Fiasp (Page 2 of 9)

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 one 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)].

6 ADVERSE REACTIONS

The following adverse reactions are also discussed elsewhere:

•

Hypoglycemia [see Warnings and Precautions (5.3)]

•

Hypokalemia [see Warnings and Precautions (5.5)]

•

Hypersensitivity and allergic reactions [see Warnings and Precautions (5.6)]

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 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 Caucasian, 2% were Black or African American and 7% were Hispanic. The mean BMI was 26.7 kg/m² 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 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 Caucasian, 6% were Black or African American and 8% were Hispanic. The mean BMI was 31.5 kg/m² 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 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 was 4.4 years. 54% were male, 81% were Caucasian, 16% were Asian and 2% were Black or African American. The mean BMI was 19.7 kg/m² 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 subjects than comparator-treated subjects.

Table 1. Adverse Reactions (%*) in Adult Patients with Type 1 Diabetes

	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

	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

	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 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 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 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 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 treated with FIASP. In Study E, allergic reactions were reported in 4% of pediatric patients with type 1 diabetes 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 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 treated with FIASP. In Study E, injection site reactions were reported in 4.2% of pediatric patients with type 1 diabetes 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 treated with FIASP gained an average of 0.7 kg and in Study B, adult patients with type 2 diabetes 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.