Medicinal products used in Diabetes

Insulin

Each unit dose blister contains 1 mg or 3 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. Produced by recombinant DNA technology in Escherichia coli.

Inhalation powder, pre-dispensed. White powder.

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.

EXUBERA is also indicated for the treatment 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

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.

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:

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 fast-acting 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.

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.

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.

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.

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.

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

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

Hypoglycaemia.

Patients must not smoke during therapy with EXUBERA and must have stopped smoking at least 6 months prior to starting EXUBERA therapy. If a patient starts or resumes smoking, EXUBERA must be discontinued immediately due to the increased risk of hypoglycaemia and an alternative treatment utilised.

Poorly controlled, unstable, or severe asthma.

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

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.

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.

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 fast-acting 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.

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 hypoglycaemia.

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 and should be advised accordingly.

Usual warning symptoms may disappear in patients with longstanding diabetes.

A few patients who have experienced hypoglycaemic reactions after transfer 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

Underlying respiratory 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 symptom.

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.

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 this 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 be repeated at one year and then annually. If at 6 months a decline of 15-20% or> 500ml from baseline 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 apart) FEV₁ decline of> 20% from baseline, EXUBERA therapy should be discontinued and the patient monitored as clinically indicated. There is no experience with the reinstitution of EXUBERA therapy in patients 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. 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.

A 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.

Administration of fluticasone prior to EXUBERA does not appear to affect insulin absorption.

Active smoking greatly enhances whereas passive exposure to tobacco smoke in non-smokers decreases the rate and extent of absorption of EXUBERA.

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.

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.

Dyspnoea

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

FEV₁ 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.

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.

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.

Pfizer Ltd

(POM)