Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1202
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Exubera (Kit)
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EXUBERA, like rapid-acting insulin analogs, has a more rapid onset of glucose-lowering activity compared to subcutaneously injected regular human insulin. EXUBERA has a duration of glucose-lowering activity comparable to subcutaneously injected regular human insulin and longer than rapid-acting insulin. EXUBERA doses should be administered immediately prior to meals (no more than 10 minutes prior to each meal). In patients with type 1 diabetes, EXUBERA should be used in regimens that include a longer-acting insulin. For patients with type 2 diabetes, EXUBERA may be used as monotherapy or in combination with oral agents or longer-acting insulin. Because of the effect of EXUBERA on pulmonary function, all patients should have pulmonary function assessed prior to initiating therapy with EXUBERA. Periodic monitoring of pulmonary function is recommended for patients being treated with EXUBERA . EXUBERA is intended for administration by inhalation and must only be administered using the EXUBERA Inhaler. Refer to the EXUBERA Medication Guide for a description of the EXUBERA Inhaler and for instructions on how to use the inhaler.<br/>Calculation of Initial Pre-Meal EXUBERA Dose: The initial dosage of EXUBERA should be individualized and determined based on the physician's advice in accordance with the needs of the patient. Recommended initial pre-meal doses are based on clinical trials in which patients were requested to eat three meals per day. Initial pre-meal doses may be calculated using the following formula: [Body weight (kg) X 0.05 mg/kg = pre-meal dose (mg)] rounded down to the nearest whole milligram number (e.g., 3.7 mg rounded down to 3 mg). Approximate guidelines for initial, pre-meal EXUBERA doses, based on patient body weight, are indicated in Table 7: A 1 mg blister of EXUBERA inhaled insulin is approximately equivalent to 3 IU of subcutaneously injected regular human insulin. A 3 mg blister of EXUBERA inhaled insulin is approximately equivalent to 8 IU of subcutaneously injected regular human insulin. Table 8 provides the approximate IU dose of regular subcutaneous human insulin for EXUBERA inhaled insulin doses from 1 mg to 6 mg. Patients should combine 1 mg and 3 mg blisters so that the least number of blisters per dose are taken (e.g., a 4 mg dose should be administered as one 1 mg blister and one 3 mg blister). Consecutive inhalation of three 1 mg unit dose blisters results in significantly greater insulin exposure than inhalation of one 3 mg unit dose blister. Therefore, three 1 mg doses should not be substituted for one 3 mg dose . When a patient is stabilized on a dosing regimen that includes 3 mg blisters, and the 3 mg blisters become temporarily unavailable, the patient can temporarily substitute two 1 mgblisters for one 3 mg blister. Blood glucose should be monitored closely. As with all insulins, additional factors that should be taken into consideration when determining the EXUBERA starting dose include, but are not limited to, patient's current glycemic control, previous response to insulin, duration of diabetes, and dietary and exercise habits.<br/>Considerations for Dose Titration: After initiating EXUBERA therapy, as with other glucose-lowering agents, dose adjustment may be required based on the patient's need (e.g., blood glucose concentrations, meal size and nutrient composition, time of day and recent or anticipated exercise). Each patient should be titrated to their optimal dosage based on blood glucose monitoring results. As for all insulins, the time course of EXUBERA action may vary in different individuals or at different times in the same individual. EXUBERA may be used during intercurrent respiratory illness (e.g., bronchitis, upper respiratory tract infection, rhinitis). Close monitoring of blood glucose concentrations and dose adjustment may be required on an individual basis. Inhaled medicinal products (e.g. bronchodilators) should be administered prior to administration of EXUBERA.
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EXUBERA consists of blisters containing human insulin inhalation powder, which are administered using the EXUBERA Inhaler. EXUBERA blisters contain human insulin produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Chemically, human insulin has the empirical formula CHNOSand a molecular weight of 5808. Human insulin has the following primary amino acid sequence: EXUBERA (insulin human [rDNA origin]) Inhalation Powder is a white to off-white powder in a unit dose blister (fill mass, see Table 1). Each unit dose blister of EXUBERA contains a 1 mg or 3 mg dose of insulin (see Table 1) in a homogeneous powder formulation containing sodium citrate (dihydrate), mannitol, glycine, and sodium hydroxide. After an EXUBERA blister is inserted into the inhaler, the patient pumps the handle of the inhaler and then presses a button, causing the blister to be pierced. The insulin inhalation powder is then dispersed into the chamber, allowing the patient to inhale the aerosolized powder. Under standardized in vitro test conditions, EXUBERA delivers a specific emitted dose of insulin from the mouthpiece of the inhaler (see Table 1). A fraction of the total particle mass is emitted as fine particles capable of reaching the deep lung. Up to 45% of the 1 mg blister contents, and up to 25% of the 3 mg blister contents, may be retained in the blister. The actual amount of insulin delivered to the lung will depend on individual patient factors, such as inspiratory flow profile. In vitro, emitted aerosol metrics are unaffected at flow rates above 10 L/min.
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Mechanism of Action: The primary activity of insulin is regulation of glucose metabolism. Insulin lowers blood glucose concentrations by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.<br/>Pharmacokinetics:<br/>Absorption: EXUBERA delivers insulin by oral inhalation. The insulin is absorbed as quickly as subcutaneously administered rapid-acting insulin analogs and more quickly than subcutaneously administered regular human insulin in healthy subjects and in patients with type 1 or type 2 diabetes (see Figure 1). Figure 1: Mean Changes in Free Insulin Serum Concentrations (��U/mL) in Patients with Type 2 Diabetes Following Administration of Single Doses of Inhaled Insulin from EXUBERA (6 mg) and Subcutaneous Regular Human Insulin (18U) In clinical studies in patients with type 1 and type 2 diabetes, after inhalation of EXUBERA, serum insulin reached peak concentration more quickly than after subcutaneous injection of regular human insulin, 49 minutes (range 30 to 90 minutes) compared to 105 minutes (range 60 to 240 minutes), respectively. In clinical studies, the absorption of subcutaneous regular human insulin declined with increasing patient body mass index (BMI). However, the absorption of insulin following inhalation of EXUBERA was independent of BMI. In a study in healthy subjects, systemic insulin exposure (AUC and C) following administration of EXUBERA increased with dose over a range of 1 to 6 mg when administered as combinations of 1 and 3 mg blisters. In a study where the dosage form of three 1 mg blisters was compared with one 3 mg blister, Cand AUC after administration of three 1 mg blisters were approximately 30% and 40% greater, respectively, than that after administration of one 3 mg blister .<br/>Distribution and Elimination: Because recombinant human insulin is identical to endogenous insulin, the systemic distribution and elimination are expected to be the same. However, this has not been confirmed for EXUBERA.<br/>Pharmacodynamics: EXUBERA, like subcutaneously administered rapid-acting insulin analogs, has a more rapid onset of glucose-lowering activity than subcutaneously administered regular human insulin. In healthy volunteers, the duration of glucose-lowering activity for EXUBERA was comparable to subcutaneously administered regular human insulin and longer than subcutaneously administered rapid-acting insulin analogs (see Figure 2). Figure 2. Mean Glucose Infusion Rate (GIR) Normalized to GIRfor Each Subject Treatment Versus Time in Healthy Volunteers *Determined as amount of glucose infused to maintain constant plasma glucose concentrations, normalized to maximum values (percent of maximum values); indicative of insulin activity. When EXUBERA is inhaled, the onset of glucose-lowering activity in healthy volunteers occurs within 10���20 minutes. The maximum effect on glucose lowering is exerted approximately 2 hours after inhalation. The duration of glucose-lowering activity is approximately 6 hours. In patients with type 1 or type 2 diabetes, EXUBERA has a greater glucose-lowering effect within the first two hours after dosing when compared with subcutaneously administered regular human insulin. The intra-subject variability of glucose-lowering activity of EXUBERA is generally comparable to that of subcutaneously administered regular human insulin in patients with type 1 and 2 diabetes.<br/>Special Populations:<br/>Pediatric Patients: In children (6���11 years) and adolescents (12���17 years) with type 1 diabetes, time to peak insulin concentration for EXUBERA was achieved faster than for subcutaneous regular human insulin, which is consistent with observations in adult patients with type 1 diabetes.<br/>Geriatric Patients: There are no apparent differences in the pharmacokinetic properties of EXUBERA when comparing patients over the age of 65 years and younger adult patients.<br/>Gender: In subjects with and without diabetes, no apparent differences in the pharmacokinetic properties of EXUBERA were observed between men and women.<br/>Race: A study was performed in 25 healthy Caucasian and Japanese non-diabetic subjects to compare the pharmacokinetic and pharmacodynamic properties of EXUBERA, versus subcutaneous injection of regular human insulin. The pharmacokinetic and pharmacodynamic properties of EXUBERA were comparable between the two populations.<br/>Obesity: The absorption of EXUBERA is independent of patient BMI.<br/>Renal Impairment: The effect of renal impairment on the pharmacokinetics of EXUBERA has not been studied. Careful glucose monitoring and dose adjustments of insulin may be necessary in patients with renal dysfunction .<br/>Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of EXUBERA has not been studied. Careful glucose monitoring and dose adjustments of insulin may be necessary in patients with hepatic dysfunction .<br/>Pregnancy: The absorption of EXUBERA in pregnant patients with gestational and pre-gestational type 2 diabetes was consistent with that in non-pregnant patients with type 2 diabetes .<br/>Smoking: In smokers, the systemic insulin exposure for EXUBERA is expected to be 2 to 5 fold higher than in non-smokers. EXUBERA is contraindicated in patients who smoke or who have discontinued smoking less than 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 hypoglycemia, and an alternative treatment must be utilized . In clinical studies of EXUBERA in 123 patients (69 of whom were smokers), smokers experienced a more rapid onset of glucose-lowering action, greater maximum effect, and a greater total glucose-lowering effect (particularly during the first 2���3 hours after dosing), compared to non-smokers.<br/>Passive Cigarette Smoke: In contrast to the increase in insulin exposure following active smoking, when EXUBERA was administered to 30 healthy non-smoking volunteers following 2 hours of exposure to passive cigarette smoke in a controlled experimental setting, insulin AUC and Cmax were reduced by approximately 20% and 30%, respectively. The pharmacokinetics of EXUBERA have not been studied in nonsmokers who are chronically exposed to passive cigarette smoke.<br/>Patients with Underlying Lung Diseases: The use of EXUBERA in patients with underlying lung disease, such as asthma or COPD, is not recommended because the safety and efficacy of EXUBERA in this population have not been established . The use of EXUBERA is contraindicated in patients with unstable or poorly controlled lung disease, because of wide variations in lung function that could affect the absorption of EXUBERA and increase the risk of hypoglycemia or hyperglycemia . In a pharmacokinetic study in 24 non-diabetic subjects with mild asthma, the absorption of insulin following administration of EXUBERA, in the absence of treatment with a bronchodilator, was approximately 20% lower than the absorption seen in subjects without asthma. However, in a study in 24 non-diabetic subjects with Chronic Obstructive Pulmonary Disease (COPD), the systemic exposure following administration of EXUBERA was approximately two-fold higher than that in normal subjects without COPD . Administration of albuterol 30 minutes prior to administration of EXUBERA in non-diabetic subjects with both mild asthma (n=36) and moderate asthma (n=31) resulted in a mean increase in insulin AUC and Cof between 25 and 50% compared to when EXUBERA was administered alone .
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EXUBERA (insulin human [rDNA origin]) Inhalation Powder is available in 1 mg and 3 mg unit dose blisters. The blisters are dispensed on perforated cards of six unit dose blisters (PVC/Aluminum). The two strengths are differentiated by color print and tactile marks that can be differentiated by touch. The 1 mg blisters and respective perforated cards are printed with green ink and the cards are marked with one raised bar. The 3 mg blisters and respective perforated cards are printed with blue ink and the cards are marked with three raised bars. Five blister cards are packaged in a clear plastic (PET) thermoformed tray. Each PET tray also contains a desiccant and is covered with a clear plastic (PET) lid. The tray of five blister cards (30 unit dose blisters) is sealed in a foil laminate pouch with a desiccant. EXUBERA (insulin human [rDNA origin]) Inhalation Powder blisters, an EXUBERA Inhaler, and replacement EXUBERA Release Units are required to initiate therapy with EXUBERA and are provided in the EXUBERA Kit. A fully assembled EXUBERA Inhaler consists of the inhaler base, a chamber, and an EXUBERA Release Unit. A fully assembledInhaler is packaged with a replacement Chamber and is available in the EXUBERA Kit and as a separate unit. The Chamber is also available as an individual component. EXUBERA Release Units are individually packaged in a sealed thermoformed tray. One EXUBERA Release Unit is included in each fully assembled Inhaler. Two additional Release Units are provided in the EXUBERA Kit and in each Combination Pack. EXUBERA Release Units are also available individually. See Tables 9 and 10 for a description of these configurations. Blister Storage Not in-use (Unopened): Store at controlled room temperature, 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [see USP Controlled Room Temperature]. Do not freeze. Do not refrigerate. In-use: Once the foil overwrap is opened, unit dose blisters should be protected from moisture, stored at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [see USP Controlled Room Temperature]. Do not freeze. Do not refrigerate. Unit dose blisters should be used within 3 months after opening the foil overwrap. Return the blisters to the overwrap to protect from moisture. Additional care should be taken to avoid humid environments, e.g. steamy bathroom following ashower. Discard blister if frozen. Inhaler Storage Store at controlled room temperature, 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [see USP Controlled Room Temperature]. Do not freeze. Do not refrigerate. The EXUBERA Inhaler can be used for up to 1 year from the date of first use. Replacing The EXUBERA Release Unit The EXUBERA Release Unit in the EXUBERA Inhaler should be changed every 2 weeks. Keep out of reach of children
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Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild to moderate episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. Severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery.
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insulin human
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Exubera (Kit)
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The safety of EXUBERA alone, or in combination with subcutaneous insulin or oral agents, has been evaluated in approximately 2500 adult patients with type 1 or type 2 diabetes who were exposed to EXUBERA. Approximately 2000 patients were exposed to EXUBERA for greater than 6 months and more than 800 patients were exposedfor more than 2 years.<br/>Non-Respiratory Adverse Events: Non-respiratory adverse events reported in���1% of 1977 EXUBERA-treated patients in controlled Phase 2/3 clinical studies, regardless of causality, include (but are not limited to) the following: Metabolic and Nutritional: hypoglycemiaBody as a whole: chest painDigestive: dry mouthSpecial senses: otitis media (type 1 pediatric diabetics)<br/>Hypoglycemia: The rates and incidence of hypoglycemia were comparable between EXUBERA and subcutaneous regular human insulin in patients with type 1 and type 2 diabetes. In type 2 patients who were not adequately controlled with single oral agent therapy, the addition of EXUBERA was associated with a higher rate of hypoglycemia than was the addition of a second oral agent.<br/>Chest pain: A range of different chest symptoms were reported as adverse reactions and were grouped under the non-specific term chest pain. These events occurred in 4.7% of EXUBERA-treated patients and 3.2% of patients in comparator groups. The majority (>90%) of these events were reported as mild or moderate. Two patients in the EXUBERA and one in the comparator group discontinued treatment due to chest pain. The incidence of all-causality adverse events related to coronary artery disease, such as angina pectoris or myocardial infarction was comparable in the EXUBERA (0.7% angina pectoris; 0.7% myocardial infarction) and comparator (1.3% angina pectoris; 0.7% myocardial infarction) treatment groups.<br/>Dry Mouth: Dry mouth was reported in 2.4% of EXUBERA-treated patients and 0.8% of patients in comparator groups. Nearly all (>98%) of dry mouth reported was mild or moderate. No patients discontinued treatment due to dry mouth.<br/>Ear Events in Pediatric Diabetics: Pediatric type 1 diabetics in EXUBERA groups experienced adverse events related to the ear more frequently than did pediatric type 1 diabetics in treatment groups receiving only subcutaneous insulin. These events included otitis media (EXUBERA 6.5%; SC 3.4%), ear pain (EXUBERA 3.9%; SC 1.4%), and ear disorder (EXUBERA 1.3%; SC 0%).<br/>Respiratory Adverse Events: Table 6 shows the incidence of respiratory adverse events for each treatment group that were reported in���1% of any treatment group in controlled Phase 2 and 3 clinical studies, regardless of causality.<br/>Cough: In 3 clinical studies, patients who completed a cough questionnaire reported that the cough tended to occur within seconds to minutes after EXUBERA inhalation, was predominantly mild in severity and was rarely productive in nature. The incidence of this cough decreased with continued EXUBERA use. In controlled clinical studies, 1.2% of patients discontinued EXUBERA treatment due to cough.<br/>Dyspnea: Nearly all (>97%) of dyspnea was reported as mild or moderate. A small number of EXUBERA-treated patients (0.4%) discontinued treatment due to dyspnea compared to 0.1% of comparator-treated patients.<br/>Other Respiratory Adverse Events���Pharyngitis, Sputum Increased and Epistaxis: The majority of these events were reported as mild or moderate. A small number of EXUBERA-treated patients discontinued treatment due to pharyngitis (0.2%) and sputum increased (0.1%); no patients discontinued treatment due to epistaxis.<br/>Pulmonary Function: The effect of EXUBERA on the respiratory system has been evaluated in over 3800 patients in controlled phase 2 and 3 clinical studies (in which 1977 patients were treated with EXUBERA). In randomized, open-label clinical trials up to two years duration, patients treated with EXUBERA demonstrated a greater decline in pulmonary function, specifically the forced expiratory volume in one second (FEV) and the carbon monoxide diffusing capacity (DL), than comparator treated patients. The mean treatment group differences in FEVand DL, were noted within the first several weeks of treatment with EXUBERA, and did not progress over the two year treatment period. In one completed controlled clinical trial in patients with type 2 diabetes following two years of treatment with EXUBERA, patients showed resolution of the treatment group difference in FEVsix weeks after discontinuation of therapy. Resolution of the effect of EXUBERA on pulmonary function in patients with type 1 diabetes has not been studied after long-term treatment. Figures 3 through 6 display the mean FEVand DLchange from baseline versus time from two ongoing randomized, open-label, two year studies in 580 patients with type 1 and 620 patients with type 2 diabetes. Figure 3: Change from Baseline FEV1 (L) in Patients with Type 1 Diabetes (Mean +/-Standard Deviation) Figure 4: Change from Baseline FEV1 (L) in Patients with Type 2 Diabetes (Mean +/- Standard Deviation) Following 2 years of EXUBERA treatment in patients with type 1 and type 2 diabetes, the difference between treatment groups for the mean change from baseline FEVwas approximately 40 mL, favoring the comparator. Figure 5: Change from Baseline DLco (mL/min/mmHg) in Patients with Type 1 Diabetes (Mean +/- Standard Deviation) Figure 6: Change from Baseline DLco (mL/min/mmHg) in Patients with Type 2 Diabetes (Mean +/- Standard Deviation) Following 2 years of EXUBERA treatment, the difference between treatment groups for the mean change from baseline DLwas approximately 0.5mL/min/mmHg (type 1 diabetes), favoring the comparator, and approximately 0.1mL/min/mmHg (type 2 diabetes), favoring EXUBERA. During the two-year clinical trials, individual patients experienced notable declines in pulmonary function in both treatment groups. A decline from baseline FEVof���20% at last observation occurred in 1.5% of EXUBERA-treated and 1.3% of comparator-treated patients. A decline from baseline DLof���20% at last observation occurred in 5.1% of EXUBERA-treated and 3.6% of comparator treated patients.
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EXUBERA is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia. EXUBERA has an onset of action similar to rapid-acting insulin analogs and has a duration of glucose-lowering activity comparable to subcutaneously administered regular human insulin. In patients with type 1 diabetes, EXUBERA should be used in regimens that include a longer-acting insulin. In patients with type 2 diabetes, EXUBERA can be used as monotherapy or in combination with oral agents or longer-acting insulins.
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Exubera
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