- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- FEV1 - Forced expiratory volume in 1 second
- T1DM - Type one diabetes
- T2DM - Type two diabetes
- 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 | ||
|---|---|---|
| Outcome | Afrezza (N=174) |
Novolog (N=170) |
| 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 |
| Dropout rate | 25% | 11% |
- ADA recommendations
- Summary
- 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 | ||
|---|---|---|
| Outcome | Afrezza (N=177) |
Placebo inhaler (N=176) |
| Change from baseline in HgA1C | -0.82% | -0.42% |
| Average daily dose of study drug | 92 units | N/A |
| Dropout rate | 15% | 21% |
- ADA recommendations
- Summary
- 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®
- Exubera® was an inhaled insulin product manufactured by Pfizer® that was on the U.S. market briefly from August 2006 to October 2007
- Exubera® was pulled from the market because of poor sales and a possible association with increased lung cancer risk
- In 2012, the FDA received final data on the FUSE study which followed patients who had been exposed to Exubera® in clinical trials
- The study found 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) [2]
- Afrezza® vs Exubera®
- Afrezza® uses a "Technosphere" delivery system which allows for quicker and more complete clearance of insulin from lung tissue
- With Exubera®, the insulin concentration in epithelial lung fluid 12 hours after a dose was about 8 – 9% of the concentration immediately after a dose. With Afrezza®, the concentration at 12 hours after a 60 unit dose was 0.3% of the concentration recorded immediately after the dose. [3]
- The Afrezza® PI reports that there have been 4 cases of lung cancer reported in patients exposed to Afrezza® in clinical trials while no cases have been reported in the comparator groups
- Summary
- It is unknown if Afrezza® increases the risk of lung cancer. Longer studies with more patients are needed to draw firm conclusions.
- Exubera® appeared to increase the risk of lung cancer slightly
- The Afrezza® delivery system has been shown to facilitate faster removal of insulin from lung tissue. This may ameliorate the potential carcinogenic property of inhaled insulin.
- Patients at increased risk for lung cancer (predominantly smokers) should not use Afrezza®
- SIDE EFFECTS
| Common side effects with Afrezza | ||
|---|---|---|
| Side effect | Afrezza® | Injectable insulin or oral meds |
| Cough | 25.6% | 5.4% |
| Throat pain or irritation | 4.4% | 0.9% |
| Headache | 3.1% | 1.8% |
| Diarrhea | 2.7% | 2.2% |
| Productive cough | 2.2% | 0.9% |
| Fatigue | 2.0% | 0.6% |
| Nausea | 2.0% | 1.0% |
- Hypoglycemia (low blood sugar)
- Too much insulin can cause hypoglycemia
- See hypoglycemia for a review of hypoglycemia and its treatment
- 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.
- The effects of Afrezza® on pulmonary function for treatment duration longer than 2 years have not been established
- It is unclear if the effect of Afrezza® on lung function is reversed upon discontinuation of the drug
- 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
- Bronchospasm
- Afrezza may cause acute bronchospasm, particularly in patients with chronic lung diseases (asthma and COPD)
- Afrezza is contraindicated in patients with asthma or COPD
- Hypokalemia (low potassium)
- Insulin causes cells to take up potassium thus lowering blood levels of potassium
- This is typically only an issue when insulin is given intravenously
- 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 [7]
- 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]
- CONTRAINDICATIONS
- Asthma
- Chronic Obstructive Pulmonary Disease (COPD)
- Other chronic lung diseases (e.g. pulmonary fibrosis, interstitial lung disease, etc.)
- PRECAUTIONS
- Kidney disease
- In some patients, worsening kidney function can increase insulin levels and potentiate its effects
- This is typically seen at the very end stage of kidney disease
- Patients with significant kidney disease should monitor blood sugars closely and be aware that dose adjustments may be necessary
- Liver disease
- In some patients, worsening liver function can increase insulin levels and potentiate its effects
- This is typically seen at the very end stage of liver disease
- Patients with significant liver disease should monitor blood sugars closely and be aware that dose adjustments may be necessary
- Lung cancer
- Afrezza may increase the risk of lung cancer in some patients
- See Afrezza® vs Exubera® above for a review
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Afrezza
- Glitazones (Actos®, pioglitazone, Avandia®, rosiglitazone) - Glitazones may cause fluid retention which can worsen congestive heart failure. This effect appears to be more severe when glitazones are used with insulin. Patients with congestive 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
- ARBs
- Disopyramide
- Fibrates (Lopid® etc.)
- Fluoxetine (Prozac®)
- MAO inhibitors
- Pentoxifylline
- 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.)
- Corticosteroids
- Danazol
- Loop diuretics
- Thiazide diuretics
- Hormones (estrogen, progesterone, oral contraceptives)
- Isoniazid (INH)
- Niacin
- Phenothiazines (Phenergan®, etc.)
- Protease inhibitors
- Somatropin (growth hormone)
- Thyroid hormone
- Drugs that may decrease or increase the effects of insulin
- Alcohol
- Beta blockers
- Clonidine
- Lithium
- Pentamidine
- Drugs that may blunt symptoms of hypoglycemia
- Beta blockers
- Clonidine
- Guanethidine
- Reserpine
- 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)
- PHARMACOKINETICS
- Onset of action: 10 - 30 minutes
- Peak effect: ∼ 53 minutes
- Duration of effect: ∼ 2.6 hours
- DOSING
- 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
- Dosing
- 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
- Refrigerated
- 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
- BIBLIOGRAPHY
- 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