PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Principal Display Panel 27 cartridges; 9 – 4 unit cartridges, 9 – 8 unit

cartridges and 9 – 12 unit cartridges and 1 inhaler (Sample Kit)

NDC 47918-903-27

Rx ONLY

afrezza**®**

(insulin human)
Inhalation Powder

4 units per
cartridge

8 units per
cartridge

12 units per
cartridge

27 single-use cartridges

FOR ORAL INHALATION ONLY

Carton Contains:

9 – 4 unit cartridges

9 – 8 unit cartridges

9 – 12 unit cartridges

1 - inhaler

Dispense the enclosed
Medication Guide
to each patient

mannkind**®**

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INDICATIONS & USAGE SECTION

Highlight: AFREZZA® is a rapid acting inhaled human insulin indicated to improve glycemic control in adult patients with diabetes mellitus. (1)

Limitations of Use:

• Not recommended for the treatment of diabetic ketoacidosis (1)
• Not recommended in patients who smoke or who have recently stopped smoking (1)

1 INDICATIONS AND USAGE

AFREZZA® is a rapid acting inhaled human insulin indicated to improve glycemic control in adult patients with diabetes mellitus.

Limitations of Use:

• AFREZZA is not recommended for the treatment of diabetic ketoacidosis [see Warning and Precautions (5.6)].
• The safety and effectiveness of AFREZZA in patients who smoke have not been established. The use of AFREZZA is not recommended in patients who smoke or who have recently stopped smoking.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Inhalation powder in single-use cartridges of: 4 units, 8 units, or 12 units (3)

3 DOSAGE FORMS AND STRENGTHS

Inhalation Powder: single-use cartridges containing 4 units, 8 units or 12 units of insulin human as white powder to be administered via oral inhalation with the AFREZZA inhaler only [see How Supplied/Storage and Handling (16)].

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CONTRAINDICATIONS SECTION

Highlight: * 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 excipients in AFREZZA (4)

4 CONTRAINDICATIONS

AFREZZA is contraindicated:

• During episodes of hypoglycemia [see Warning and Precautions (5.3)].
• 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 excipients in AFREZZA [see Warnings and Precautions (5.7)]

BOXED WARNING SECTION

**WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG

DISEASE**

WARNINGS AND PRECAUTIONS SECTION

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, 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)].

Risk Mitigation Strategies for Hypoglycemia

Patients and caregivers should 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 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.

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ADVERSE REACTIONS SECTION

Highlight: 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 at 1-877-323-8505 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 1. Common Adverse Reactions That Occurred in ≥ 2% in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) 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.

Table 2. Common Adverse Reactions That Occurred in ≥ 2% in Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including AFREZZA [see Warnings and Precautions (5.3)]. The incidence of severe and non-severe hypoglycemia in AFREZZA-treated patients versus placebo-treated patients with type 2 diabetes is shown in Table 3. A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia.

Table 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo- Controlled Study of Patients with Type 2 Diabetes

Cough

Approximately 27% of patients treated with AFREZZA reported cough, compared to approximately 5% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (3% of AFREZZA-treated patients).

Pulmonary Function Decline

In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients treated with AFREZZA had a 40 mL (95% CI: -80, -1) greater decline from baseline in forced expiratory volume in one second (FEV1) compared to patients treated with comparator anti-diabetes treatments. The decline occurred during the first 3 months of therapy and persisted over 2 years (Figure 2). A decline in FEV1 of ≥ 15% occurred in 6% of AFREZZA-treated patients compared to 3% of comparator-treated patients [see Warnings and Precautions (5.4)].

Figure 2. Mean (+/-SE) Change in FEV1(Liters) from Baseline for Type 1 and Type 2 Diabetes Patients

Weight Gain

Weight gain has occurred with some insulin therapies, including AFREZZA. Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria. In a clinical trial of patients with type 2 diabetes [see Clinical Studies (14.3)], there was a mean 0.49 kg weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss among placebo-treated patients.

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.

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

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.

Results

At Week 24, treatment with mealtime AFREZZA and basal insulin provided a mean reduction in HbA1c that met the pre-specified non-inferiority margin of 0.4%. AFREZZA and basal insulin provided less HbA1c reduction than insulin aspart and basal insulin, and the difference was statistically significant. More patients in the insulin aspart and basal insulin group achieved the HbA1c target of ≤7% (Table 5).

Table 5. Results at Week 24 in an Active-Controlled Study of Mealtime AFREZZA plus Basal Insulin in Adults with Type 1 Diabetes

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.

Results

At Week 24, treatment with AFREZZA plus OADs provided a mean reduction in HbA1c that was statistically significantly greater compared to the HbA1c reduction observed in the placebo plus OADs group (Table 6).

Table 6. Results at Week 24 in a Placebo-Controlled Study of AFREZZA in Adults with Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Agents

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OVERDOSAGE SECTION

10 OVERDOSAGE

Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.8)].

Mild episodes of hypoglycemia due to insulin overdose can usually be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed.

Severe episodes of hypoglycemia (due to insulin overdose) with coma, seizure, or neurologic impairment may be treated with intramuscular or subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia should be corrected appropriately.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

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).

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SPL MEDGUIDE SECTION

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INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USE
AFREZZA® (uh-FREZZ-uh)
(insulin human)
inhalation powder, for oral inhalation use

This “Instructions for Use” contains information on how to use AFREZZA® (insulin human) Inhalation Powder.

Read this Instructions for Use before you start using AFREZZA and each time you get a new AFREZZA Inhaler. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Your healthcare provider should show you how to use your AFREZZA Inhaler the right way before you use it for the first time.

Important information about AFREZZA:

*AFREZZA comes in 3 strengths (see Figure A): * 4 units (blue cartridge) * 8 units (green cartridge) * 12 units (yellow cartridge)

• If your prescribed AFREZZA dose is higher than 12 units, you will need to use more than 1 cartridge.
• If you need to use more than 1 cartridge for your dose, throw away the used cartridge before getting a new one. You can tell when a cartridge has been used, because the cup has moved to the center. *Do not try to open the AFREZZA cartridges. The AFREZZA Inhaler opens the cartridge automatically during use. *AFREZZA cartridges should only be used with the AFREZZA Inhaler. Do not try to breathe in the AFREZZA insulin powder in any other way.Do not put cartridges in your mouth anddo not swallow cartridges.
• Use only 1 AFREZZA Inhaler at a time. The same inhaler should be used for the 4 unit, 8 unit or 12 unit cartridges.
• Store the inhaler in a clean, dry place with the mouthpiece cover on until your next dose.
• Throw away your AFREZZA Inhaler after 15 days and get a new one.

If you are having problems with your AFREZZA Inhaler or if it breaks and you need a new one, call 1-877-323-8505.

Know your AFREZZA Inhaler:

Know your AFREZZA cartridges:

Manufactured by: MannKind Corporation
Danbury, CT 06810

US License No. #2190

© 2016 – 2023 MannKind Corporation

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: 02/2023

AFREZZA is a registered trademark of MannKind Corporation

Patent: www.mannkindcorp.com/patent-notices

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