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Afrezza

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Afrezza

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 CONTRAINDICATIONS].

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 established.

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 adjusted.

Hypoglycemia

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 co-administered medication [see DRUG INTERACTIONS]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations].

Risk Mitigation Strategies for Hypoglycemia

Patients and caregivers must be educated to recognize and manage hypoglycemia. Selfmonitoring 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, AFREZZAtreated 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].

Lung Cancer

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.

Diabetic Ketoacidosis

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 Limitations of Use].

Hypersensitivity Reactions

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].

Hypokalemia

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 PPAR-gamma Agonists

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 PPARgamma agonist must be considered.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Instructions

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 WARNINGS AND PRECAUTIONS].

Advise patients that if they experience any respiratory difficulty after inhalation of AFREZZA, they should report it to their physician immediately for assessment.

Hypoglycemia

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 WARNINGS AND PRECAUTIONS].

Decline in Pulmonary Function and Monitoring

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 WARNINGS AND PRECAUTIONS].

Lung Cancer

Inform patients to promptly report any signs or symptoms potentially related to lung cancer [see WARNINGS AND PRECAUTIONS].

Diabetic Ketoacidosis

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 WARNINGS AND PRECAUTIONS].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions can occur with insulin therapy including AFREZZA. Inform patients on the symptoms of hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

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

Pregnancy

Teratogenic Effects

Pregnancy Category C

AFREZZA has not been studied in pregnant women. AFREZZA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

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 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 at all dose groups (at human systemic exposure following a 99 mg AFREZZA dose, 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, 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).

Nursing Mothers

Many drugs are excreted in human milk. A study in rats indicated that the carrier is excreted in milk at approximately 10% of maternal exposure levels. It is therefore highly likely that the insulin and carrier in AFREZZA is excreted in human milk. A decision should be made whether to discontinue nursing or suspend use of the drug since AFREZZA has not been studied in lactating women.

Pediatric Use

AFREZZA has not been studied in patients younger than 18 years of age.

Geriatric Use

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.

Hepatic Impairment

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 WARNINGS AND PRECAUTIONS].

Renal Impairment

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 WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 7/10/2014
This monograph has been modified to include the generic and brand name in many instances.

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