Insulin human (inhaled)

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 )]. Switching from another insulin to AFREZZA [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.2 )] 7 DRUG INTERACTIONS Table 6 presents clinically significant drug interactions with AFREZZA. Table 6.

Clinically Significant Drug Interactions with AFREZZA Antidiabetic agents, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blocking Agents, Disopyramide, Fibrates, Fluoxetine, Monoamine Oxidase Inhibitors, Pentoxifylline, Pramlintide, Salicylates, Somatostatin Analogs (e.g., octreotide), and Sulfonamide Antibiotics Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may increase the risk of hypoglycemia.

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. Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may reduce the blood glucose lowering effect of AFREZZA.

Alcohol, Beta-blockers, Clonidine, and Lithium Salts Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs. Mechanism and Clinical Effect(s) Concomitant use with AFREZZA may either increase or decrease the blood glucose lowering effect of AFREZZA. Pentamidine Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs.

Mechanism and Clinical Effect(s) Concomitant use of pentamidine with AFREZZA may cause hypoglycemia, which may sometimes be followed by hyperglycemia Beta-blockers, Clonidine, Guanethidine, and Reserpine Prevention or Management Monitor blood glucose more frequently and modify AFREZZA dosage, as clinically indicated, when used concomitantly with these drugs.

Mechanism and Clinical Effect(s) Concomitant use of these drugs with AFREZZA may blunt the signs and symptoms of hypoglycemia, making it more difficult to recognize See full prescribing information for details regarding concomitant use of drugs that may ( 7 ): Decrease blood glucose lowering effect of AFREZZA Increase or decrease the blood glucose lowering effect of AFREZZA Blunt signs and symptoms of hypoglycemia

8.1 Pregnancy 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 ) . 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%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for DKA, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia- related morbidity. Data Human Data 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. 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…