- ACRONYMS AND DEFINITIONS
- DRUGS IN CLASS
- Inhaled insulin
- Afrezza® contains human insulin produced from recombinant technology utilizing E Coli. The insulin is absorbed onto carrier particles for inhalation and delivery into the lungs where it is absorbed into the bloodstream.
- MECHANISM OF ACTION
- Beta-cells (also called islet cells) in the pancreas secrete insulin in response to rising blood sugar
- Insulin stimulates cells in various tissues (e.g. muscle, liver, fat) to absorb sugar from the blood for energy
- Type one diabetics lose the ability to produce insulin. Type two diabetics produce insulin, but their tissues are resistant to its effects.
- Afrezza is a synthetic insulin
- FDA-APPROVED INDICATIONS
- Type one and type two diabetes
- Afrezza is not a substitute for long-acting insulin. Afrezza must be used in combination with long-acting insulin in patients with type 1 diabetes mellitus.
- Afrezza is not recommended for the treatment of diabetic ketoacidosis
- The safety and efficacy 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.
- TYPE ONE DIABETES
|Mealtime Afrezza vs mealtime Novolog in inadequately controlled T1DM for 24 weeks|
|Change from baseline in HgA1C||-0.21%||-0.40%|
|Average daily dose of basal insulin||37 units||31.6 units|
|Average daily dose of study drug||115 units||26 units|
- ADA recommendations
- Mealtime Afrezza has a much smaller effect on blood sugar when compared to Novolog. In the study above, Afrezza at a ratio of around 4 units to 1 unit of Novolog was inferior at lowering A1C levels even with a higher dose of basal insulin in the Afrezza group.
- Patients would have to inhale very large doses of Afrezza® to achieve the same effect as injectable insulin. This can be both cumbersome and expensive.
- The perceived advantage of Afrezza (greater compliance/acceptance because of no needle sticks) also was not realized in this study as the Afrezza group had a higher dropout rate
- TYPE TWO DIABETES
|Mealtime Afrezza vs Placebo in inadequately controlled T2DM for 24 weeks|
|Change from baseline in HgA1C||-0.82%||-0.42%|
|Average daily dose of study drug||92 units||N/A|
- ADA recommendations
- In the study above, Afrezza had a modest effect on A1C levels. There are a number of therapies currently available for type 2 diabetes that are more effective and less cumbersome than Afrezza. Afrezza has limited value and is not widely prescribed.
- AFREZZA VS EXUBERA
- Exubera, an inhaled insulin product manufactured by Pfizer, was on the U.S. market briefly from August 2006 to October 2007. It was discontinued because of poor sales and a possible association with lung cancer. In 2012, the FDA published collective data on patients exposed to Exubera in clinical trials. The data showed the following:
- Exubera-exposed patients - 12 cases of lung cancer in 11,180 patients-years
- Comparator-exposed patients - 3 cases of lung cancer in 10,468 patients-years
- Incidence density ratio - 3.75 (CI 1.01-20.68) 
- The Afrezza delivery system differs from the Exubera system in that it allows for faster insulin clearance from lung tissue after dosing. In studies, the concentration of insulin 12 hours after a 60-unit dose of Afrezza was 0.3% the concentration recorded immediately after the dose. With Exubra, the concentration at 12 hours was 8 - 9%. Theoretically, better insulin clearance lowers carcinogenic potential. 
- In trials, 2 cases of lung cancer occurred in Afrezza-treated patients over 2,750 patient-years of exposure compared to 0 cases in comparator groups. After trials were completed, 2 more cases were reported in Afrezza-treated patients. In two of the cases, the patients had a history of heavy tobacco use.
- It's unknown if Afrezza causes a slight increase in the risk of lung cancer. At-risk patients (e.g. smokers) should not use it.
- SIDE EFFECTS
|Common side effects with Afrezza|
|Side effect||Afrezza®||Injectable insulin or oral meds|
|Throat pain or irritation||4.4%||0.9%|
- Hypoglycemia (low blood sugar)
- Afrezza, like injectable insulin, can cause hypoglycemia if dosed incorrectly. Monitor blood sugars closely during therapy. See hypoglycemia management for recommendations on managing low blood sugars.
- Decline in pulmonary function
- Afrezza causes a decline in lung function over time as measured by FEV1. In clinical trials lasting up to 2 years, Afrezza-treated patients had a decline in FEV1 that was 40 mL (95%CI [-80 to -1]) greater than comparator-treated patients. A decline in FEV1 of ≥ 15% occurred in 6% of Afrezza-treated patients compared to 3% of comparator-treated patients. It is unknown if these effects are reversible upon discontinuation.The effects of Afrezza on pulmonary function for treatment durations longer than 2 years have not been established.
- Pulmonary function tests are recommended at baseline, after the first 6 months of therapy, and annually thereafter in all patients. For patients with ≥ 20% decline in FEV₁ , Afrezza® should be discontinued.
- Diabetic ketoacidosis (DKA)
- In trials with type 1 diabetics, the incidence of DKA was 0.43% in Afrezza-treated patients compared to 0.14% in placebo-treated patients. Type 1 diabetics should always use a basal insulin with Afrezza, and patients at increased risk of DKA (e.g. acute infection) should monitor blood sugars closely and consider switching to an injectable bolus insulin.
- Afrezza may cause acute bronchospasm, particularly in patients with chronic lung disease, including asthma and COPD. In a study where asthmatics were given Afrezza while their bronchodilators were held, 29% experienced wheezing after dosing. Do not use Afrezza in patients with asthma or COPD.
- Hypokalemia (low potassium)
- Insulin causes an acute shift of potassium into cells, lowering serum concentrations. Monitor potassium levels in patients at increased risk of hypokalemia (e.g. concomitant diuretics, intravenous insulin) and those receiving potassium-sensitive medications (e.g. digoxin).
- Weight gain
- Insulin therapy can induce weight gain in many patients (4 - 9 pounds on average)
- This effect is due to the increased utilization of glucose by the body 
- Insulin antibodies
- All insulins have the potential to induce an immune response
- The immune response can lead to the production of antibodies against the insulin
- This was a larger issue with older insulins (derived from pigs and cows), but modern insulins still have the potential to invoke antibody production
- In studies, increases in anti-insulin antibodies were observed more frequently with Afrezza than with subcutaneously injected insulins. Presence of antibodies did not appear to affect efficacy. [5,6]
- Chronic Obstructive Pulmonary Disease (COPD)
- Other chronic lung diseases (e.g. pulmonary fibrosis, interstitial lung disease, etc.)
- Kidney disease
- Worsening kidney function can reduce insulin clearance and cause blood sugars to fall, particularly during end-stage disease. Patients with significant renal impairment should monitor blood sugars closely and adjust insulin doses if necessary.
- Liver disease
- Liver disease may increase insulin sensitivity. Patients with significant disease should monitor blood sugars closely and adjust insulin doses if necessary.
- Lung cancer
- See Afrezza vs Exubera for a review of lung cancer risk with Afrezza
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Glitazones (Actos®, pioglitazone, Avandia®, rosiglitazone) - glitazones can cause fluid retention that exacerbates congestive heart failure, and concomitant insulin appears to worsen this effect. Patients with heart failure who require insulin should not take glitazones.
- Drugs that may potentiate the effects of insulin
- Other diabetes medications (e.g. sulfonylureas, GLP-1 analogs, metformin)
- ACE inhibitors
- Fibrates (Lopid® etc.)
- Fluoxetine (Prozac®)
- MAO inhibitors
- Salicylates (aspirin)
- Somatostatin analogs (e.g., octreotide)
- Sulfa antibiotics (Bactrim®, etc.)
- Tramadol (Ultram®) [PubMed 25485799]
- Drugs that may decrease the effects of insulin
- Antipsychotics (clozapine, olanzapine)
- Beta agonists (albuterol, etc.)
- Loop diuretics
- Thiazide diuretics
- Hormones (estrogen, progesterone, oral contraceptives)
- Isoniazid (INH)
- Phenothiazines (Phenergan®, etc.)
- Protease inhibitors
- Somatropin (growth hormone)
- Thyroid hormone
- Drugs that may decrease or increase the effects of insulin
- Drugs that may blunt symptoms of hypoglycemia
- Metabolism and clearance
- Insulin is metabolized by Insulin-Degrading Enzyme (IDE), also called "insulysin" and "insulinase"
- IDE is present in a number of tissues
- LONG-TERM SAFETY
- Afrezza® was FDA-approved in 2014 and has no long-term safety record
- Legitimate long-term concerns are risk of lung cancer (see Afrezza® vs Exubera® above) and effects on pulmonary function (see decline in pulmonary function above)
- Onset of action: 10 - 30 minutes
- Peak effect: ∼ 53 minutes
- Duration of effect: ∼ 2.6 hours
- Dosage forms
- Afrezza® is available as 4 unit and 8 unit single-use cartridges
- The drug is inhaled through an inhaler device provided with the cartridges
- Afrezza is available in the following configurations:
- 60 four unit cartridges
- 90 four unit cartridges
- 90 eight unit cartridges
- 60 four unit cartridges and 30 eight unit cartridges
- 30 four unit cartridges and 60 eight unit cartridges
- 90 four unit cartridges and 90 eight unit cartridges
- Afrezza® is a mealtime (prandial) insulin. It should be administered at the start of a meal.
- It is recommended that all patients undergo spirometry (FEV1) testing to identify potential lung disease before starting Afrezza®
- See insulin dosing for more on dosing insulin
- Insulin-naïve patients:
- Start with 4 units of Afrezza® at each meal
- Patients on subcutaneous mealtime (prandial) insulin:
- The following table is provided in the PI for converting between prandial injected insulins and Afrezza®
- Of note, in the T1DM study detailed above, Afrezza at a ratio of 4 units to 1 unit of Novolog® still did not achieve the same effect as Novolog
|Mealtime injected insulin dose||Afrezza® dose|
|≤ 4 units||4 units|
|5 - 8 units||8 units|
|9 - 12 units||12 units|
|13 - 16 units||16 units|
|17 - 20 units||20 units|
|21 - 24 units||24 units|
- Storage and handling
- Afrezza® comes in a sealed foil package with 2 blister cards inside
- Each blister card has 5 rows of 3 cartridges
- 3 cartridges are under one blister
- Before use, cartridge and inhaler should be at room temperature for 10 minutes
- Inhaler should be thrown away after 15 days
- Sealed foil package - good until expiration date
- Sealed blister cards + strips - must be used within 1 month
- Room temperature
- Sealed foil package - must be used within 10 days
- Sealed blister cards + strips - must be used within 10 days
- Opened strips - must be used within 3 days
- 1 - PMID 20821847
- 2 - Afrezza® NDA
- 3 - PMID 20609958 - Lancet commentary
- 4 - PMID 20609970 - Lancet study
- 5 - Afrezza® PI
- 6 - PMID 17785428
- 7 - PMID 18945920