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 (FEV1) in all patients to identify potential lung disease [see Contraindications (4) and Warnings and Precautions (5.1)].

2.2 Important Administration and Discard Instructions

Only administer AFREZZA via oral inhalation using the AFREZZA Inhaler. Administer AFREZZA at the beginning of each meal. Administer AFREZZA using a single inhalation per cartridge (if the dose is greater than the contents of a single cartridge, more than one cartridge is needed) [see Dosage and Administration (2.3)]. For additional administration instructions on how to use the AFREZZA Inhaler [see Dosage and Administration (2.6)] and see the Instructions for Use.

The AFREZZA Inhaler can be used for up to 15 days from the date of first use. After 15 days of use, the inhaler must be discarded and replaced with a new inhaler.

2.3 Recommended Starting Mealtime Dosage

For insulin naïve patients, start on 4 units of AFREZZA at the beginning of each meal.

For patients using subcutaneous, mealtime (prandial) insulin:

• Determine the appropriate AFREZZA dose for each meal by converting from the injected insulin dose using Figure 1.
• When switching from another insulin to AFREZZA, a different insulin dose may be needed requiring increased frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].

For patients 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. When switching from another insulin to AFREZZA, a different insulin dose may be needed. When switching a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].
• 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.

For AFREZZA doses exceeding the contents of a single cartridge at mealtime, inhalations from more than one cartridge are necessary. To achieve the required total mealtime dose, use a combination of 4 unit, 8 unit, and 12 unit cartridges. Examples of cartridge combinations for doses of up to 24 units are shown in Figure 1. For doses above 24 units, use combinations of different multiple cartridges.

2.4 Mealtime Dosage Modification

• Modify the AFREZZA dosage based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal.
• Dosage modifications 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 (8.6, 8.7)].
• Carefully monitor blood glucose control in patients requiring high AFREZZA doses. If blood glucose control is not achieved with increased AFREZZA doses in these patients, consider discontinuing AFREZZA.

2.5 Dosage Modifications for Drug Interactions

Dosage modification may be needed when:

• AFREZZA is used concomitantly with certain drugs that increase and/or decrease the glucose lowering effect [see Drug Interactions (7.1, 7.2, 7.3)].
• Switching from another insulin to AFREZZA [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)]

2.6 Administration Instructions

Refer patients to the Instructions for Use for detailed instructions and visuals on how to prepare, administer, and store AFREZZA; use the AFREZZA cartridges; and use the AFREZZA inhaler. Critical administration instructions are as follows:

• Keep the inhaler level with the 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, replace the cartridge before use.
• Hold the inhaler away from the mouth and fully exhale.
• After the inhaler is placed in the mouth and the lips form a seal, tilt the inhaler down towards the chin while keeping the head level.
• With the mouth closed around the mouthpiece, inhale deeply through the inhaler.
• Hold the breath for as long as comfortable and at the same time remove the inhaler from the mouth.
• After holding the breath, exhale and continue to breathe normally.

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 all patients with a medical history, physical examination, and spirometry (FEV1) 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 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 AFREZZA dose in patients with asthma. In a subset study of patients with COPD (n=8), a mean decline in FEV1 of 200 mL was observed 18 minutes after a single AFREZZA dose.

5.2 Hypoglycemia or Hyperglycemia with 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. For patients with type 2 diabetes, dosage modifications of concomitant oral antidiabetic treatment may be needed [see Drug Interactions (7.1, 7.2, and 7.3)].

5.3 Hypoglycemia

Glucose monitoring is essential for patients receiving insulin therapy. 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 patients and change over time in the same patient. 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 (7.4)], or in patients who experience recurrent hypoglycemia.

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 (8.6, 8.7)].

5.4 Decline in Pulmonary Function

AFREZZA causes a decline in pulmonary 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 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, diabetic ketoacidosis (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 in combination 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 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 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.

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 should be considered.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure of 3,017 patients to AFREZZA and include 1,026 patients with type 1 diabetes and 1,991 patients with type 2 diabetes. The mean exposure duration was 8.2 months for patients with type 1 diabetes and those with type 2 diabetes. In the overall population:

• 1,874 patients were exposed to AFREZZA for 6 months and 724 patients for greater than one year.
• 620 and 1,254 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; 51% of the population were males; 83% were White, 5% were Black or African American, and 2% were Asian; 10% 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% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had a history of cardiovascular disease.

Table 1 shows the frequency of 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 2 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on comparator, and occurred in at least 2% of patients treated with AFREZZA.

6.2 Postmarketing Experience

The following adverse reaction has been identified during post approval use of AFREZZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: bronchospasm.

7.1 Drugs That May Increase the Risk of Hypoglycemia

The risk of hypoglycemia associated with AFREZZA use may be increased with antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Dose modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs.

7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of AFREZZA

The glucose lowering effect of AFREZZA may be decreased when given concomitantly with atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs.

7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of AFREZZA

The glucose lowering effect of AFREZZA may be increased or decreased when co-administered with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs.

7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms

The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are given concomitantly with AFREZZA.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of AFREZZA to improve glycemic control in pediatric patients with diabetes mellitus has not been established. AFREZZA has not been studied in pediatric patients.

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 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 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 C257H383N65O77S6 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. 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 is shown in Figure 3(A), and key characteristics regarding the timing of the effects are described in Table 4:

On average, the pharmacodynamics effect of AFREZZA, measured as area under the glucose infusion rate – time curve (AUC GIR) increased linearly with doses up to 48 units (106, 387, and 1581 mg/kg for 4, 12, and 48 units doses, respectively).

Intrapatient variability in AUC GIR and GIRmax was approximately 28% (95% CI 21-42%) and 27% (95% CI 20-40%), respectively.

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 (Cmax) 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104 week carcinogenicity study, rats were given doses up to 46 mg/kg/day of the carrier and up to 1.23 mg/kg/day of insulin, by nose-only inhalation. No increased incidence of tumors was observed at systemic exposures equivalent to the insulin at a daily AFREZZA dose of 99 mg, based on a comparison of relative body surface areas across species.

No increased incidence of tumors was observed in a 26 week carcinogenicity study in transgenic mice (Tg-ras-H2) given doses up to 75 mg/kg/day of carrier and up to 5 mg/kg/day of AFREZZA.

AFREZZA was not genotoxic in Ames bacterial mutagenicity assay and in the chromosome aberration assay, using human peripheral lymphocytes with or without metabolic activation. The carrier alone was not genotoxic in the in vivo mouse micronucleus assay.

In fertility study in male and female rats at subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier (vehicle without insulin), there were no adverse effects on male fertility at doses up to 100 mg/kg/day. In female rats dosed 2 weeks prior to mating until gestation day 7, there was increased pre- and post-implantation loss at 100 mg/kg/day but not at 30 mg/kg/day (21 times and 6 times, respectively the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC).

14.1 Overview of Clinical Studies of AFREZZA in Adults for Diabetes Mellitus

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

AFREZZA has been studied in adults with type 2 diabetes in combination with oral antidiabetic drugs. The efficacy of AFREZZA in type 2 diabetes patients was compared to placebo inhalation.

14.2 Adults with Type 1 Diabetes

Patients with inadequately controlled type 1 diabetes participated in a 24-week, open-label, active-controlled study 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.

14.3 Adults with Type 2 Diabetes

A total of 479 adult patients with type 2 diabetes 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. 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.

Storage:

Not in Use: Refrigerated Storage 2-8ºC (36-46ºF)

In Use: Room Temperature Storage 25ºC (77ºF), excursions permitted 15-30ºC (59-86ºF)

Do not put a blister card or strip back into the refrigerator after being stored at room temperature.

Common Adverse Reactions

Inform patients that the most common adverse reactions associated with the use of AFREZZA are hypoglycemia, cough, and throat pain or irritation.

Pregnancy

Advise women with diabetes to inform their physician if they are pregnant or are planning to become pregnant while using AFREZZA.

Acute Bronchospasm in Patients with Chronic Lung Disease

Advise patients that if they experience any respiratory difficulty after inhalation of AFREZZA, they should report it to their healthcare provider immediately for assessment.

Hypoglycemia

Instruct patients on self-management procedures including glucose monitoring, proper inhalation technique, and management of hypoglycemia and hyperglycemia especially at initiation of AFREZZA therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, or skipped meals.

Instruct patients on the management of hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.3)].

Decline in Pulmonary Function

Inform patients that AFREZZA can cause a decline in lung function [see Warnings and Precautions (5.4)].

Lung Cancer

Inform patients to promptly report any signs or symptoms potentially related to lung cancer [see Warnings and Precautions (5.5)].

Diabetic Ketoacidosis

Instruct patients to carefully monitor their blood glucose during illness, infection, and other risk situations for diabetic ketoacidosis and to contact their healthcare provider if their blood glucose control worsens [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions can occur with insulin therapy including AFREZZA. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.7)].

Manufactured by: MannKind Corporation, Danbury, CT 06810
US License No. #2190
© 2016 – 2023 MannKind Corporation

AFREZZA is a registered trademark of MannKind Corporation
Patent: www.mannkindcorp.com/patent-notices