Afrezza
Insulin Human · Kit · Respiratory (inhalation)
Uses
1 INDICATIONS AND USAGE AFREZZA ® is indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus. AFREZZA ® is a rapid acting inhaled human insulin indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus. ( 1 ) Limitations of Use : Not recommended for the treatment of diabetic ketoacidosis (DKA) ( 1 ) Not recommended in patients who smoke or who have recently stopped smoking ( 1 ) Limitations of Use: AFREZZA is not recommended for the treatment of diabetic ketoacidosis (DKA) [see Warnings 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 [see Warnings and Precautions ( 5.5 )].
Dosage and administration
Only administer via oral inhalation using the AFREZZA inhaler ( 2.2 ) Administer at the beginning of each meal ( 2.2 ) See full prescribing information for the recommended starting mealtime dosage in insulin-naïve patients and patients who are using subcutaneous mealtime insulin, or pre-mixed insulin ( 2.3 ) Modify the mealtime AFREZZA dosage based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal ( 2.4 ) If blood glucose control is not achieved with increased AFREZZA dosages, consider discontinuing AFREZZA ( 2.4 ) 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. 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. 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 ), Dosage Forms and Strengths ( 3 )]. To administer AFREZZA: 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. The AFREZZA Inhaler can be used for up to 15 days from the date of first use. After 15 days of use, discard the inhaler and replace it with a new inhaler. 2.3 Recommended Starting Mealtime Dosage of AFREZZA Insulin naïve patients The initial dosage of AFREZZA is 4 units inhaled at the beginning of each meal. Switching from Other Mealtime (prandial) Insulin Regimens to AFREZZA When switching from another insulin to AFREZZA, a different insulin dosage may be needed and increased frequency of blood glucose monitoring and monitoring for signs and symptoms of hypoglycemia may be needed [see Warnings and Precautions ( 5.2 , 5.3 ), Clinical Pharmacology ( 12.2 , 12.3 )]. Subcutaneous, Mealtime (prandial) Insulin: Follow the recommendations in Table 1 to convert each injected mealtime insulin dosage (or bolus dosage for patients using insulin pumps) to the recommended mealtime dosage of AFREZZA. Subcutaneous, Pre-Mixed Insulin: Refer to the prescribing information for the pre-mixed insulin to estimate the mealtime subcutaneous insulin dosage based on the product’s pharmacokinetic and pharmacodynamic properties. Follow the recommendations in Table 1 to convert each estimated injected mealtime dosage to an AFREZZA mealtime dose. If basal insulin is clinically indicated, refer to the prescribing information for the chosen basal insulin for dosage recommendations. Table 1. Recommended Starting Mealtime Dosage of AFREZZA when Switching from Other Mealtime Insulin Regimens Current Subcutaneous Mealtime Insulin Dosage Starting Dosage of AFREZZA Up to 3 units 4 units 4 to 5 units 8 units 6 to 7 units 12 units 8 or more units 16 units * For AFREZZA doses exceeding the contents of a single cartridge at mealtime, use more than one cartridge. To achieve the required total mealtime dosage, use a combination of 4 unit, 8 unit, and 12 unit cartridges. When titrating dosages above 16 units after the initial conversion dosage, use combinations of different cartridges [see Dosage and Administration ( 2.4 ), Dosage Forms and Strengths ( 3 ), How Supplied/Storage and Handling ( 16 )]. 2.4 Mealtime AFREZZA Dosage Modification Modify the mealtime 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 )]. Increase the frequency of blood glucose monitoring during titration of AFREZZA. If blood glucose control is not achieved with increased AFREZZA dosages, 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 )]. Switching from another insulin to AFREZZA [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.2 )]
Dosage forms and strengths
Inhalation Powder: 3 single-use cartridges of insulin human as white powder labeled “afrezza”. Each AFREZZA inhalation cartridge delivers: 4 units (blue cartridge) 8 units (green cartridge) 12 units (yellow cartridge) Inhalation powder in single-use cartridges of: 4 units, 8 units, or 12 units ( 3 )
Contraindications
4 CONTRAINDICATIONS AFREZZA is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )]. In patients with chronic lung disease, such as asthma or COPD, because of the risk of acute bronchospasm [see Warnings and Precautions ( 5.1 )]. In patients with a previous severe hypersensitivity reaction to any regular human insulin product or any of the inactive ingredients in AFREZZA. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with AFREZZA [see Warnings and Precautions ( 5.7 )]. During episodes of hypoglycemia ( 4 ) Chronic lung disease, such as asthma, or COPD ( 4 ) Hypersensitivity to any regular human insulin product or any of the inactive ingredients in AFREZZA ( 4 )
Warnings and precautions
Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen : Make 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, oral antidiabetic treatment dosage modifications may be needed. ( 5.2 ) Hypoglycemia (may be life-threatening): Increase frequency of glucose monitoring in patients at higher risk for hypoglycemia and those who have reduced symptomatic awareness of hypoglycemia. ( 5.3 ) Decline in Pulmonary Function : Assess pulmonary function (e.g., spirometry (FEV 1 )) at baseline, after 6 months of therapy, and annually, 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 ( 5.4 ) Lung Cancer : 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. ( 5.5 ) Diabetic Ketoacidosis : In patients at risk for DKA, increase the frequency of glucose monitoring and consider changing to alternate route of insulin delivery. ( 5.6 ) 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. ( 5.7 ) Hypokalemia (may be life-threatening): Monitor potassium levels in patients at risk of hypokalemia. ( 5.8 ) Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.9 ) 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. Risk Factors and Mitigation Strategies for Hypoglycemia The risk of hypoglycemia after use of AFREZZA is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal [See Clinical Pharmacology ( 12.3 )] . The glucose lowering effect time course of AFREZZA may vary in different individuals or at different times in the same individual and depends on many conditions [see Clinical Pharmacology ( 12.2 )] . 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 concomitantly 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 )]. Advise patients to recognize and manage hypoglycemia and self-monitor glucose. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of glucose monitoring is recommended. 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.
Side effects
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 )] 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. 6.1 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. Adverse Reactions in Clinical Trials in Adults with Type 1 or Type 2 Diabetes Mellitus The data described below reflect exposure of 3,017 adult patients to AFREZZA and include 1,026 patients with type 1 diabetes mellitus and 1,991 patients with type 2 diabetes mellitus. The mean exposure duration was 8.2 months for patients with type 1 diabetes mellitus and those with type 2 diabetes mellitus [see Clinical Studies ( 14.2 , 14.3 )] . In the overall population: 1,874 patients with type 1 or type 2 diabetes mellitus were exposed to AFREZZA for 6 months and 724 patients for greater than one year. 620 and 1,254 patients with type 1 or type 2 diabetes mellitus, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 or type 2 diabetes mellitus, respectively, were exposed to AFREZZA for greater than one year (median exposure was 1.8 years). AFREZZA was studied in placebo and active-controlled adult trials (n = 3 and n = 10, respectively). The mean age of the adult population was 50 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 or Latino ethnicity. At baseline, the type 1 diabetes mellitus population had diabetes mellitus for an average of 17 years and had a mean HbA1c of 8.3%, and the type 2 diabetes mellitus population had diabetes mellitus for an average of 11 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 2 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in adults with type 2 diabetes mellitus patients that occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA. Table 2. Common Adverse Reactions That Occurred in ≥ 2% in Adult Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Adverse Reaction AFREZZA (n = 1,991) % Placebo a (n = 290) % Non-placebo comparators (n=1,363) % Cough 26 20 5 Throat pain or irritation 4 4 1 Headache 3 3 2 Diarrhea 3 1 2 Productive cough 2 1 1 Fatigue 2 1 1 Nausea 2 0.3 1 a Carrier particle without insulin was used as placebo [see Description ( 11.1 )]. Table 3 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in adults with type 1 diabetes mellitus. These adverse reactions occurred more commonly on AFREZZA than on comparator and occurred in at least 2% of patients treated with AFREZZA. Table 3. Common Adverse Reactions That Occurred in ≥ 2% in Adult Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA Adverse Reaction AFREZZA (n=1,026) % Subcutaneous Insulin (n = 835) % Cough 29 5 Throat pain or irritation 6 2 Headache 5 3 Pulmonary function test decreased 3 1 Bronchitis 3 2 Urinary tract infection 2 2 Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients treated with AFREZZA [see Warnings and Precautions ( 5.3 )] . The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia across clinical trials of AFREZZA or with the incidence of hypoglycemia for other insulin products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. The incidence of severe and non-severe hypoglycemia in AFREZZA-treated patients versus placebo-treated patients with type 2 diabetes mellitus is shown in Table 4 . 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 4. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Adult Patients with Type 2 Diabetes Mellitus Hypoglycemia Severity AFREZZA (N=177) Placebo (N=176) Severe Hypoglycemia 5% 2% Non-Severe Hypoglycemia 67% 30% Other Adverse Reactions in Adults with Type 1 or Type 2 Diabetes MellitusOther Adverse Reactions in Adults with Type 1 or Type 2 Diabetes Mellitus Cough Approximately 27% of adults treated with AFREZZA reported cough, compared to approximately 5% of patients treated with comparator.
Drug interactions
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 )]. Switching from another insulin to AFREZZA [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.2 )] 7 DRUG INTERACTIONS Table 6 presents clinically significant drug interactions with AFREZZA. Table 6. Clinically Significant Drug Interactions with AFREZZA Antidiabetic agents, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blocking Agents, Disopyramide, Fibrates, Fluoxetine, Monoamine Oxidase Inhibitors, Pentoxifylline, Pramlintide, Salicylates, Somatostatin Analogs (e.g., octreotide), and Sulfonamide Antibiotics Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may increase the risk of hypoglycemia. 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. Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may reduce the blood glucose lowering effect of AFREZZA. Alcohol, Beta-blockers, Clonidine, and Lithium Salts Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use with AFREZZA may either increase or decrease the blood glucose lowering effect of AFREZZA. Pentamidine Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of pentamidine with AFREZZA may cause hypoglycemia, which may sometimes be followed by hyperglycemia Beta-blockers, Clonidine, Guanethidine, and Reserpine Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may blunt the signs and symptoms of hypoglycemia, making it more difficult to recognize See full prescribing information for details regarding concomitant use of drugs that may ( 7 ): Decrease blood glucose lowering effect of AFREZZA Increase or decrease the blood glucose lowering effect of AFREZZA Blunt signs and symptoms of hypoglycemia
Use in specific populations
8.1 Pregnancy Risk Summary Limited available data with AFREZZA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. Available information from published studies with human insulin use during pregnancy has not reported a clear association with human insulin and adverse developmental outcomes ( see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy ( see Clinical Considerations ). In animal reproduction studies, there were no adverse developmental outcomes with subcutaneous administration of carrier particles (vehicle without insulin) to pregnant rats during organogenesis at doses 21 times the human daily dose of 99 mg AFREZZA, based on AUC (see Data ) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for DKA, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia- related morbidity. Data Human Data There are limited data with AFREZZA use in pregnant women. Published data do not report a clear association with human insulin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when human insulin is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and lack of blinding. Animal Data In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 6 through 17 (organogenesis), no major malformations were observed at doses up to 100 mg/kg/day (21 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC). In pregnant rabbits given subcutaneous doses of 2, 10, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through 19 (organogenesis), adverse maternal effects were observed in all dose groups (at human systemic exposure following a daily dose of 99 mg AFREZZA, based on AUC). In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through lactation day 20 (weaning), decreased epididymis and testes weights were observed in F1 male offspring, however, no decrease in fertility was noted, and impaired learning were observed in F1 pups at > 30 mg/kg/day (6 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC). 8.2 Lactation Risk Summary There are no data on the presence of AFREZZA in human milk, the effects on the breastfed infant, or the effects on milk production. One small published study reported that exogenous subcutaneous insulin was present in human milk. No adverse effects in infants were noted. The carrier particles are present in rat milk ( see Data ). Potential adverse reactions that are related to inhalational administration of AFREZZA are unlikely to be associated with potential exposure of AFREZZA through breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AFREZZA and any potential adverse effects on the breastfed infant from AFREZZA or from the underlying maternal condition. Data Subcutaneous administration of the carrier particle in lactating rats resulted in excretion of the carrier particle in rat milk at levels that were approximately 10% of the maternal exposure. Given the results of the rat study, it is highly likely that the insulin and carrier in AFREZZA are excreted in human milk. 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 )] . The overall safety profile in pediatric patients was similar to adults [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of AFREZZA have not been established in pediatric patients less than 6 years of age. 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.
Pregnancy
8.1 Pregnancy Risk Summary Limited available data with AFREZZA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. Available information from published studies with human insulin use during pregnancy has not reported a clear association with human insulin and adverse developmental outcomes ( see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy ( see Clinical Considerations ). In animal reproduction studies, there were no adverse developmental outcomes with subcutaneous administration of carrier particles (vehicle without insulin) to pregnant rats during organogenesis at doses 21 times the human daily dose of 99 mg AFREZZA, based on AUC (see Data ) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for DKA, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia- related morbidity. Data Human Data There are limited data with AFREZZA use in pregnant women. Published data do not report a clear association with human insulin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when human insulin is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and lack of blinding. Animal Data In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 6 through 17 (organogenesis), no major malformations were observed at doses up to 100 mg/kg/day (21 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC). In pregnant rabbits given subcutaneous doses of 2, 10, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through 19 (organogenesis), adverse maternal effects were observed in all dose groups (at human systemic exposure following a daily dose of 99 mg AFREZZA, based on AUC). In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through lactation day 20 (weaning), decreased epididymis and testes weights were observed in F1 male offspring, however, no decrease in fertility was noted, and impaired learning were observed in F1 pups at > 30 mg/kg/day (6 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC).
Pediatric use
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 )] . The overall safety profile in pediatric patients was similar to adults [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of AFREZZA have not been established in pediatric patients less than 6 years of age.
Geriatric use
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.
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. In the event of an overdose of AFREZZA, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Description
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 257 H 383 N 65 O 77 S 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. Primary Amino Acid Sequence 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.
Mechanism of action
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.
How supplied
(insulin human) Inhalation Powder is available as 4 unit, 8 unit and 12 unit single-use cartridges. Three cartridges are contained in a single cavity of a blister strip. Each card contains 5 blister strips (each containing three cartridges) separated by perforations for a total of 15 cartridges. Two cards of the same cartridge strength are packaged in a foil laminate overwrap (30 cartridges per foil package). The cartridges are color-coded, blue for 4 units, green for 8 units and yellow for 12 units. Each cartridge is marked with “afrezza” and “4 units”, “8 units” or “12 units”. The AFREZZA Inhaler is individually packaged in a clear overwrap. The inhaler is fully assembled with a removable mouthpiece cover. 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. AFREZZA (insulin human) Inhalation Powder is available in the following configurations: NDC Cartridge Strength Quantity of Cartridges per Strength Total Quantity of Cartridges per Kit Total Units in Kit Number of Inhalers 47918-874-90 4 units 90 90 360 Units 2 47918-878-90 8 units 90 90 720 Units 2 47918-891-90 12 units 90 90 1,080 Units 2 47918-898-18 8 units, 12 units 90 180 1,800 Units 2 47918-880-18 (Titration Pack) 4 units, 8 units 90 180 1,080 Units 2 47918-902-18 (Titration Pack) 4 units, 8 units, 12 units 60 180 1,440 Units 2 Storage : Not in Use: Refrigerated Storage 2ºC to 8ºC (36ºF to 46ºF) * If a foil package, blister card or strip is not refrigerated, the contents must be used within 10 days. Sealed (Unopened) Foil Package May be stored until the Expiration Date* Sealed (Unopened) Blister Cards and Strips Must be used within 1 month* In Use: Room Temperature Storage 25ºC (77ºF), excursions permitted 15ºC to 30ºC (59ºF to 86ºF) Sealed (Unopened) Blister Cards and Strips Must be used within 10 days Opened Strips Must be used within 3 days Do not put a blister card or strip back into the refrigerator after being stored at room temperature. Inhaler Storage : Store refrigerated or at room temperature 2ºC to 25ºC (36ºF to 77ºF); excursions permitted. Inhaler may be stored refrigerated, but should be at room temperature before use. Handling : Before use, cartridges should be at room temperature for 10 minutes.
Patient information
Advise the patient to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use ). Instruct patients to use AFREZZA only with the AFREZZA inhaler. 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 [see Warnings and Precautions ( 5.1 )] . 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 [see Warnings and Precautions ( 5.3 )] . 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. Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions ( 5.2 )]. 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 DKA 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 – 2026 MannKind Corporation AFREZZA is a registered trademark of MannKind Corporation Patent: www.mannkindcorp.com/patent-notices
Label text from the FDA structured product label by Mannkind Corporation (revised May 30, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Insulin Human in 3 products
Afrezza NDC products (7)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 47918-874 | Insulin Human 4 [arb'U]/1 Powder, Metered | Mannkind Corporation | BLA |
| 47918-878 | Insulin Human 8 [arb'U]/1 Powder, Metered | Mannkind Corporation | BLA |
| 47918-880 | Kit | Mannkind Corporation | BLA |
| 47918-891 | Insulin Human 12 [arb'U]/1 Powder, Metered | Mannkind Corporation | BLA |
| 47918-898 | Kit | Mannkind Corporation | BLA |
| 47918-902 | Kit | Mannkind Corporation | BLA |
| 47918-904 | Kit | Mannkind Corporation | BLA |
Frequently asked questions
What is Afrezza used for?
1 INDICATIONS AND USAGE AFREZZA ® is indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus. AFREZZA ® is a rapid acting inhaled human insulin indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus. ( 1 ) Limitations of Use : Not recommended for the treatment of diabetic…
What are the side effects of Afrezza?
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… See the full label for the complete list.
Who makes Afrezza?
Afrezza is listed by 1 labeler in the FDA NDC directory, including Mannkind Corporation.