Afrezza (吸入式胰岛素)2014年6月27日，FDA正式批准吸入性胰岛素制剂（Afrezza）用于改善成人糖尿病患者的血糖控制。Afrezza是一种迅速起效的吸入性胰岛素输入设备，在进餐前或进餐后20分钟给药，由美国康涅狄格州丹伯里MannKind公司制造。
在美国估计2580万（1880万已确诊和700万未诊断）糖尿病患者，糖尿病患病率约8.3%。长期的高血糖水平可增加心脏病、失明、神经和肾损伤等严重并发症风险。
FDA药品评价和研究中心代谢和内分泌产品部主任Jean-Marc Guettier博士说：“很多糖尿病患者需要使用餐时胰岛素来控制血糖水平，Afrezza提供了一种新的餐时胰岛素给药方式，可成为这类患者的新治疗选择。”
Afrezza的药物安全性和有效性临床试验在3,017例成人糖尿病患者（1,026例1型糖尿病和1,991例2型糖尿病）中展开。在1型糖尿病患者中进行的一项比较Afrezza和门冬胰岛素分别与基础胰岛素联用的疗效对比研究显示，基础胰岛素和餐时Afrezza联合治疗24周后可明显降低HbA1c水平，尽管Afrezza降低HbA1c的幅度不及门冬胰岛素，但已达到预先设定的0.4%非劣效性边界。在2型糖尿病患者中进行的Afrezza和安慰剂吸入分别与口服降糖药联用的疗效对比研究显示，Afrezza联合口服降糖药治疗24周后可显著降低HbA1c水平，降低幅度明显大于安慰剂组。
Afrezza并非长效胰岛素替代物，因此Afrezza在治疗1型糖尿病患者时必须与长效胰岛素联用。不建议Afrezza用于治疗糖尿病酮症酸中毒，也不建议在吸烟患者中使用。
Afrezza的黑框警告：Afrezza用于哮喘和慢性阻塞性肺疾病(COPD)患者时可出现支气管痉挛。因此，不用对哮喘或COPD等慢性肺疾病患者使用Afrezza。
在临床试验中，Afrezza的常见不良反应有低血糖、咳嗽、喉痛或刺激。
FDA要求制药商进行的Afrezza上市后研究：
● 一项在儿童患者中评价药代动力学，安全性和疗效的临床试验；

● 一项评价Afrezza潜在肺恶性病风险的临床试验(这项试验还将评估Afrezza的心血管风险和对肺功能的长期影响)；
● 两项药代动力学-药效学正常血糖钳夹[euglycemic glucose-clamp]临床试验，一项研究剂量-反应特征，另一项研究受试者间变异性特征。
AFREZZA® (insulin human) Inhalation Powder.
Initial U.S. Approval: 06/2014
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE
See full prescribing information for complete boxed warning.
Acute bronchospasm has been observed in patients with asthma and COPD using AFREZZA. (5.1)
AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD. (4)
Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients. (2.5), (5.1)
INDICATIONS AND USAGE
AFREZZA® is a rapid acting inhaled insulin indicated to improve glycemic control in adult patients with diabetes mellitus. (1)
Important limitations of use:
In patients with type 1 diabetes, must use with a long-acting insulin. (1)
Not recommended for the treatment of diabetic ketoacidosis. (1)
Not recommended in patients who smoke (1)
DOSAGE AND ADMINISTRATION
Administer using a single inhalation per cartridge (2.1)
Administer at the beginning of a meal (2.2)
Dosing must be individualized (2.2)
Before initiating, perform a detailed medical history, physical examination, and spirometry (FEV1) in all patients to identify potential lung disease (2.5)
DOSAGE FORMS AND STRENGTHS
AFREZZA is available as single-use cartridges of: (3)
4 units
8 units
CONTRAINDICATIONS
During episodes of hypoglycemia (4)
Chronic lung disease, such as asthma, or chronic obstructive pulmonary disease (4)
Hypersensitivity to regular human insulin or any of the AFREZZA excipients (4)
WARNINGS AND PRECAUTIONS
Acute Bronchospasm: Acute bronchospasm has been observed in patients with asthma and COPD. Before initiating, perform spirometry (FEV1) in all patients. Do not use in patients with chronic lung disease (2.5, 4, 5.1)
Change in Insulin Regimen: Carry out under close medical supervision and increase frequency of blood glucose monitoring. (5.2)
Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. (5.3, 6, 7, 8.5, 8.6)
Decline in Pulmonary Function: Assess pulmonary function (e.g., spirometry) before initiating, after 6 months of therapy, and annually, even in the absence of pulmonary symptoms. (2.5, 5.4)
Lung Cancer: AFREZZA should not be used in patients with active lung cancer. In patients with a history of lung cancer or at risk for lung cancer, the benefit of AFREZZA use should outweigh this potential risk. (5.5)
Diabetic Ketoacidosis: More patients using AFREZZA experienced diabetic ketoacidosis in clinical trials. In patients at risk for DKA, monitor and change to alternate route of insulin delivery, if indicated. (5.6)
Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including AFREZZA. Discontinue AFREZZA, monitor and treat if indicated. (5.7)
Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.8)
Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. (5.9)
ADVERSE REACTIONS
The most common adverse reactions associated with AFREZZA (2% or greater incidence) are hypoglycemia, cough, and throat pain or irritation (6)
To report SUSPECTED ADVERSE REACTIONS, contact MannKind Corporation at (1-877-323-8505) or FDA at (1-800-FDA-1088) or www.fda.gov/medwatch.
DRUG INTERACTIONS
Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. (7.1, 7.2, 7.3)
Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. (7.3, 7.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 7/2014
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FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Route of Administration
2.2 Dosage Information
2.3 AFREZZA Administration for Doses Exceeding 8 units
2.4 Dosage Adjustment due to Drug Interactions
2.5 Lung Function Assessment Prior to Administration
2.6 Important Administration Instructions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Acute Bronchospasm in Patients with Chronic Lung Disease
5.2 Changes in Insulin Regimen
5.3 Hypoglycemia
5.4 Decline in Pulmonary Function
5.5 Lung Cancer
5.6 Diabetic Ketoacidosis
5.7 Hypersensitivity Reactions
5.8 Hypokalemia
5.9 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Drugs That May Increase the Risk of Hypoglycemia
7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of AFREZZA
7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of AFREZZA
7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Teratogenic Effects: Pregnancy Category C
8.2 Nursing Mothers
8.3 Pediatric Use
8.4 Geriatric Use
8.5 Hepatic Impairment
8.6 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
11.1 AFREZZA Cartridges
11.2 AFREZZA Inhaler
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
14 CLINICAL STUDIES
14.1 Overview of Clinical Studies of AFREZZA for Diabetes Mellitus
14.2 Type 1 Diabetes
14.3 Type 2 Diabetes
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Medication Guide
17.2 Instruction for Use
*
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE
Acute bronchospasm has been observed in patients with asthma and COPD using AFREZZA. [see Warnings and Precautions (5.1)]
AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD. [see Contraindications (4)]
Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients [see Dosage and Administration (2.5), Warnings and Precautions (5.1)]
1 INDICATIONS AND USAGE
AFREZZA® is a rapid acting inhaled insulin indicated to improve glycemic control in adult patients with diabetes mellitus.
Limitations of Use:
AFREZZA is not a substitute for long-acting insulin. AFREZZA must be used in combination with long-acting insulin in patients with type 1 diabetes mellitus.
AFREZZA is not recommended for the treatment of diabetic ketoacidosis [see Warning and Precautions (5.6)].
The safety and efficacy of AFREZZA in patients who smoke has not been established. The use of AFREZZA is not recommended in patients who smoke or who have recently stopped smoking.
2 DOSAGE AND ADMINISTRATION
2.1 Route of Administration
AFREZZA should only be administered via oral inhalation using the AFREZZA Inhaler. AFREZZA is administered using a single inhalation per cartridge.
2.2 Dosage Information
Administer AFREZZA at the beginning of the meal.
Dosage adjustment may be needed when switching from another insulin to AFREZZA [see Warnings and Precautions (5.2)].
Starting Mealtime Dose:
Insulin Naïve Individuals: Start on 4 units of AFREZZA at each meal.
Individuals Using Subcutaneous Mealtime (Prandial) Insulin: Determine the appropriate AFREZZA dose for each meal by converting from the injected dose using Figure 1.

 

Individuals Using Subcutaneous Pre-mixed Insulin: Estimate the mealtime injected dose by dividing half of the total daily injected pre-mixed insulin dose equally among the three meals of the day. Convert each estimated injected mealtime dose to an appropriate AFREZZA dose using Figure 1. Administer half of the total daily injected pre-mixed dose as an injected basal insulin dose.
Figure 1. Mealtime AFREZZA Dose Conversion Table
Mealtime Dose Adjustment
Adjust the dosage of AFREZZA based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal.
Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5, 8.6)] .
Carefully monitor blood glucose control in patients requiring high doses of AFREZZA. If, in these patients, blood glucose control is not achieved with increased AFREZZA doses, consider use of subcutaneous mealtime insulin.
2.3 AFREZZA Administration for Doses Exceeding 8 units
For AFREZZA doses exceeding 8 units, inhalations from multiple cartridges are necessary. To achieve the required total mealtime dose, patients should use a combination of 4 unit and 8 unit cartridges. Examples of cartridge combinations for doses of up to 24 units are shown in Figure 1. For doses above 24 units, combinations of different multiple cartridges can be used.
2.4 Dosage Adjustment due to Drug Interactions
Dosage adjustment may be needed when AFREZZA is coadministered with certain drugs [see Drug Interactions (7)].
2.5 Lung Function Assessment Prior to Administration
AFREZZA is contraindicated in patients with chronic lung disease because of the risk of acute bronchospasm in these patients. Before initiating AFREZZA, perform a medical history, physical examination and spirometry (FEV1) in all patients to identify potential lung disease [see Contraindications (4) and Warnings and Precautions (5.1)].
2.6 Important Administration Instructions
See Patient Instructions for Use for complete administration instructions with illustrations.
Keep the inhaler level and white mouthpiece on top and purple base on the bottom after a cartridge has been inserted into the inhaler. Loss of drug effect can occur if the inhaler is turned upside down, held with the mouthpiece pointing down, shaken (or dropped) after the cartridge has been inserted but before the dose has been administered. If any of the above occur, the cartridge should be replaced before use.
3 DOSAGE FORMS AND STRENGTHS
AFREZZA (insulin human) Inhalation Powder is available as 4 unit and 8 unit single use cartridges to be administered via oral inhalation with the AFREZZA Inhaler only. [see How Supplied/Storage and Handling (16)].
4 CONTRAINDICATIONS
AFREZZA is contraindicated in patients with the following:
During episodes of hypoglycemia
Chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD), because of the risk of acute bronchospasm [see Warnings and Precautions (5.1)].
Hypersensitivity to regular human insulin or any of the AFREZZA excipients [see Warnings and Precautions (5.7)].
5 WARNINGS AND PRECAUTIONS
5.1 Acute Bronchospasm in Patients with Chronic Lung Disease
Because of the risk of acute bronchospasm, AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD [see Contraindications (4)].
Before initiating therapy with AFREZZA, eva luate all patients with a medical history, physical examination and spirometry (FEV1) to identify potential underlying lung disease.
Acute bronchospasm has been observed following AFREZZA dosing in patients with asthma and patients with COPD. In a study of patients with asthma, bronchoconstriction and wheezing following AFREZZA dosing was reported in 29% (5 out of 17) and 0% (0 out of 13) of patients with and without a diagnosis of asthma, respectively. In this study, a mean decline in FEV1 of 400 mL was observed 15 minutes after a single dose in patients with asthma. In a study of patients with COPD (n=8), a mean decline in FEV1 of 200 mL was observed 18 minutes after a single dose of AFREZZA. The long-term safety and efficacy of AFREZZA in patients with chronic lung disease has not been established.
5.2 Changes in Insulin Regimen
Glucose monitoring is essential for patients receiving insulin therapy. Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. These changes should be made under close medical supervision and the frequency of blood glucose monitoring should be increased. Concomitant oral antidiabetic treatment may need to be adjusted.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction associated with insulins, including AFREZZA. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. AFREZZA has a distinct time action profile [see Clinical Pharmacology (12)], which impacts the timing of hypoglycemia. Hypoglycemia can happen suddenly and symptoms may differ across individuals and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using certain medications [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.5, 8.6)].
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
5.4 Decline in Pulmonary Function
AFREZZA causes a decline in lung function over time as measured by FEV1. In clinical trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-treated patients experienced a small [40 mL (95% CI: -80, -1)] but greater FEV1 decline than comparator-treated patients. The FEV1 decline was noted within the first 3 months, and persisted for the entire duration of therapy (up to 2 years of observation). In this population, the annual rate of FEV1 decline did not appear to worsen with increased duration of use. The effects of AFREZZA on pulmonary function for treatment duration longer than 2 years has not been established. There are insufficient data in long term studies to draw conclusions regarding reversal of the effect on FEV1 after discontinuation of AFREZZA. The observed changes in FEV1 were similar in patients with type 1 and type 2 diabetes.
Assess pulmonary function (e.g., spirometry) at baseline, after the first 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms. In patients who have a decline of ≥ 20% in FEV1 from baseline, consider discontinuing AFREZZA. Consider more frequent monitoring of pulmonary function in patients with pulmonary symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough. If symptoms persist, discontinue AFREZZA. [see Adverse Reactions (6)].
5.5 Lung Cancer
In clinical trials, two cases of lung cancer, one in controlled trials and one in uncontrolled trials (2 cases in 2,750 patient-years of exposure), were observed in participants exposed to AFREZZA while no cases of lung cancer were observed in comparators (0 cases in 2,169 patient-years of exposure). In both cases, a prior history of heavy tobacco use was identified as a risk factor for lung cancer. Two additional cases of lung cancer (squamous cell) occurred in non-smokers exposed to AFREZZA and were reported by investigators after clinical trial completion. These data are insufficient to determine whether AFREZZA has an effect on lung or respiratory tract tumors. In patients with active lung cancer, a prior history of lung cancer, or in patients at risk for lung cancer, consider whether the benefits of AFREZZA use outweigh this potential risk.
5.6 Diabetic Ketoacidosis
In clinical trials enrolling subjects with type 1 diabetes, diabetic ketoacidosis (DKA) was more common in subjects receiving AFREZZA (0.43%; n=13) than in subjects receiving comparators (0.14%; n=3). In patients at risk for DKA, such as those with an acute illness or infection, increase the frequency of glucose monitoring and consider delivery of insulin using an alternate route of administration if indicated [see Limitations of Use (1)].
5.7 Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including AFREZZA. If hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. AFREZZA is contraindicated in patients who have had hypersensitivity reactions to AFREZZA or any of its excipients [see Contraindications (4)].
5.8 Hypokalemia
All insulin products, including AFREZZA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations and patients receiving intravenously administered insulin).
5.9 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including AFREZZA, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
Acute bronchospasm in patients with chronic lung disease [see Warnings and Precautions (5.1)]
Hypoglycemia [see Warnings and Precautions (5.3)]
Decline in pulmonary function [see Warnings and Precautions (5.4)]
Lung cancer [see Warnings and Precautions (5.5)]
Diabetic ketoacidosis [see Warnings and Precautions (5.6)]
Hypersensitivity reactions [see Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying designs, the incidence of adverse reactions reported in one clinical trial may not be easily compared to the incidence reported in another clinical trial, and may not reflect what is observed in clinical practice.
The data described below reflect exposure of 3017 patients to AFREZZA and include 1026 patients with type 1 diabetes and 1991 patients with type 2 diabetes. The mean exposure duration was 8.17 months for the overall population and 8.16 months and 8.18 months for type 1 and 2 diabetes patients, respectively. In the overall population, 1874 were exposed to AFREZZA for 6 months and 724 for greater than one year. 620 and 1254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for greater than one year (median exposure = 1.8 years). AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively).
The mean age of the population was 50.2 years and 20 patients were older than 75 years of age. 50.8% of the population were men; 82.6% were White, 1.8% were Asian, and 4.9% were Black or African American. 9.7% were Hispanic. At baseline, the type 1 diabetes population had diabetes for an average of 16.6 years and had a mean HbA1c of 8.3%, and the type 2 diabetes population had diabetes for an average of 10.7 years and had a mean HbA1c of 8.8%. At baseline, 33.4% of the population reported peripheral neuropathy, 32.0% reported retinopathy and 19.6% had a history of cardiovascular disease.
Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in type 2 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA.
Table 1. Common Adverse Reactions in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA