and 40% greater, respectively, than that of inhaling from one 3 mg blister, indicating that three 1 mg blisters are not interchangeable with one 3 mg blister (see sections 2, 4.2 and 4.4).

An approximately 40% higher bioavailability of three 1 mg unit dose blisters compared to one 3 mg unit dose blister was observed in healthy subjects. An explanation for the differences in bioavailability appears to be the different energy to mass ratio between the 1 and 3 mg unit blisters since with less powder in the blister the inhaler is more efficient in breaking up or de-agglomerating the powder leading to a larger proportion of smaller aerodynamic particle sizes for the 1 mg (see sections 2 and 4.4).

Distribution

Following oral inhalation of a single dose of human insulin approximately 30% of th content remains in the blister or device, 20% is deposited in the oropharynx, 10% in the conducting airways and 40% reaches the deep lung.

Animal studies did not show that inhaled human insulin accumulates in the lung.

Special Populations

Smoking

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 hypoglycaemia (see sections 4.3 and 4.5).

When EXUBERA was administered to healthy volunteers following 2-hours of passive exposure to

setting, insulin AUC and Cmax were reduced by section 4.5).

Respiratory Diseases (Underlying Lung Disease)

In non-diabetic subjects with mild to moderate asthma, AUC and Cmax for inhaled human insulin in the absence of treatment with a bronchodilator was slightly less than in subjects without asthma.

In non-diabetic subjects with COPD, the absorption of inhaled human insulin appeared greater compared with that in subjects without COPD (see section 4.4).

Administration of salbutamol 30 minutes prior to EXUBERA in non-diabetic subjects with mildmoderate asthma resulted in an increase in insulin AUC and Cmax of between 25 and 51% compared to when EXUBERA was administered alone (see sections 4.2 and 4.5).

Administration of fluticasone 30 minutes prior to EXUBERA did not affect the pharmacokinetics of EXUBERA in non-diabetic subjects with mild-moderate asthma (see section 4.5).

Renal impairment

The effect of renal impairment on the absorption of inhaled human insulin has not been studied (see section 4.2).

Hepatic impairment

The effect of hepatic impairment on the absorption of inhaled human insulin has not been studied (see section 4.2).

Gender

In subjects with diabetes and in subjects without diabetes, no apparent differences in absorption of inhaled human insulin were observed between men and women.

Children and adolescents

In children (6–11 years) and adolescents (12–17 years) with type 1 diabetes, inhaled human insulin was absorbed more rapidly than fast-acting human insulin. Bioavailability of inhaled human insulin relative to subcutaneously administered fast-acting human insulin was comparable to that of adult subjects with type 1 diabetes (see section 4.2).

Elderly

In older subjects with type 2 diabetes, inhaled human insulin was absorbed more rapidly than subcutaneously administered fast-acting human insulin. Bioavailability of inhaled human insulin relative to subcutaneously administered fast-acting human insulin was comparable to those in younger adult subjects with type 2 diabetes.

Inhalation toxicity studies in rats and monkeys for up to 6 months gave no evidence for a special risk to the respiratory tract due to insulin inhalation powder.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Mannitol

Glycine

Sodium Citrate (as dihydrate)

Sodium Hydroxide

6.2 Incompatibilities

Not applicable.

ears

After first opening the foil overwrap: 3 months.

6.4 Special precautions for storage

Store below 30oC. Store in the original package in order to protect from moisture.

After opening the foil overwrap: Store below 25oC.

Do not refrigerate or freeze the unit dose blisters.

The inhaler and its components should be stored and used in a dry place.

Do not refrigerate or freeze the insulin inhaler.

6.5 Nature and contents of container

One blister card contains 6 perforated unit dose blisters (PVC/Aluminium). Five blister cards are in a clear plastic (PET) thermoformed tray with a desiccant and covered with a clear plastic (PET) lid. The tray is sealed in a foil laminate pouch with a desiccant.

Packaging sizes supplied:

Cardboard box containing 30 × 1 PVC/Aluminium perforated unit dose blisters (1 pouch)

Cardboard box containing 60 × 1 PVC/Aluminium perforated unit dose blisters (2 pouches)

Cardboard box containing 90 × 1 PVC/Aluminium perforated unit dose blisters (3 pouches)

Cardboard box containing 180 × 1 PVC/Aluminium perforated unit dose blisters (6 pouches)

Cardboard box containing 270 × 1 PVC/Aluminium perfor

Cardboard box containing 60 × 1 PV 2 spare Insulin Release Units (IRU)

Cardboard box containing 270 × 1 PVC/Aluminium perforated unit dose blisters (9 pouches) and 6 spare Insulin Release Units (IRU)

A kit containing 90 × 1 PVC/Aluminium perforated unit dose blisters (3 pouches), 1 insulin inhaler, 1 spare chamber and 6 spare Insulin Release Units (IRU)

Additional insulin inhaler, insulin release units and chamber packages are available.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

EXUBERA unit dose blisters must only be used with the insulin inhaler.

The insulin inhaler should be replaced annually.

in Release Unit (IRU) should be replaced once every 2 weeks.

the insulin inhaler is inadvertently exposed to extremely moist conditions during use this usually ads to a subsequent decreased insulin dose delivered from the inhaler. In this case, the Insulin elease Unit (IRU) must be changed prior to the next inhalation (see section 4.4).

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited

Ramsgate Road, Sandwich, Kent, CT13, 9NJ

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/327/001

EU/1/05/327/002

EU/1/05/327/003

EU/1/05/327/004

EU/1/05/327/005

EU/1/05/327/006

EU/1/05/327/007

EU/1/05/327/008

10. DATE OF REVISION OF THE TEXT