5.1 Acute Bronchospasm
in Patients with Chronic Lung Disease
Additions and/or revisions underlined:
Because of the risk of acute bronchospasm, AFREZZA is
contraindicated in patients with chronic lung disease such as asthma or COPD [see
Contraindications (4)]. 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 in AFREZZA-treated
patients with asthma and COPD. In a study of patients with asthma whose
bronchodilators were temporarily withheld for assessment, 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
AFREZZA dose in patients with asthma. In a subset study of patients with
COPD (n=8), a mean decline in FEV1 of 200 mL was observed 18 minutes after a
single AFREZZA dose.
5.2
Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen
Subsection
title revised
Additions and/or
revisions underlined:
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
Warnings and Precautions (5.3)] or hyperglycemia. These changes should
be made under close medical supervision and the frequency of blood glucose
monitoring should be increased. For patients with type 2 diabetes, dosage
modifications of concomitant oral antidiabetic treatment may be needed [see Drug Interactions (7.1, 7.2, and 7.3)].
5.3
Hypoglycemia
Additions and/or
revisions underlined:
Glucose monitoring is
essential for patients receiving insulin therapy. 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 (12)],
which impacts the timing of hypoglycemia. Hypoglycemia can happen suddenly, and
symptoms may differ across patients and change over time in the
same patient. 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 (7.4)], or in patients who experience
recurrent hypoglycemia.
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 co-administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of
hypoglycemia [see Use in Specific
Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers should 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.
5.4 Decline in
Pulmonary Function
Additions and/or revisions underlined:
AFREZZA causes a decline in pulmonary
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.
…
5.5 Lung Cancer
Additions and/or
revisions underlined:
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 patients exposed to AFREZZA
while no cases of lung cancer were observed
in patients exposed
to 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 and lung
blastoma) 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.
5.6 Diabetic
Ketoacidosis
Additions and/or
revisions underlined:
In clinical trials enrolling patients
with type 1 diabetes, diabetic ketoacidosis (DKA) was more common in AFREZZA-treated patients (0.43%; n=13) than in comparator-treated patients
(0.14%; n=3). Patients with type 1 diabetes should always use AFREZZA in combination with basal insulin. In patients at risk for DKA, such as
those with an acute illness or infection, increase the frequency of glucose
monitoring and consider discontinuing AFREZZA and giving insulin using
an alternate route of administration.
5.8 Hypokalemia
Additions and/or
revisions underlined:
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 AFREZZA-treated 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).
5.9
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists ADVERSE
REACTIONS
Additions and/or
revisions underlined:
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 should be considered.
8.1 Pregnancy
Additions and/or
revisions underlined:
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).
…
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 greater than or equal to 30 mg/kg/day
(6 times the human systemic exposure at a daily dose of 99 mg AFREZZA,
based on AUC).
8.2 Lactation
Additions and/or
revisions underlined:
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.
…
8.4 Pediatric Use
Additions and/or
revisions underlined:
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.
8.5 Geriatric Use
Additions and/or
revisions underlined:
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 (14)]. 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.
8.6 Hepatic Impairment
Additions and/or
revisions underlined:
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 (5.3)].
8.7 Renal Impairment
Additions and/or revisions underlined:
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 (5.3)].
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