İHALE DÜNYASI
İHALE DÜNYASI
11.1 AFREZZA Cartridges Human insulin is a rapid acting human insulin produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Chemically, human insulin has the empirical formula C 257 H 383 N 65 O 77 S 6 and a molecular weight of 5808. Human insulin has the following primary amino acid sequence: AFREZZA (human insulin) inhalation powder is available in single-use plastic cartridges filled with a white powder containing insulin (human), which is administered via oral inhalation using the AFREZZA Inhaler only. Insulin is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP) and polysorbate 80. AFREZZA Inhalation Powder is a dry powder supplied as 4 unit, 8 unit or 12 unit cartridges. Primary Amino Acid Sequence 11.2 AFREZZA Inhaler The AFREZZA Inhaler is breath-powered by the patient. When the patient inhales through the device, the powder is aerosolized and delivered to the lung. The amount of AFREZZA delivered to the lung will depend on individual patient factors.
AFREZZA (R) is a rapid acting inhaled human insulin indicated to improve glycemic control in adult patients with diabetes mellitus. Limitations of Use: AFREZZA is not recommended for the treatment of diabetic ketoacidosis [see Warning and Precautions ( 5.6 )] . The safety and effectiveness 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. AFREZZA (R) is a rapid acting inhaled human insulin indicated to improve glycemic control in adult patients with diabetes mellitus. ( 1 ) Limitations of Use: Not recommended for the treatment of diabetic ketoacidosis ( 1 ) Not recommended in patients who smoke or who have recently stopped smoking ( 1 )
Only administer via oral inhalation using the AFREZZA inhaler ( 2.2 ) Administer at the beginning of each meal ( 2.2 ) See full prescribing information for the recommended starting mealtime dosage in insulin-naive patients and patients who are using subcutaneous mealtime insulin or pre-mixed insulin ( 2.3 ) Modify dosage based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal ( 2.3 ) If blood glucose control is not achieved in patients requiring high AFREZZA doses, consider discontinuing AFREZZA ( 2.4 ) 2.1 Lung Function Assessment Prior to Administration AFREZZA is contraindicated in patients with chronic lung disease because of the risk of acute bronchospasm in these patients. Before initiating AFREZZA, perform a medical history, physical examination and spirometry (FEV 1 ) in all patients to identify potential lung disease [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. 2.2 Important Administration and Discard Instructions Only administer AFREZZA via oral inhalation using the AFREZZA Inhaler. Administer AFREZZA at the beginning of each meal. Administer AFREZZA using a single inhalation per cartridge (if the dose is greater than the contents of a single cartridge, more than one cartridge is needed) [see Dosage and Administration ( 2.3 )]. For additional administration instructions on how to use the AFREZZA Inhaler [see Dosage and Administration ( 2.6 )] and see the Instructions for Use . The AFREZZA Inhaler can be used for up to 15 days from the date of first use. After 15 days of use, the inhaler must be discarded and replaced with a new inhaler. 2.3 Recommended Starting Mealtime Dosage For insulin naive patients, start on 4 units of AFREZZA at the beginning of each meal. For patients using subcutaneous, mealtime ( prandial) insulin: Determine the appropriate AFREZZA dose for each meal by converting from the injected insulin dose using Figure 1 . When switching from another insulin to AFREZZA, a different insulin dose may be needed requiring increased frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )]. For patients using subcutaneous, pre-mixed insulin : Estimate the mealtime injected dose by dividing half of the total daily injected pre-mixed insulin dose equally among the three meals of the day. When switching from another insulin to AFREZZA, a different insulin dose may be needed. When switching a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )]. Convert each estimated injected mealtime dose to an appropriate AFREZZA dose using Figure 1 . Administer half of the total daily injected pre-mixed dose as an injected basal insulin dose. For AFREZZA doses exceeding the contents of a single cartridge at mealtime, inhalations from more than one cartridge are necessary. To achieve the required total mealtime dose, use a combination of 4 unit, 8 unit, and 12 unit cartridges. Examples of cartridge combinations for doses of up to 24 units are shown in Figure 1 . For doses above 24 units, use combinations of different multiple cartridges. Figure 1. Mealtime AFREZZA Starting Dose Conversion Table Figure 1 2.4 Mealtime Dosage Modification Modify the AFREZZA dosage based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal. Dosage modifications may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )]. Carefully monitor blood glucose control in patients requiring high AFREZZA doses. If blood glucose control is not achieved with increased AFREZZA doses in these patients, consider discontinuing AFREZZA. 2.5 Dosage Modifications for Drug Interactions Dosage modification may be needed when: AFREZZA is used concomitantly with certain drugs that increase and/or decrease the glucose lowering effect [see Drug Interactions ( 7.1 , 7.2 , 7.3 )]. Switching from another insulin to AFREZZA [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.2 )] 2.6 Administration Instructions Refer patients to the Instructions for Use for detailed instructions and visuals on how to prepare, administer, and store AFREZZA; use the AFREZZA cartridges; and use the AFREZZA inhaler. Critical administration instructions are as follows: Keep the inhaler level with the white mouthpiece on top and purple base on the bottom after a cartridge has been inserted into the inhaler. Loss of drug effect can occur if the inhaler is turned upside down, held with the mouthpiece pointing down, shaken, or dropped after the cartridge has been inserted but before the dose has been administered. If any of the above occur, replace the cartridge before use. Hold the inhaler away from the mouth and fully exhale. After the inhaler is placed in the mouth and the lips form a seal, tilt the inhaler down towards the chin while keeping the head level. With the mouth closed around the mouthpiece, inhale deeply through the inhaler. Hold the breath for as long as comfortable and at the same time remove the inhaler from the mouth. After holding the breath, exhale and continue to breathe normally.
AFREZZA is contraindicated: During episodes of hypoglycemia [see Warning and Precautions ( 5.3 )]. Chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD), because of the risk of acute bronchospasm [see Warnings and Precautions ( 5.1 )] Hypersensitivity to regular human insulin or any of the excipients in AFREZZA [see Warnings and Precautions ( 5.7 )] During episodes of hypoglycemia ( 4 ) Chronic lung disease, such as asthma, or chronic obstructive pulmonary disease ( 4 ) Hypersensitivity to regular human insulin or any of the excipients in AFREZZA ( 4 )
The following serious adverse reactions are described below and elsewhere in the labeling: Acute bronchospasm in patients with chronic lung disease [see Warnings and Precautions ( 5.1 )] Hypoglycemia [see Warnings and Precautions ( 5.3 )] Decline in pulmonary function [see Warnings and Precautions ( 5.4 )] Lung cancer [see Warnings and Precautions ( 5.5 )] Diabetic ketoacidosis [see Warnings and Precautions ( 5.6 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.7 )] The most common adverse reactions associated with AFREZZA (2% or greater incidence) are hypoglycemia, cough, and throat pain or irritation ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact MannKind at 1-877-323-8505 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure of 3,017 patients to AFREZZA and include 1,026 patients with type 1 diabetes and 1,991 patients with type 2 diabetes. The mean exposure duration was 8.2 months for patients with type 1 diabetes and those with type 2 diabetes. In the overall population: 1,874 patients were exposed to AFREZZA for 6 months and 724 patients for greater than one year. 620 and 1,254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for greater than one year (median exposure = 1.8 years). AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively). The mean age of the population was 50.2 years and 20 patients were older than 75 years of age; 51% of the population were males; 83% were White, 5% were Black or African American, and 2% were Asian; 10% were Hispanic. At baseline, the type 1 diabetes population had diabetes for an average of 16.6 years and had a mean HbA1c of 8.3%, and the type 2 diabetes population had diabetes for an average of 10.7 years and had a mean HbA1c of 8.8%. At baseline, 33% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had a history of cardiovascular disease. Table 1 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in type 2 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA. Table 1. Common Adverse Reactions That Occurred in ? 2% in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA *Carrier particle without insulin was used as placebo [see Description ( 11.1 )] . AFREZZA (n = 1,991) Placebo* (n = 290) Non-placebo comparators (n=1,363) Cough 25.6% 4.4% 3.1% 2.7% 2.2% 2.0% 2.0% 19.7% 3.8% 2.8% 1.4% 1.0% 0.7% 0.3% 5.4% 0.9% 1.8% 2.2% 0.9% 0.6% 1.0% Throat pain or irritation Headache Diarrhea Productive cough Fatigue Nausea Table 2 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on comparator, and occurred in at least 2% of patients treated with AFREZZA. Table 2. Common Adverse Reactions That Occurred in ? 2% in Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA AFREZZA (n=1026) Subcutaneous Insulin (n = 835) Cough 29.4% 4.9% Throat pain or irritation 5.5% 1.9% Headache 4.7% 2.8% Pulmonary function test decreased 2.8% 1.0% Bronchitis 2.5% 2.0% Urinary tract infection 2.3% 1.9% Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including AFREZZA [see Warnings and Precautions ( 5.3 )] . The incidence of severe and non-severe hypoglycemia in AFREZZA-treated patients versus placebo-treated patients with type 2 diabetes is shown in Table 3 . A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia. Table 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Patients with Type 2 Diabetes AFREZZA (N=177) Placebo (N=176) Severe Hypoglycemia 5.1% 1.7% Non-Severe Hypoglycemia 67% 30% Cough Approximately 27% of patients treated with AFREZZA reported cough, compared to approximately 5% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (3% of AFREZZA-treated patients). Pulmonary Function Decline In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients treated with AFREZZA had a 40 mL (95% CI: -80, -1) greater decline from baseline in forced expiratory volume in one second (FEV 1 ) compared to patients treated with comparator anti-diabetes treatments. The decline occurred during the first 3 months of therapy and persisted over 2 years ( Figure 2 ). A decline in FEV 1 of ? 15% occurred in 6% of AFREZZA-treated patients compared to 3% of comparator-treated patients [see Warnings and Precautions ( 5.4 )]. Figure 2. Mean (+/-SE) Change in FEV 1 (Liters) from Baseline for Type 1 and Type 2 Diabetes Patients Figure 2 Weight Gain Weight gain has occurred with some insulin therapies, including AFREZZA. Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria. In a clinical trial of patients with type 2 diabetes [see Clinical Studies ( 14.3 )] , there was a mean 0.49 kg weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss among placebo-treated patients. 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of AFREZZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: bronchospasm.
Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen : Carry out under close medical supervision and increase frequency of blood glucose monitoring. For patients with type 2 diabetes mellitus, oral antidiabetic treatment dosage modifications may be needed. ( 5.2 ) Hypoglycemia (may be life-threatening): Increase frequency of glucose monitoring in patients at higher risk for hypoglycemia and those who have reduced symptomatic awareness of hypoglycemia. ( 5.3 ) Decline in Pulmonary Function : Assess pulmonary function (e.g., spirometry (FEV 1 )) before initiating, after 6 months of therapy, and annually, even in the absence of pulmonary symptoms. In patients who have a decline of ? 20% in FEV 1 from baseline, consider discontinuing AFREZZA. ( 2.5 , 5.4 ) Lung Cancer : 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. ( 5.5 ) Diabetic Ketoacidosis : In patients at risk for DKA, increase the frequency of glucose monitoring and consider changing to alternate route of insulin delivery. ( 5.6 ) 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. ( 5.7 ) Hypokalemia (may be life-threatening): Monitor potassium levels in patients at risk of hypokalemia. ( 5.8 ) Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs) : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.9 ) 5.1 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 ( 4 )] . Before initiating therapy with AFREZZA, evaluate all patients with a medical history, physical examination, and spirometry (FEV 1 ) 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 FEV 1 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 FEV 1 of 200 mL was observed 18 minutes after a single AFREZZA dose. 5.2 Hypoglycemia or Hyperglycemia with 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 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 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 AFREZZA causes a decline in pulmonary function over time as measured by FEV 1 . 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 FEV 1 decline than comparator-treated patients. The FEV 1 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 FEV 1 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 FEV 1 after discontinuation of AFREZZA. The observed changes in FEV 1 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 FEV 1 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 ( 6 )] . 5.5 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 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 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. 5.7 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 ( 6 )] . AFREZZA is contraindicated in patients who have had hypersensitivity reactions to AFREZZA or any of its excipients [see Contraindications ( 4 )] . 5.8 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 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 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. --- BOXED WARNING: WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and COPD [see Warnings and Precautions ( 5.1 )] . AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD [see Contraindications ( 4 )]. Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV 1 ) to identify potential lung disease in all patients [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 )]. WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE See full prescribing information for complete boxed warning. Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and COPD. ( 5.1 ) AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD. ( 4 ) Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV 1 ) to identify potential lung disease in all patients. ( 2.5 ), ( 5.1 )
Drugs that may increase the risk of hypoglycemia ( 7.1 , 7.3 ) Drugs that may decrease blood glucose lowering effect of AFREZZA ( 7.2 , 7.3 ) Drugs that may affect hypoglycemic signs and symptoms ( 7.4 ) 7.1 Drugs That May Increase the Risk of Hypoglycemia The risk of hypoglycemia associated with AFREZZA use may be increased with antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Dose modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs. 7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of AFREZZA The glucose lowering effect of AFREZZA may be decreased when given concomitantly with atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline) and thyroid hormones. Dose adjustment and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs. 7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of AFREZZA The glucose lowering effect of AFREZZA may be increased or decreased when co-administered with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs. 7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are given concomitantly with AFREZZA.
