Dosage & Administration
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Afrezza Prescribing Information
- Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and COPD [see Warnings and Precautions ].
- AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD[see Contraindications ].
- Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients[see Dosage and Administration , Warnings and Precautions ].
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 ].
- 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.
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 and Warnings and Precautions ].
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 ]. For additional administration instructions on how to use the AFREZZA Inhaler [see Dosage and Administration ] 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.
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 ].
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 ].
- 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.
Figure 1. Mealtime AFREZZA Starting Dose Conversion Table
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 and Use in Specific Populations ].
- 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.
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 ].
- Switching from another insulin to AFREZZA [see Dosage and Administration and Warnings and Precautions ]
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.
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 ].
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 diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, 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 ³ 30 mg/kg/day (6 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC).
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.
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.
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 ]. 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.
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 ].
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 ].
AFREZZA is contraindicated:
- During episodes of hypoglycemia [see Warning and Precautions ].
- Chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD), because of the risk of acute bronchospasm [see Warnings and Precautions ]
- Hypersensitivity to regular human insulin or any of the excipients in AFREZZA [see Warnings and Precautions ]