INSULIN ASPART: 22,014 Adverse Event Reports & Safety Profile

Insulin aspart protamine and insulin aspart is a human insulin analog containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart. Insulin aspart is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker’s yeast). Insulin aspart has the empirical formula C 256 H 381 N 65 O 79 S 6 and a molecular weight of

5825.8 Da.

Figure

1. Structural formula of insulin aspart Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is a uniform, white and cloudy, sterile injectable suspension for subcutaneous use. Each mL contains 100 units of insulin aspart and the inactive ingredients: disodium hydrogen phosphate dihydrate (1.25 mg), glycerol (16.0 mg), metacresol (1.72 mg), phenol (1.50 mg), protamine sulfate (0.32 mg), sodium chloride (0.877 mg), zinc (19.6 mcg), and Water for Injection, USP.

Insulin Aspart

Protamine and Insulin Aspart Mix 70/30 has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH. Molecular chain of insulin aspart.

AND USAGE Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is a mixture of insulin aspart protamine and insulin aspart indicated to improve glycemic control in adult patients with diabetes mellitus. Limitations of Use:

• Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is not recommended for the treatment of diabetic ketoacidosis.
• The proportions of rapid-acting and long-acting insulins in Insulin Aspart Protamine and Insulin Aspart Mix 70/30 are fixed and do not allow for basal versus prandial dose adjustments.

Insulin Aspart

Protamine and Insulin Aspart Mix 70/30 is a mixture of insulin aspart protamine, an intermediate-acting human insulin analog, and insulin aspart, a rapid-acting human insulin analog, indicated to improve glycemic control in adult patients with diabetes mellitus. Limitations of Use:

• Not recommended for the treatment of diabetic ketoacidosis.
• The proportions of rapid-acting and long-acting insulins are fixed and do not allow for basal versus prandial dose adjustments (1) .

AND ADMINISTRATION See Full Prescribing Information for important preparation, administration, and dosage instructions ( 2.1, 2.2, 2.3, 2.4, 2.5 ).

• Subcutaneous injection ( 2.2 ): o Inject subcutaneously within 5-10 minutes before a meal into the abdominal area, thigh, buttocks or upper arm. o Rotate injection sites within the same region from one injection to the next to reduce 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 NovoLog (insulin aspart) can be used. Use in accordance with the insulin pump instructions for use. o Administer by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. o Rotate the injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. o Do not mix with other insulins or diluents in the pump.
• Intravenous Administration ( 2.2 ) : o Dilute Insulin Aspart to concentrations from 0.05 unit/mL to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags. o Insulin Aspart is stable in infusion fluids such as 0.9% Sodium Chloride Injection, USP.
• Individualize and adjust the dosage of Insulin Aspart based on route of administration, the individual's metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.4 ).
• Dosage adjustments 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 ( 2.4 ).

2.1 Important Preparation and Administration Instructions

• Always check insulin labels before administration. This product is NovoLog (insulin aspart) [see Warnings and Precautions ( 5.4 )] .
• Inspect Insulin Aspart visually before use. It should appear clear and colorless. Do not use Insulin Aspart if particulate matter or coloration is seen.
• In patients with visual impairment, use: o Insulin Aspart FlexPen with caution in those who may rely on audible clicks to dial their dose. o PenFill cartridges with caution.
• Do not mix Insulin Aspart with other insulins when administering using a continuous subcutaneous infusion pump.

2.2 Preparation and Administration Instructions for the Approved Routes of Administration Subcutaneous Injection

• Inject Insulin Aspart subcutaneously within 5-10 minutes before a meal into the abdominal area, thigh, buttocks or upper arm.
• 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 Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 , 6.3 )].
• Dial the Insulin Aspart FlexPen dials in 1-unit increments.
• Generally use Insulin Aspart (administered by subcutaneous injection) in regimens with an intermediate- or long-acting insulin.
• May dilute this Insulin Aspart product with Insulin Diluting Medium for NovoLog for subcutaneous injection. Diluting one part Insulin Aspart to: o Nine parts diluent will yield a concentration one-tenth that of Insulin Aspart (equivalent to U-10). o One part diluent will yield a concentration one-half that of Insulin Aspart (equivalent to U-50).

Continuous Subcutaneous

Infusion (Insulin Pump)

• Can use this Insulin Aspart product with the continuous subcutaneous insulin infusion pumps labeled for use with NovoLog (insulin aspart). Refer to the insulin pump user manual to see if NovoLog can be used.

Use Insulin

Aspart in accordance with the insulin pump system’s instructions for use.

• Train patients using continuous subcutaneous insulin infusion pump therapy to administer insulin by injection and have alternate insulin therapy available in case of pump failure.
• Administer Insulin Aspart 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 or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6.1, 6.3)].
• Instruct patients to follow healthcare provider recommendations when setting basal and meal time infusion rate.
• Change the Insulin Aspart in the reservoir at least every 7 days or according to the pump user manual, whichever is shorter. Follow the NovoLog-specific information for in-use time because NovoLog-specific information may differ from general pump manual instructions.
• Change the infusion set and the infusion set insertion site according to the manufacturer’s user manual.
• Do not dilute or mix Insulin Aspart when administering by continuous subcutaneous infusion.
• Do not expose Insulin Aspart in the pump reservoir to temperatures greater than 98.6°F (37°C).

Intravenous

Administration

• Administer Insulin Aspart 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, 5.6) and How Supplied/Storage and Handling (16.2)].
• Dilute Insulin Aspart to concentrations from 0.05 unit/mL to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags.

Insulin

Aspart is stable in infusion fluids such as 0.9% Sodium Chloride Injection, USP.

2.3 Dosage Recommendations

• Individualize the dosage of Insulin Aspart based on the route of administration, the patient’s metabolic needs, blood glucose monitoring results and glycemic control goal.
• Dosage adjustments 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 ( 5.2 , 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )] .
• When switching from another insulin to Insulin Aspart, a different dosage of Insulin Aspart may be needed [see Warnings and Precautions ( 5.2 )] .
• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].

2.4 Dosage Modifications for Drug Interactions Dosage modification may be needed when Insulin Aspart is used concomitantly with certain drugs <span class="opacity-50 text-xs">[see Drug Interactions (7)]</span> .

2.5 Instructions for Mixing Insulin Aspart with Other Insulins The table below includes instructions regarding mixing Insulin Aspart with other insulins. Subcutaneous injection route

• Insulin Aspart may only be mixed with NPH insulin preparations.
• If Insulin Aspart is mixed with NPH insulin, withdraw Insulin Aspart into the syringe first and inject immediately after mixing. Continuous subcutaneous infusion route (Insulin Pump) Do not mix Insulin Aspart with any other insulin.

Insulin Aspart Protamine and Insulin Aspart Mix 70/30 is contraindicated:

• During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )]
• In patients with hypersensitivity to Insulin Aspart Protamine and Insulin Aspart Mix 70/30 or one of its excipients [see Warnings and Precautions ( 5.5 )]
• Do not use during episodes of hypoglycemia (4) .
• Do not use in patients with hypersensitivity to Insulin Aspart Protamine and Insulin Aspart Mix 70/30 or one of its excipients (4) .

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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 )]</span> . 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.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 , 6.2 )]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. 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) <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> , 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), How Supplied/Storage and Handling ( 16.2 ), and Patient Counseling Information ( 17 )]</span>.

INTERACTIONS The table below presents clinically significant drug interactions with Insulin Aspart Protamine and Insulin Aspart Mix 70/30 Table 3: Clinically Significant Drug Interactions with Insulin Aspart Protamine and Insulin Aspart Mix 70/30 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 analog (e.g., octreotide), and sulfonamide antibiotics Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Aspart Protamine and Insulin Aspart is concomitantly administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Aspart Protamine and Insulin Aspart 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 adjustment and increased frequency of glucose monitoring may be required when Insulin Aspart Protamine and Insulin Aspart is concomitantly administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Aspart Protamine and Insulin Aspart 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 Insulin Aspart Protamine and Insulin Aspart is concomitantly 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 Insulin Aspart Protamine and Insulin Aspart is concomitantly administered with these drugs.

• Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics (7) .
• Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, 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 (7) .
• Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine (7) .
• Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine (7) .