Afrezza Titration Pack- 90 (4 Unt), 90 (8 Unt)

2.1 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 (FEV ₁) in all patients to identify potential lung disease [see Contraindications ( 4) and Warnings and Precautions ( 5.1)].

2.2 Important Administration Information

Prior to initiation, train patients and/or their caregiver(s) on proper administration of AFREZZA. After training, adult and pediatric patients aged 10 and older may self-administer AFREZZA if the healthcare provider determines that it is appropriate.

2.3 Recommended Starting Mealtime Dosage of AFREZZA

2.4 Mealtime AFREZZA Dosage Modification

2.5 Dosage Modifications for Drug Interactions

Dosage modification may be needed when:

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, evaluate patients with a medical history, physical examination, and spirometry (FEV ₁) to identify potential underlying lung disease.

Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and COPD. In a study of patients with asthma whose bronchodilators were temporarily withheld for assessment, bronchoconstriction and wheezing following AFREZZA dosing was reported in 29% (5/17) and 0% (0/13) of patients with and without a diagnosis of asthma, respectively. In this study, a mean decline in FEV ₁ of 400 mL was observed 15 minutes after a single AFREZZA dose in patients with asthma. In a subset study of 8 patients with COPD, a mean decline in FEV ₁ of 200 mL was observed 18 minutes after a single AFREZZA dose.

5.2 Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen

Changes in an insulin regimen (e.g., insulin strength, manufacturer, injection site or type, or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3)] or hyperglycemia. If clinically indicated, make any necessary changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. For patients with type 2 diabetes mellitus, dosage modifications of concomitant oral antidiabetic treatment may be needed [see Drug Interactions ( 7)] .

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).

AFREZZA's time action profile impacts the timing of hypoglycemia following inhalation of the drug product [see Clinical Pharmacology ( 12.3)] . Hypoglycemia can occur suddenly, and symptoms may differ across patients and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes mellitus, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7)], or in patients who experience recurrent hypoglycemia.

5.4 Decline in Pulmonary Function

AFREZZA causes a decline in pulmonary function over time as measured by FEV ₁. 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 FEV ₁ decline than comparator-treated patients. The FEV ₁ 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 FEV ₁ 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 FEV ₁ after discontinuation of AFREZZA. The observed changes in FEV ₁ were similar in patients with type 1 and type 2 diabetes mellitus.

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 FEV ₁ 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 ( 6.1 )] .

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 patients exposed to AFREZZA while no cases of lung cancer were observed in patients exposed to 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 and lung blastoma) 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 patients with type 1 diabetes mellitus, DKA was more common in AFREZZA-treated patients (0.43%; n=13) than in comparator-treated patients (0.14%; n=3). Patients with type 1 diabetes should always use AFREZZA concomitantly with basal insulin. In patients at risk for DKA, such as those with an acute illness or infection, increase the frequency of glucose monitoring and consider discontinuing AFREZZA and giving insulin using an alternate route of administration.

5.7 Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with AFREZZA.

If hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions ( 6.1)] . AFREZZA is contraindicated in patients with a previous severe hypersensitivity reaction to any regular human insulin product or any of the inactive ingredients in AFREZZA [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 AFREZZA-treated 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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of AFREZZA to improve glycemic control have been established in pediatric patients 6 years of age and older with diabetes mellitus. Use of AFREZZA for this indication is supported by evidence from an adequate and well controlled trial in pediatric patients aged 6 years and older with type 1 or type 2 diabetes mellitus and from trials in adults with type 1 or type 2 diabetes mellitus [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.2 , 14.3 , 14.4)] .

8.5 Geriatric Use

In the AFREZZA clinical studies , 671 (12%) patients were 65 years of age or older, of which 42 (0.8%) were 75 years of age or older. In these studies, 381 (13%) of AFREZZA-treated patients were 65 years of age or older, of which 20 (0.7%) were 75 years of age or older. No overall differences in effectiveness of AFREZZA have been observed between patients 65 years of age and older and younger adult patients [see Clinical Studies ( 14)] . Clinical studies of AFREZZA did not include sufficient numbers of patients 65 years of age and older to determine whether there were differences in safety between these patients and younger adult patients.

Pharmacokinetic and pharmacodynamic studies to assess the effect of age on pharmacokinetics or pharmacodynamics on insulin human, respectively, have not been conducted.

8.6 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of AFREZZA has not been studied. Frequent glucose monitoring and a lower dosage may be necessary in AFREZZA-treated patients with hepatic impairment [see Dosage and Administration ( 2.2 , 2.3 ) and Warnings and Precautions ( 5.3)] .

8.7 Renal Impairment

The effect of renal impairment on the pharmacokinetics of AFREZZA has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Frequent glucose monitoring and a lower dosage may be necessary in AFREZZA-treated patients with renal impairment [see Dosage and Administration ( 2.2 , 2.3 ) and Warnings and Precautions ( 5.3)] .

11.1 AFREZZA Cartridges

Human insulin is a rapid acting human insulin produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Chemically, human insulin has the empirical formula C ₂₅₇H ₃₈₃N ₆₅O ₇₇S ₆ and a molecular weight of 5808. Human insulin has the following primary amino acid sequence:

AFREZZA (human insulin) inhalation powder is available in single-use plastic cartridges filled with a white powder containing insulin (human), which is administered via oral inhalation using the AFREZZA Inhaler only.

Insulin is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP) and polysorbate 80.

AFREZZA Inhalation Powder is a dry powder supplied as 4 unit, 8 unit or 12 unit cartridges.

11.2 AFREZZA Inhaler

The AFREZZA Inhaler is breath-powered by the patient. When the patient inhales through the device, the powder is aerosolized and delivered to the lung. The amount of AFREZZA delivered to the lung will depend on individual patient factors.

12.1 Mechanism of Action

Insulin lowers blood glucose levels in adult patients with diabetes mellitus by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

12.2 Pharmacodynamics

The time course of insulin action (i.e., glucose lowering) may vary considerably in different patients or within the same patient, or when switching from subcutaneous mealtime insulin to AFREZZA. The average pharmacodynamic profile [i.e., glucose lowering effect measured by glucose infusion rate (GIR) over time in a euglycemic clamp study] after administration of a single AFREZZA dose of 4, 12, and 48 units in 30 patients with type 1 diabetes mellitus is shown in Figure 2(A), and key characteristics regarding the timing of the effects are described in Table 7:

12.3 Pharmacokinetics

The area under the plasma concentration versus time curve (AUC) of insulin increased dose proportionally up to 48 units. Intrapatient variability of AUC and peak concentration (C _max) of insulin was approximately 16% (95% CI 12-23%) and 21% (95% CI 16-30%), respectively.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of insulin human or of other insulin human products.

Increases in anti-insulin antibody concentrations were observed in patients treated with AFREZZA. Increases in anti-insulin antibodies were observed more frequently in patients treated with AFREZZA than in patients treated with subcutaneously injected mealtime insulin. There was no clinically significant effect of anti-drug antibodies on safety or effectiveness (as measured by HbA1c and fasting plasma glucose) of AFREZZA over the treatment duration of the studies which spanned 3 to 24 months.

14.1 Overview of Clinical Studies of AFREZZA Adult and Pediatric Patients 6 Years of Age and Older with Diabetes Mellitus

AFREZZA has been studied in adults with type 1 diabetes mellitus in combination with basal insulin. The efficacy of AFREZZA, in combination with basal insulin, in adult patients with type 1 diabetes mellitus was compared to insulin aspart in combination with basal insulin.

14.2 Adults with Type 1 Diabetes Mellitus

Patients with inadequately controlled type 1 diabetes mellitus participated in a 24-week, open-label, active-controlled study (NCT01445951) to evaluate the glucose lowering effect of mealtime AFREZZA used in combination with a basal insulin. Following a 4-week basal insulin optimization period, 344 patients were randomized to AFREZZA by oral inhalation (n=174) or insulin aspart given subcutaneously (n=170) at each meal of the day. All patients received basal insulin. Mealtime insulin doses were titrated to glycemic goals for the first 12 weeks and kept stable for the last 12 weeks of the study. The trial population had the following characteristics: mean age was 38, 56% were female, 96% were White, 3% were Black or African American, less than 1% were Asian, less than 1% were Native Hawaiian or Pacific Islander, less than 1% were other races, and 10% were Hispanic or Latino ethnicity.

14.3 Adults with Type 2 Diabetes Mellitus

A total of 479 adult patients with type 2 diabetes mellitus inadequately controlled on optimal/maximally tolerated doses of metformin only, or 2 or more oral antidiabetic (OAD) agents participated in a 24-week, double-blind, placebo-controlled study (NCT01451398). Following a 6-week run-in period, 353 patients were randomized to AFREZZA by oral inhalation (n=177) or an inhaled placebo powder without insulin (n=176). Insulin doses were titrated for the first 12 weeks and kept stable for the last 12 weeks of the study. OADs doses were kept stable in the study. The trial population had the following characteristics: mean age was 57, 56% were female, 87% were White, 11% were Black or African American, less than 1% were Asian, less than 1% were American Indian or Alaska Native, 1% were other races, and 24% were Hispanic or Latino ethnicity.

14.4 Pediatric Patients 6 Years of Age and Older with Type 1 and Type 2 Diabetes Mellitus

The efficacy of AFREZZA was assessed in an open-label 26-week, randomized active-controlled trial in 230 pediatric patients with type 1 or type 2 diabetes mellitus (NCT04974528). All patients were required to take basal insulin during the study. Patients were randomized (1:1) to receive either mealtime AFREZZA or RAA (insulin aspart, lispro, or glulisine; per investigator’s choice) for 26 weeks. The primary efficacy endpoint was change in HbA1c from baseline to Week 26, with a pre-specified non-inferiority margin of 0.4% for the between-group difference in HbA1c. The mean age of patients was 12.6 years (range: 4 to 17 years in the RAA arm; 6 to 17 years in the AFREZZA arm). The majority (97.8%) had type 1 diabetes mellitus; a small subset (2.2%) had type 2 diabetes mellitus. The trial population had the following characteristics: 38% were female, 77% were White, 10% were Black or African American, 3% were Asian, 6% were multiracial, and 20% were Hispanic or Latino ethnicity.