afrezza® – inhaled human insulin manufacturer: mannkind corporation fda approval date: june 27,...

Afrezza® – inhaled human insulin

Manufacturer: MannKind Corporation

FDA Approval Date: June 27, 2014


Clinical Application

• Indications:• A rapid-acting, pre-meal time insulin for

Type 1 and 2 diabetics.

• Place in therapy:• An inhaled alternative to vial and syringe

for meal-time insulins. Type 1 diabetics must use in combination with long-acting agent.



• Contraindications:• During episodes of hypoglycemia

• In patients who have chronic lung disease



• Warnings and Precautions• Use with caution for patients who have

recently (<6 months) stopped smoking

• Decline in pulmonary function observed over time

• Incidence of lung cancer was observed in controlled and uncontrolled trials

• More patients using inhaled insulin experienced ketoacidosis

• Life-threatening hypokalemia



• Black Block Warning• Acute bronchospams reported in patients with

asthma and COPD using inhaled insulin.

• REMS established to ensure benefits outweigh risk

• Contraindictation in patients with chronic lung disease

• Before initiating Afrezza all patients need detailed medical history, PE and spirometry to identify potential lung disease



• Pregnancy:• Category C

• Lactation:• Excretion in breast milk unknown; use is

not recommended


Drug Facts

• Pharmaceutics:• Combination drug-devices product

• Human insulin produced by recombinant DNA technology

• Insulin dissolved into carrier particles

• Dry powder in packed in cartridges and dispersed through an inhaler


Drug Facts

• Pharmacology:• Recombinant regular human insulin

lowers blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle fat and inhibiting hepatic glucose production.


Drug Facts


Drug Interactions

• Drug Interactions – Precipitant Drugs: • None

• Drug Interactions – Object Drugs: • None


Adverse Effects


Monitoring Parameters

• Efficacy Monitoring:• Blood glucose, A1c

• Toxicity Monitoring:• Pulmonary function tests before initiating, after

6 months of therapy and annually, even in absence of pulmonary symptoms.

• Fluid retention and heart failure with concomitant use of thiazolidinediones

• Hypokalemia

Afrezza® - inhaled human insulin

Prescription Information

• Dosing: • Insulin naïve patients: 4 units, titrate to blood

glucose

• Conversion chart available for patients currently using insulin

• Dosing adjustments based on response

• Cost:• Unknown

• Comes to market early 2015


Literature Review

• Open-label, active-controlled, non-inferiority on Type 1 diabetics

• Combination with basal insulin Afrezza or insulin aspart at every meal for 24 weeks. Titrated to glycemic goals.

• 52 week trial also looked at efficacy and safety of Afrezza vs. RAA

MannKind Corporation. FDA Briefing Document


Literature Review

• Primary endpoint• Absolute change in A1c from baseline to

week 24

• Secondary Endpoints• FPG

• 7-point glucose

• Weight

• Hypoglycemia



Literature Review

• N = 344



Literature ReviewIntervention A1c Goal Attainment FPG Weight

24 week Afrezza vs RAA

Afrezza + basal insulin Goal %-25.57 (7.624)

mg/dL-0.39 (0.438) kg

p=0.4955< 7.0% 18.3%

<6.5% 7.6%

RAA+ basal insulin Goal %10.15 (7.396)

mg/dL0.93 (0.441) kg

p=0.0079< 7.0% 30.7%

<6.5% 12.7%

52 week Afrezza vs RAA

Afrezza + basal insulin Goal %

-35.5 (3.33) mg/dL

-0.5 (0.32) kgp=0.0009

< 8.0 51%

< 7.0% 16.3%

<6.5% 7.4%

RAA+ basal insulin Goal %

-20.6 (3.24) mg/dL

1.4 (0.30) kg< 8.0 56.2%

< 7.0% 16%

<6.5% 7.3%MannKind Corporation. FDA Briefing Document


Literature Review

• Open-label, active-controlled, non-inferiority on Type 2 diabetics

• Combination with OAD or basal insulin

• Two part trial • Afrezza vs inhaled placebo for 24 weeks

• Afrezza vs BPR 70/30



Literature Review

• Primary endpoint• Absolute change in A1c from baseline to

week 24 or to week 52

• Secondary endpoints• A1c goal attainment

• Fasting Plasma Glucose

• Weight



Literature Review

• N = 618



Literature ReviewIntervention HbA1c Goal Attainment FPG Weight

24 week Afrezza vs inhaled placebo

Afrezza + OAD Goal %-11.20 (3.776)

mg/dL0.49 (0.333) kg

p=0.0060< 7.0% 37.7%

<6.5% 15.9%

Placebo +OAD Goal %-3.78 (3.864)

mg/dL-1.13 (0.347) kg

p=0.0001< 7.0% 19.0%

<6.5% 4.2%

52 week Afrezza vs. 70/30

Afrezza + basal Goal %

-26.7 (2.69) mg/dL

0.9 (0.32) kgP=0.0056

<8.0% 56.8%

< 7.0% 22.1%

<6.5% 8%

BPR 70/30 Goal %

-12.9 (2.56) mg/dL

2.5 (0.29) kgP<0.0001

<8.0% 60.9%

< 7.0% 26.8%

<6.5% 12.4%



Literature Review



Conclusions• In Type 1 DM, Afrezza was found non-inferior to RAA.

There was a -0.20 change in A1c in 24-week trial.

• In Type 2 DM, Afrezza was found non-inferior to placebo and 70/30, with a -0.74% change in A1c in a 52-week trial

• Hypoglycemia occurred less in Afrezza when compared to all other interventions

• Afrezza patients saw less weight gain

• Afrezza patients saw greater decrease in FBG



Summary• Afrezza is a dry powder human oral insulin inhaler.

• Indicated for pre-meal time, rapid insulin delivery for type 1 and type 2 diabetics. Must be used in combination with long-acting agent for patients with type 1-diabetes.

• Afrezza should be avoided in smokers, patients with chronic pulmonary and patients with increased risk of lung cancer.

• Afrezza has a tmax of 12-15 minutes and a duration of 28-39 minutes.

• Afrezza comes in 4-unit and 8-unit dose packs and cartridges.

• Common side effects include hypoglycemia, cough, throat irritation/pain and a decline in FEV1


References

1. www.Afrezza.com

2. Afrezza package insert. MannKind Corporation. June 2014.

3. Regular human insulin. Lexicomp Drug Information. Accessed through UpToDate. Accessed on Aug. 20, 2014.

4. Neumiller J, et al. A Review of Inhaled Technosphere Insulin. Annals of Pharmacotherapy 2010, July/August Volume 44.

5. Briefing Document for the Endocrinologic and Metabolic Drug Advisory Committee, FDA. MannKind Corporation. April 1, 2014. Accessed by fda.gov. Accessed on Aug 20, 2014.

afrezza® – inhaled human insulin manufacturer: mannkind corporation fda approval date: june 27,...

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