Included as part of the PRECAUTIONS section.
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
Before initiating therapy with AFREZZA, evaluate all
patients with a medical history, physical examination and spirometry (FEV1) to
identify potential underlying lung disease.
Acute bronchospasm has been observed following AFREZZA
dosing in patients with asthma and patients with COPD. In a study of patients
with asthma, bronchoconstriction and wheezing following AFREZZA dosing was
reported in 29% (5 out of 17) and 0% (0 out of 13) of patients with and without
a diagnosis of asthma, respectively. In this study, a mean decline in FEV1 of
400 mL was observed 15 minutes after a single dose in patients with asthma. In
a study of patients with COPD (n=8), a mean decline in FEV1 of 200 mL was
observed 18 minutes after a single dose of AFREZZA. The long-term safety and
efficacy of AFREZZA in patients with chronic lung disease has not been
Changes In Insulin Regimen
Glucose monitoring is essential for patients receiving
insulin therapy. Changes in insulin strength, manufacturer, type, or method of
administration may affect glycemic control and predispose to hypoglycemia [see
Hypoglycemia] or hyperglycemia. These changes should be made
under close medical supervision and the frequency of blood glucose monitoring
should be increased. Concomitant oral antidiabetic treatment may need to be
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).
The timing of hypoglycemia usually reflects the
time-action profile of the administered insulin formulation. AFREZZA has a
distinct time action profile [see CLINICAL PHARMACOLOGY], which impacts
the timing of hypoglycemia. Hypoglycemia can happen suddenly and symptoms may
differ across individuals and change over time in the same individual.
Symptomatic awareness of hypoglycemia may be less pronounced in patients with
longstanding diabetes, in patients with diabetic nerve disease, in patients
using certain medications [see DRUG INTERACTIONS], or in patients who
experience recurrent hypoglycemia. 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
coadministered medication [see DRUG INTERACTIONS]. Patients with renal
or hepatic impairment may be at higher risk of hypoglycemia [see Use In Specific
Risk Mitigation Strategies For Hypoglycemia
Patients and caregivers must be educated to recognize and
manage hypoglycemia. Self-monitoring of blood glucose plays an essential role
in the prevention and management of hypoglycemia. In patients at higher risk
for hypoglycemia and patients who have reduced symptomatic awareness of
hypoglycemia, increased frequency of blood glucose monitoring is recommended.
Decline In Pulmonary Function
AFREZZA causes a decline in lung function over time as
measured by FEV1. 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 FEV1 decline than comparator-treated
patients. The FEV1 decline was noted within the first 3 months, and persisted
for the entire duration of therapy (up to 2 years of observation). In this
population, the annual rate of FEV1 decline did not appear to worsen with
increased duration of use. The effects of AFREZZA on pulmonary function for
treatment duration longer than 2 years has not been established. There are
insufficient data in long term studies to draw conclusions regarding reversal
of the effect on FEV1 after discontinuation of AFREZZA. The observed changes in
FEV1 were similar in patients with type 1 and type 2 diabetes.
Assess pulmonary function (e.g., spirometry) at baseline,
after the first 6 months of therapy, and annually thereafter, even in the
absence of pulmonary symptoms. In patients who have a decline of ≥ 20% in
FEV1 from baseline, consider discontinuing AFREZZA. Consider more frequent
monitoring of pulmonary function in patients with pulmonary symptoms such as
wheezing, bronchospasm, breathing difficulties, or persistent or recurring
cough. If symptoms persist, discontinue AFREZZA. [see ADVERSE REACTIONS].
In clinical trials, two cases of lung cancer, one in
controlled trials and one in uncontrolled trials (2 cases in 2,750
patient-years of exposure), were observed in participants exposed to AFREZZA
while no cases of lung cancer were observed in comparators (0 cases in 2,169
patient-years of exposure). In both cases, a prior history of heavy tobacco use
was identified as a risk factor for lung cancer. Two additional cases of lung
cancer (squamous cell) occurred in non-smokers exposed to AFREZZA and were
reported by investigators after clinical trial completion. These data are
insufficient to determine whether AFREZZA has an effect on lung or respiratory
tract tumors. 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.
In clinical trials enrolling subjects with type 1 diabetes,
diabetic ketoacidosis (DKA) was more common in subjects receiving AFREZZA
(0.43%; n=13) than in subjects receiving comparators (0.14%; n=3). In patients
at risk for DKA, such as those with an acute illness or infection, increase the
frequency of glucose monitoring and consider delivery of insulin using an
alternate route of administration if indicated [see INDICATIONS AND USAGE].
Severe, life-threatening, generalized allergy, including
anaphylaxis, can occur with insulin products, including AFREZZA. If
hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of
care and monitor until symptoms and signs resolve [see ADVERSE REACTIONS].
AFREZZA is contraindicated in patients who have had hypersensitivity reactions
to AFREZZA or any of its excipients [see CONTRAINDICATIONS].
All insulin products, including AFREZZA, cause a shift in
potassium from the extracellular to intracellular space, possibly leading to
hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular
arrhythmia, and death. Monitor potassium levels in patients at risk for
hypokalemia (e.g., patients using potassium-lowering medications, patients
taking medications sensitive to serum potassium concentrations and patients
receiving intravenously administered insulin).
Fluid Retention And Heart Failure With Concomitant Use Of
Thiazolidinediones (TZDs), which are peroxisome
proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related
fluid retention, particularly when used in combination with insulin. Fluid
retention may lead to or exacerbate heart failure. Patients treated with
insulin, including AFREZZA, and a PPAR-gamma agonist should be observed for
signs and symptoms of heart failure. If heart failure develops, it should be
managed according to current standards of care, and discontinuation or dose
reduction of the PPAR-gamma agonist must be considered.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide and Instructions for Use).
Instruct patients to read the
Medication Guide before starting AFREZZA therapy and to reread it each time the
prescription is renewed, because information may change. Instruct patients to
inform their healthcare provider or pharmacist if they develop any unusual
symptom, or if any known symptom persists or worsens.
Inform patients of the
potential risks and benefits of AFREZZA and of alternative modes of therapy.
Inform patients about the importance of adherence to dietary instructions,
regular physical activity, periodic blood glucose monitoring and HbA1c testing,
recognition and management of hypoglycemia and hyperglycemia, and assessment
for diabetes complications. Advise patients to seek medical advice promptly
during periods of stress such as fever, trauma, infection, or surgery, as medication
requirements may change.
Instruct patients to use
AFREZZA only with the AFREZZA inhaler.
Inform patients that the most
common adverse reactions associated with the use of AFREZZA are hypoglycemia,
cough, and throat pain or irritation.
Advise women with diabetes to
inform their physician if they are pregnant or are planning to become pregnant
while using AFREZZA.
Acute Bronchospasm In Patients With
Chronic Lung Disease
Advise patients to inform their
physicians if they have a history of lung disease, because AFREZZA should not
be used in patients with chronic lung disease (e.g., asthma, COPD, or other
chronic lung disease(s)) [see CONTRAINDICATIONS and WARNING
Advise patients that if they
experience any respiratory difficulty after inhalation of AFREZZA, they should
report it to their physician immediately for assessment.
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, and skipped meals.
Instruct patients on the
management of hypoglycemia. 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 [see WARNING AND
Decline In Pulmonary Function And
Inform patients that AFREZZA
can cause a decline in lung function and their lung function will be evaluated
by spirometry before initiation of AFREZZA treatment [see WARNING AND
Inform patients to promptly
report any signs or symptoms potentially related to lung cancer [see WARNING
Instruct patients to carefully
monitor their blood glucose during illness, infection, and other risk
situations for diabetic ketoacidosis and to contact their healthcare provider
if their blood glucose control worsens [see WARNING AND PRECAUTIONS].
Advise patients that
hypersensitivity reactions can occur with insulin therapy including AFREZZA.
Inform patients on the symptoms of hypersensitivity reactions [see WARNING
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 104 week carcinogenicity study, rats were given
doses up to 46 mg/kg/day of the carrier and up to 1.23 mg/kg/day of insulin, by
nose-only inhalation. No increased incidence of tumors was observed at systemic
exposures equivalent to the insulin at a maximum daily AFREZZA dose of 99 mg
based on a comparison of relative body surface areas across species.
In a 26 week carcinogenicity study, transgenic mice
(Tg-ras-H2) given doses up to 75 mg/kg/day of carrier and up to 5 mg/kg/day of
AFREZZA. No increased incidence of tumors was observed.
AFREZZA was not genotoxic in Ames bacterial mutagenicity
assay and in the chromosome aberration assay, using human peripheral
lymphocytes with or without metabolic activation. The carrier alone was not
genotoxic in the in vivo mouse micronucleus assay.
In female rats given subcutaneous doses of 10, 30, and
100 mg/kg/day of carrier (vehicle without insulin) beginning 2 weeks prior to
mating until gestation day 7, there were no adverse effects on male fertility
at doses up to 100 mg/kg/day (a systemic exposure 14-21 times that following
the maximum daily AFREZZA dose of 99 mg based on AUC). In female rats there was
increased pre- and post-implantation loss at 100 mg/kg/day but not at 30
mg/kg/day (14-21 times higher systemic exposure than the maximum daily AFREZZA
dose of 99 mg based on AUC).
Use In Specific Populations
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 14-21
times the maximum recommended daily dose (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%,
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.
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.
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 up to 100
mg/kg/day (a systemic exposure 14-21 times the human systemic exposure,
resulting from the maximum recommended daily dose of 99 mg AFREZZA based on
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 at all
dose groups (at human systemic exposure following a 99 mg AFREZZA dose, based
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,
however, no decrease in fertility was noted, and impaired learning were
observed in pups at ≥ 30 mg/kg/day (a systemic exposure 6 times human
systemic exposure at the maximum daily AFREZZA dose of 99 mg based on AUC).
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 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 effects 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.
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.
AFREZZA has not been studied in patients younger than 18
years of age.
In the AFREZZA clinical studies, 381 patients were 65
years of age or older, of which 20 were 75 years of age or older. No overall
differences in safety or effectiveness were observed between patients over 65
and younger patients.
Pharmacokinetic/pharmacodynamic studies to assess the
effect of age have not been conducted.
The effect of hepatic impairment on the pharmacokinetics
of AFREZZA has not been studied. Frequent glucose monitoring and dose
adjustment may be necessary for AFREZZA in patients with hepatic impairment [see
WARNING AND PRECAUTIONS].
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 dose adjustment may be necessary for AFREZZA in
patients with renal impairment [see WARNING AND PRECAUTIONS].