Fiasp

1 INDICATIONS AND USAGE FIASP is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. • FIASP is a rapid-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus ( 1 ).

2 DOSAGE AND ADMINISTRATION • Individualize and adjust the dosage of FIASP based on route of administration, individual’s metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.3 ). • Dosage adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns, changes in renal or hepatic function or during acute illness ( 2.3 ). • Subcutaneous injection ( 2.2 ): o Inject at the start of a meal or within 20 minutes after starting a meal into the abdomen, upper arm, or thigh. o Rotate injection sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. o Should generally be used in regimens with an intermediate- or long-acting insulin. • Continuous Subcutaneous Infusion (Insulin Pump) ( 2.2 ): o Refer to the insulin infusion pump user manual to see if FIASP can be used. Use in accordance with the insulin pumps’ instructions for use. o Administer by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. • Intravenous Infusion: Administer only under medical supervision after diluting to concentrations from 0.5 to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags ( 2.2 ). 2.1 Important Preparation and Administration Instructions • Always check insulin label before administration [see Warnings and Precautions ( 5.4 ) ] . • Inspect FIASP visually before use. It should appear clear and colorless. Do not use FIASP if particulate matter or coloration is seen. • Use FIASP FlexTouch pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. • Use PenFill cartridges with caution in patients with visual impairment. • Do not mix FIASP with any other insulin. 2.2 Route of Administration Instructions Subcutaneous Injection: • Inject FIASP at the start of a meal or within 20 minutes after starting a meal subcutaneously into the abdomen, upper arm, or thigh. • Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Adverse Reactions ( 6.1 , 6.2 )]. • FIASP given by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin. • Instruct patients on basal-bolus treatment who forget a mealtime dose to monitor their blood glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal. • The FIASP FlexTouch pen dials in 1 unit increments. Continuous Subcutaneous Infusion (Insulin Pump): • Refer to the continuous subcutaneous insulin infusion pump user manual to see if FIASP or FIASP PumpCart can be used with the insulin pump. Use FIASP and FIASP PumpCart in accordance with the insulin pump system’s instructions for use. • Administer FIASP by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not infuse into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) Adverse Reactions ( 6.1 )]. • Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions ( 5.8 )]. • Change FIASP in the pump reservoir at least every 6 days or replace the PumpCart cartridge at least every 4 days, or according to the pump user manual, whichever is shorter. Follow the FIASP-specific information for in-use time because FIASP-specific information may differ from general insulin pump user manual instructions. • Change the infusion sets and the infusion set insertion site according to the manufacturers user manual. • Do not mix with other insulins or diluents in the insulin pump. • Do not expose FIASP in the pump reservoir to temperatures greater than 37°C (98.6°F). Intravenous Administration: • Administer FIASP intravenously only under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.5 )] . • Dilute FIASP to concentrations from 0.5 unit/mL to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags. • FIASP is stable at room temperature at 20°C to 25°C (68°F to 77°F) for 24 hours in 0.9% sodium chloride or 5% dextrose infusion fluids. 2.3 Dosage Recommendations • Individualize the dosage of FIASP based on the route of administration, patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal. • If converting from another mealtime insulin to FIASP, the initial change can be done on a unit-to-unit basis. • Dose adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions ( 5.2 , 5.3 ) and Drug Interactions ( 7 ), and Use in Specific Populations ( 8.6 , 8.7 )] . • Closely monitor blood glucose when converting insulins used in insulin pumps as individualization of insulin pump parameters may be necessary to minimize the risk of hypoglycemia and hyperglycemia [see Warnings and Precautions ( 5.2 , 5.3 ) and Adverse Reactions ( 6.1 )] • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )]. • Dosage adjustment may be needed when FIASP is co-administered with certain drugs [see Drug Interactions ( 7 )].

4 CONTRAINDICATIONS FIASP is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . • In patients with known hypersensitivity to insulin aspart or any of the excipients in FIASP [see Warnings and Precautions ( 5.6 )] . • During episodes of hypoglycemia ( 4 ). • Hypersensitivity to insulin aspart or any of the excipients in FIASP ( 4 ).

5 WARNINGS AND PRECAUTIONS • Never share a FIASP FlexTouch pen, PenFill cartridge or PenFill cartridge device between patients, even if the needle is changed ( 5.1 ). • Hyperglycemia or hypoglycemia with changes in insulin regimen : Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring ( 5.2 ). • Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness ( 5.3 ). • Hypoglycemia due to medication errors : Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection ( 5.4 ). • Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated ( 5.5 ). • Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue FIASP, monitor and treat if indicated ( 5.6 ). • 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. 7). • Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction: Monitor glucose and administer FIASP by subcutaneous injection if pump malfunction occurs ( 5.8 ). 5.1 Never Share a FIASP FlexTouch Pen, PenFill Cartridge or PenFill Cartridge Device Between Patients FIASP FlexTouch disposable pen, PenFill cartridge and PenFill cartridge devices should never be shared between patients, even if the needle is changed. Patients using FIASP vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6.1 , 6.2 )]. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes mellitus, dosage adjustments in concomitant anti-diabetic treatment may be needed. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of all insulin therapies, including FIASP [see Adverse Reactions ( 6.1 )] . Severe hypoglycemia can cause seizures, may lead to unconsciousness, 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). FIASP, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications ( 4 )]. Hypoglycemia can happen suddenly and symptoms may differ in each individual 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 medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )] , or in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulin preparations, the glucose lowering effect time course of FIASP may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.2 )]. 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 ( 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 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. 5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups between insulin products have been reported. To avoid medication errors between FIASP and other insulins, instruct patients to always check the insulin label before each injection. 5.5 Hypokalemia All insulin products, including FIASP, can 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 if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to potassium concentrations). 5.6 Hypersensitivity and Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including FIASP [see Adverse Reactions ( 6.1 )] . If hypersensitivity reactions occur, discontinue FIASP; treat per standard of care and monitor until symptoms and signs resolve. FIASP is contraindicated in patients who have had hypersensitivity reactions to insulin aspart, or any of the excipients in FIASP [see Contraindications ( 4 )] . 5.7 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 FIASP, 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. 5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction Pump or infusion set malfunctions can lead to a rapid onset of hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim therapy with subcutaneous injection of FIASP may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see Dosage and Administration ( 2.2 ), How Supplied/Storage and Handling ( 16.2 ), and Patient Counseling Information ( 17 )].

7 DRUG INTERACTIONS Table 5 includes clinically significant drug interactions with FIASP. Table 5. Clinically Significant Drug Interactions with FIASP Drugs That May Increase the Risk of Hypoglycemia Drugs: 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. Intervention: Dose reductions and increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of FIASP Drugs: 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. Intervention: Dose increases and increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of FIASP Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine. Intervention: Increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. • Drugs that Increase Hypoglycemia Risk or Increase or Decrease Blood Glucose Lowering Effect: Adjustment of dosage may be needed; closely monitor blood glucose ( 7 ). • Drugs that Blunt Hypoglycemia Signs and Symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine) : Increased frequency of glucose monitoring may be required ( 7 ).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen [see Warnings and Precautions ( 5.2 )] • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • Hypokalemia [see Warnings and Precautions ( 5.5 )] • Hypersensitivity and allergic reactions [see Warnings and Precautions ( 5.6 )] Adverse reactions observed with FIASP include: hypoglycemia, allergic reactions, hypersensitivity, injection/infusion site reactions, lipodystrophy, and weight gain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 actually observed in clinical practice. The data in Table 1 reflect the exposure of 763 adult patients with type 1 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 25 weeks [see Clinical Studies ( 14.2 )] . The mean age was 44.4 years and the mean duration of diabetes was 19.9 years. 59% were male, 93% were White, and 2% were Black or African American; and 7% were Hispanic or Latino. The mean BMI was 26.7 kg/m 2 and the mean HbA 1c at baseline was 7.6%. The data in Table 2 reflect the exposure of 341 adult patients with type 2 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 24 weeks [see Clinical Studies ( 14 )] . The mean age was 59.6 years and the mean duration of diabetes was 13.2 years. 47% were male, 80% were White, and 6% were Black or African American; and 8% were Hispanic or Latino. The mean BMI was 31.5 kg/m 2 and the mean HbA 1c at baseline was 8.0%. The data in Table 3 reflect the exposure of 519 pediatric patients with type 1 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 26 weeks [see Clinical Studies ( 14.3 )] . The mean age was 11.7 years and the mean duration of diabetes mellitus was 4.4 years. 54% were male, 81% were White, 16% were Asian and 2% were Black or African American. The mean BMI was 19.7 kg/m 2 and the mean HbA 1c at baseline was 7.6%. Common adverse reactions, excluding hypoglycemia, were defined as events occurring in ≥5% and occurring at the same rate or greater for FIASP-treated patients than comparator-treated patients. Table 1. Adverse Reactions (%*) in Adult Patients with Type 1 Diabetes Mellitus Mealtime FIASP + Insulin detemir (N=386) Postmeal FIASP + Insulin detemir (N=377) Nasopharyngitis 20.2 23.9 Upper respiratory tract infection 9.1 7.4 Nausea 4.9 5.0 Diarrhea 5.4 3.2 Back pain 5.2 4.0 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Table 2. Adverse Reactions (%*) in Adult Patients with Type 2 Diabetes Mellitus FIASP + Insulin glargine (N=341) Urinary tract infection 5.9 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Table 3: Adverse Reactions (%*) in Pediatric Patients with Type 1 Diabetes Mellitus Mealtime FIASP + Insulin degludec (N=261) Postmeal FIASP + Insulin degludec (N=258) Viral upper respiratory tract infection Upper respiratory tract infection Influenza Rhinitis Headache Pyrexia Vomiting 23.0 8.4 7.7 3.8 6.1 8.4 3.4 20.5 12.4 5.8 6.2 10.1 6.2 8.1 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including FIASP. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for FIASP with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that occur in clinical practice. Incidence rates for severe hypoglycemia in adults with type 1 and type 2 diabetes mellitus and pediatric patients with type 1 diabetes mellitus treated with FIASP in clinical trials are shown in Table 4 [see Clinical Studies ( 14 )] . Table 4. Proportion (%) of Patients with Type 1 Diabetes and Type 2 Diabetes Mellitus Experiencing at Least One Episode of Severe Hypoglycemia in Adult and Pediatric Clinical Trials Study A (Type 1) Adults Study B (Type 2) Adults Study E (Type 1) Pediatric Study D (Type 1 CSII) Mealtime FIASP + Insulin detemir (N=386) Postmeal FIASP + Insulin detemir (N=377) FIASP + Insulin glargine (N=341) Mealtime FIASP + Insulin degludec (N=261) Postmeal FIASP + Insulin degludec (N=258) FIASP (N=236) Severe hypoglycemia* 6.7 8.0 3.2 1.1 3.1 4.7 *Severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions Blood glucose confirmed hypoglycemia was defined as a self-measured glucose calibrated to plasma of less than 56 mg/dL. In Study D, adult patients with type 1 diabetes mellitus treated with FIASP in a pump reported a higher rate of blood glucose confirmed hypoglycemic episodes within the first hour after a meal compared to patients treated with NovoLog [see Clinical Trials ( 14.5 )] . In Study E, pediatric patients with type 1 diabetes mellitus treated with mealtime and postmeal FIASP reported a higher rate of blood glucose confirmed hypoglycemic episodes compared to patients treated with NovoLog; the imbalance was greater during the nocturnal period [see Use in Specific Populations ( 8.4 ), Clinical Trials ( 14.3 )]. Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including FIASP, and may be life threatening. In the clinical program, generalized hypersensitivity reactions (manifested by generalized skin rash and facial edema) were reported in 0.4% of adult patients treated with FIASP. Allergic skin manifestations reported with FIASP in 1.7% of adult patients from the clinical program include eczema, rash, rash pruritic, urticaria and dermatitis. In Study D, allergic reactions were reported in 4.2% of adult patients with type 1 diabetes mellitus treated with FIASP. In Study E, allergic reactions were reported in 4% of pediatric patients with type 1 diabetes mellitus treated with FIASP. Lipodystrophy Administration of insulin, including FIASP, has resulted in lipohypertrophy (enlargement or thickening of tissue) and lipoatrophy (depression in the skin). In the clinical program, lipodystrophy was reported in 0.4% of adult patients and 2.1% of pediatric patients treated with FIASP [see Dosage and Administration ( 2.2 )] . Injection/Infusion Site Reactions As with other insulin therapy, patients may experience rash, redness, inflammation, pain, bruising or itching at the site of FIASP injection or infusion. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of FIASP. In the clinical program, injection site reactions occurred in 1.6% of adult patients treated with FIASP. In Study A, adult patients with type 1 diabetes mellitus treated with FIASP reported 2.2% injection site reactions. In Study D, infusion site reactions were reported in 10.2% of adult patients with type 1 diabetes mellitus treated with FIASP. In Study E, injection site reactions were reported in 4.2% of pediatric patients with type 1 diabetes mellitus treated with FIASP. Weight Gain Weight gain can occur with insulin therapy, including FIASP, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. In Study A, adult patients with type 1 diabetes mellitus treated with FIASP gained an average of 0.7 kg and in Study B, adult patients with type 2 diabetes mellitus treated with FIASP gained an average of 2.7 kg. Peripheral Edema Insulin, including FIASP, may cause sodium retention and edema, particularly if previous poor metabolic control is improved by intensified insulin therapy. In the clinical program, peripheral edema occurred in 0.8% of adult patients treated with FIASP. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of insulin aspart. 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. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

8.1 Pregnancy Risk Summary There are no available data with FIASP in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects or adverse maternal or fetal 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, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8- times and equal to the human subcutaneous dose of 1.0 unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin [see Data] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA 1c >7% and has been reported to be as high as 20-25% in women with a HbA 1c >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 diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart starting during the late 2 nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials. Animal Data Fertility, embryo-fetal and pre-and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of 1.0 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1.0 unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 unit/kg/day for rats and equal to the human subcutaneous dose of 1.0 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.