Kirsty

Description for Kirsty

Insulin aspart-xjhz is a rapid-acting human insulin analog 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 Pichia pastoris. Insulin aspart- xjhz has the empirical formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.

Figure 1. Structural formula of insulin aspart-xjhz.

KIRSTY (insulin aspart-xjhz) injection is a sterile, clear, and colorless solution for subcutaneous or intravenous use. Each mL contains 100 units of insulin aspart-xjhz, and the inactive ingredients dibasic sodium phosphate (0.997 mg), glycerin (16 mg), m-cresol (1.72 mg), phenol (1.50 mg), sodium chloride (0.58 mg), zinc (19.6 mcg), and Water for Injection, USP. KIRSTY has a pH of 7.0-7.8. Hydrochloric acid 1% and/or sodium hydroxide 1% may be added to adjust pH.

Side Effects for Kirsty

The following adverse reactions are also discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.3)]
• Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
• Hypokalemia [see Warnings and Precautions (5.6)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The safety of insulin aspart was evaluated in two treat-to-target trials of 6 months duration, conducted in patients with type 1 diabetes or type 2 diabetes [see Clinical Studies (14)].

The data in Table 1 reflect the exposure of 596 patients with type 1 diabetes to insulin aspart in one clinical trial with a mean exposure duration to insulin aspart of 24 weeks. The mean age was 39 years. Fifty-one percent were male, 94% were Caucasian, 2% were Black and 4% were other races. The mean body mass index (BMI) was 25.6 kg/m². The mean duration of diabetes was 15.7 years and the mean HbA1c at baseline was 7.9%.

The data in Table 2 reflect the exposure of 91 patients with type 2 diabetes to insulin aspart in one clinical trial with a mean exposure duration to insulin aspart of 24 weeks. The mean age was 57 years. Sixty-three percent were male, 76% were Caucasian, 9% were Black and 15% were other races. The mean BMI was 29.7 kg/m². The mean duration of diabetes was 12.7 years and the mean HbA1c at baseline was 8.1%.

Common adverse reactions were defined as events that occurred in ≥5%, excluding hypoglycemia, of the population studied. Common adverse events that occurred at the same rate or greater for insulin aspart-treated patients than in comparator-treated patients during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are listed in Table 1 and Table 2, respectively.

Table 1: Adverse reactions that occurred in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparator

	Insulin Aspart + NPH (%) (n= 596)	Regular Human Insulin + NPH (%) (n= 286)
Headache	12	10
Injury accidental	11	10
Nausea	7	5
Diarrhea	5	3

Table 2: Adverse reactions that occurred in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparator

	Insulin Aspart + NPH (%) (n= 91)	Human Regular Insulin + NPH (%) (n= 91)
Hyporeflexia	11	7
Onychomycosis	10	5
Sensory disturbance	9	7
Urinary tract infection	8	7
Chest pain	5	3
Headache	5	3
Skin disorder	5	2
Abdominal pain	5	1
Sinusitis	5	1

Severe Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin aspart products. 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 insulin aspart with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.

Severe hypoglycemia was defined as hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. The incidence of severe hypoglycemia in:

• Adult and pediatric patients with type 1 diabetes mellitus who received subcutaneous insulin aspart was 17% at 24 weeks and 6% at 24 weeks, respectively [see Clinical Studies (14)].
• Adult patients with type 2 diabetes mellitus who received subcutaneous insulin aspart was 10% at 24 weeks.
• Adult and pediatric patients with type 1 diabetes mellitus, who received insulin aspart via continuous subcutaneous insulin infusion by external pump was 2% at 16 weeks and 10% at 16 weeks respectively.

No severe hypoglycemic episodes were reported in adult patients with type 2 diabetes mellitus receiving insulin aspart via continuous subcutaneous insulin infusion by external pump at 16 weeks.

Allergic Reactions

Some patients taking insulin, including insulin aspart products have experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported.

Adverse Reactions Associated with Insulin Initiation and Glucose Control Intensification

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy

Administration of insulin, including insulin aspart products, subcutaneously and via subcutaneous insulin infusion by external pump, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration (2.2)].

Peripheral Edema

Insulins, including insulin aspart products, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Weight Gain

Weight gain has occurred with insulins, including insulin aspart products, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other insulin aspart products may be misleading.

In a 6-month study with a 6-month extension in adult subjects with type 1 diabetes, 99.8% of patients who received insulin aspart were positive for anti-insulin antibodies (AIA) at least once during the study, including 97.2% that were positive at baseline. A total of 92.1% of patients who received insulin aspart were positive for anti-drug antibodies (ADA) at least once during the study, including 64.6% that were positive at baseline.

In a phase 3 type 1 diabetes clinical trial of insulin aspart, initial increase in titers of antibodies to insulin, followed by a decrease to baseline values, was observed in regular human insulin and insulin aspart treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose.

Post Marketing Experience

The following adverse reactions have been identified during post-approval use of insulin aspart products. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported in which other insulins have been accidentally substituted for insulin aspart products.

Localized cutaneous amyloidosis at the injection site has occurred with insulin aspart products. 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.

Drug Interactions for Kirsty

The table below presents clinically significant drug interactions with KIRSTY.

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 KIRSTY is concomitantly administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of KIRSTY
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 KIRSTY is concomitantly administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of KIRSTY
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 KIRSTY 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 KIRSTY is concomitantly administered with these drugs.

Warnings for Kirsty

Included as part of the PRECAUTIONS section.

Precautions for Kirsty

Never Share a KIRSTY Prefilled Pen between Patients

KIRSTY prefilled pens should never be shared between patients, even if the needle is changed. Patients using KIRSTY vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

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, 6.3)].

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, dosage adjustments of concomitant anti-diabetic products may be needed.

Hypoglycemia

Hypoglycemia is the most common adverse reaction of all insulins, including insulin aspart products. 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).

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. As with all insulins, the glucose lowering effect time course of insulin aspart products 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 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 concomitantly 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; increased frequency of blood glucose monitoring is recommended. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia; increased frequency of blood glucose monitoring is recommended.

Hypoglycemia Due to Medication Errors

Accidental mix-ups between insulin products have been reported. To avoid medication errors between KIRSTY and other insulins, instruct patients to always check the insulin label before each injection.

Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including insulin aspart products. If hypersensitivity reactions occur, discontinue KIRSTY; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. KIRSTY is contraindicated in patients who have had hypersensitivity reactions to insulin aspart products or any of the excipients in KIRSTY [see Contraindications (4)].

Hypokalemia

All insulins, including insulin aspart products, 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 serum potassium concentration).

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 KIRSTY, 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.

Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction

Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with KIRSTY 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 How Supplied/Storage and Handling (16.2) and Patient Counseling Information (17)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin aspart products. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with insulin aspart at 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 units/kg/day, based on units/body surface area, respectively). At a dose of 200 units/kg/day, insulin aspart increased the incidence of mammary gland tumors in females when compared to untreated controls. The relevance of these findings to humans is unknown.

Insulin aspart was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.

In fertility studies in male and female rats, at subcutaneous doses up to 200 units/kg/day (approximately 32 times the human subcutaneous dose, based on units/body surface area), no direct adverse effects on male and female fertility, or general reproductive performance of animals was observed.

Overdose Information for Kirsty

Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

Contraindications for Kirsty

KIRSTY is contraindicated

• During episodes of hypoglycemia [see Warnings and Precautions (3)]
• In patients with hypersensitivity to insulin aspart products or any of the excipients in KIRSTY [see Warnings and Precautions (5.5)]

Clinical Pharmacology for Kirsty

Mechanism of Action

The primary activity of insulin, including insulin aspart products, is the regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

Pharmacodynamics

Pharmacodynamics of insulin aspart After Subcutaneous Administration

The pharmacodynamic profile of insulin aspart given subcutaneously in 22 patients with type 1 diabetes is shown in Figure 2. The maximum glucose-lowering effect of insulin aspart occurred between 1 and 3 hours after subcutaneous injection (0.15 units/kg). The duration of action for insulin aspart is 3 to 5 hours. The time course of action of insulin and insulin analogs such as insulin aspart products may vary considerably in different individuals or within the same individual. The parameters of insulin aspart activity (time of onset, peak time and duration) as designated in Figure 2 should be considered only as general guidelines. The rate of insulin absorption and onset of activity is affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.3)].

Figure 2. Serial mean serum glucose collected up to 6 hours following a single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes.

Pharmacodynamics of insulin aspart After Intravenous Administration

A double-blind, randomized, two-way crossover study in 16 patients with type 1 diabetes demonstrated that intravenous infusion of insulin aspart resulted in a blood glucose profile that was similar to that after intravenous infusion with regular human insulin. Insulin aspart or human insulin was infused until the patient’s blood glucose decreased to 36 mg/dL, or until the patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as the time of autonomic reaction (R) (see Figure 3).

Figure 3. Mean blood glucose profiles following intravenous infusion of insulin aspart (hatched curve) and regular human insulin (solid curve) in 16 patients with type 1 diabetes. R represents the time of autonomic reaction.

Pharmacokinetics

Pharmacokinetics of subcutaneous administration of insulin aspart is presented below.

Absorption and Bioavailability

In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total n=40), the median time to maximum concentration of insulin aspart in these trials was 40 to 50 minutes versus 80 to 120 minutes, for regular human insulin respectively.

The relative bioavailability of insulin aspart (0.15 units/kg) compared to regular human insulin indicates that the two insulins are absorbed to a similar extent.

In a clinical trial in patients with type 1 diabetes, insulin aspart and regular human insulin, both administered subcutaneously at a dose of 0.15 units/kg body weight, reached mean maximum concentrations of 82 and 36 mU/L, respectively.

Distribution

Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.

Figure 4. Serial mean serum free insulin concentration collected up to 6 hours following a single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes.

Metabolism and Elimination

In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects between 18 and 40 years of age received an intravenous infusion of either insulin aspart or regular human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for the two groups with mean values of 1.2 L/h/kg for the insulin aspart group and 1.2 L/h/kg for the regular human insulin group.

After subcutaneous administration in normal male volunteers (n=24), insulin aspart was eliminated with an average apparent half-life of 81 minutes.

Specific Populations

Pediatric Patients: The pharmacokinetic and pharmacodynamic properties of insulin aspart and regular human insulin were evaluated in a single dose study in 18 pediatric patients with type 1 diabetes in 2 age groups: 6-12 years, n=9 and 13-17 years (Tanner grade ≥ 2), n=9. The relative differences in pharmacokinetics and pharmacodynamics in the pediatric patients with type 1 diabetes in both age groups between insulin aspart and regular human insulin were similar to those in healthy adult subjects and adults with type 1 diabetes.

Geriatric Patients: The pharmacokinetic and pharmacodynamic properties of insulin aspart and regular human insulin were investigated in a single dose study in 18 subjects with type 2 diabetes who were ≥ 65 years of age. The relative differences in pharmacokinetics and pharmacodynamics in geriatric patients with type 2 diabetes between insulin aspart and regular human insulin were similar to those in younger adults.

Male and Female Patients: In healthy volunteers given a single subcutaneous dose of insulin aspart 0.06 units/kg, no difference in insulin aspart levels was seen between males and females based on comparison of AUC_(0-10h) or C_max.

Obese Patients: A single subcutaneous dose of 0.1 units/kg insulin aspart was administered in a study of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m²). The pharmacokinetic parameters, AUC and C_max, of insulin aspart were generally unaffected by BMI in the different groups – BMI 19-23 kg/m² (n=4); BMI 23-27 kg/m² (n=7); BMI 27-32 kg/m² (n=6) and BMI >32 kg/m² (n=6). Clearance of insulin aspart was reduced by 28% in patients with BMI >32 kg/m² compared to patients with BMI <23 kg/m².

Patients with Renal Impairment: A single subcutaneous dose of 0.08 units/kg insulin aspart was administered in a study to subjects with either normal renal function (n=6) creatinine clearance (CLcr) (> 80 mL/min) or mild (n=7; CLcr = 50-80 mL/min), moderate (n=3; CLcr = 30-50 mL/min) or severe (but not requiring hemodialysis) (n=2; CLcr = <30 mL/min) renal impairment. In this study, there was no apparent effect of creatinine clearance values on AUC and C_max of insulin aspart.

Patients with Hepatic Impairment: A single subcutaneous dose of 0.06 units/kg insulin aspart was administered in an open-label, single-dose study of 24 subjects (n=6/group) with different degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this study, there was no correlation between the degree of hepatic impairment and any insulin aspart pharmacokinetic parameter.

Animal Toxicology and/or Pharmacology

In standard biological assays in mice and rabbits, one unit of insulin aspart has the same glucose- lowering effect as one unit of regular human insulin.

Patient Information for Kirsty

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Never Share a KIRSTY Prefilled Pen Device Between Patients

Advise patients that they must never share a KIRSTY prefilled pen with another person even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens. Advise patients using KIRSTY vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of KIRSTY therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia [see Warnings and Precautions (5.3)].

Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.

Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].

Hypoglycemia with Medication Errors

Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with insulin aspart products. Inform patients of the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.4)].

Patients Using Continuous Subcutaneous Insulin Pumps

• Train patients in both intensive insulin therapy with multiple injections and in the function of their pump and pump accessories.
• This KIRSTY product can be used with continuous subcutaneous insulin infusion pumps labeled for use with KIRSTY or NOVOLOG -refer to the insulin pump user manual to see if KIRSTY or NOVOLOG can be used with the insulin pump, in which case KIRSTY can be used with the pump. See recommended infusion sets in the insulin pump user manual.
• Instruct patients to replace insulin in the reservoir at least every 7 days or according to the user manual, whichever is shorter; infusion sets and infusion set insertion sites should be changed according to the manufacturer’s user manual. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin
• Instruct patients to discard insulin exposed to temperatures higher than 37°C (98.6°F).
• Instruct patients to inform physician and select a new site for infusion if infusion site becomes erythematous, pruritic, or thickened.
• Instruct patients of the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their physician [see Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)].
• Instruct patients of the risk of hypoglycemia from pump malfunction. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their physician [see Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)].

Kirsty™ is a trademark of Biosimilars New Co Ltd; a Biocon Biologics Company. Copyright © 2023 Biocon Biologics Inc. All rights reserved.

Manufactured by:
Biocon Biologics Inc.
245 Main st, 2nd Floor
Cambridge, MA 02142, U.S.A.
U.S License No. 2324
Product of Malaysia

INSTRUCTIONS FOR USE

INSTRUCTIONS FOR USE
KIRSTY [kir-stee]
(insulin aspart-xjhz)
injection, for subcutaneous use
Prefilled Pen

Introduction

Please read the following instructions carefully before using your KIRSTY Prefilled Pen.

Do not share your KIRSTY Prefilled Pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.

KIRSTY Prefilled Pen is a disposable, single-patient-use, dial-a-dose insulin pen. You can select doses from 1 to 80 units in increments of 1 unit.

Only use needles that are compatible for use with KIRSTY Prefilled Pen which are sold separately, including needles from Embecta (such as Embecta UltraFine).

Getting ready

Make sure you have the following items:

• KIRSTY Prefilled Pen
• a new sterile needle (see Step B)
• Alcohol swabs

KIRSTY Prefilled Pen

Needle (example)

Preparing your KIRSTY Prefilled Pen

• Wash your hands with soap and water.
• Before you start to prepare your injection, check the label to make sure that you are taking the right type of insulin. This is especially important if you take more than 1 type of insulin.
• KIRSTY should look clear and colorless. Do not use your KIRSTY Prefilled Pen if the liquid contains particles or is colored.

Pull off the pen cap (see diagram A). Wipe the rubber stopper with an alcohol swab.
Attaching the needle Remove the protective tab from a disposable needle. Screw the needle tightly onto your Prefilled Pen. It is important that the needle is put on straight (see diagram B). Never place a disposable needle on your KIRSTY Prefilled Pen until you are ready to take your injection.
Pull off the big outer needle cap (see diagram C).
Pull off the inner needle cap and throw it away (dispose of it) (see diagram D).

Giving the airshot before each injection

Before each injection small amounts of air may collect in the cartridge during normal use. To avoid injecting air and to ensure proper dosing:

Turn the dose selector to select 2 units (see diagram E).
Hold your KIRSTY Prefilled Pen with the needle pointing up. Tap the cartridge gently with your finger a few times to make any air bubbles collect at the top of the cartridge (see diagram F).
Keep the needle pointing upwards, press the push-button all the way in (see diagram G). The dose selector returns to 0. A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure no more than 6 times. If you do not see a drop of insulin after 6 times, do not use the KIRSTY Prefilled Pen and contact Biocon Biologics Inc. at 1-833- 986-1468. A small air bubble may remain at the needle tip, but it will not be injected.
Selecting your dose Check and make sure that the dose selector is set at 0.
Turn the dose selector to the number of units you need to inject. The pointer should line up with your dose. The dose can be corrected either up or down by turning the dose selector in either direction until the correct dose lines up with the pointer (see diagram H). When turning the dose selector, be careful not to press the push-button as insulin will come out. You cannot select a dose larger than the number of units left in the cartridge. You will hear a click for every single unit dialed. Do not set the dose by counting the number of clicks you hear because you may get an incorrect dose.

Giving the injection

Do the injection exactly as shown to you by your healthcare provider. Your healthcare provider should tell you if you need to pinch the skin before injecting. Wipe the skin with an alcohol swab and let the area dry.

KIRSTY can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs (thighs), or upper arms.

Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.

Insert the needle into your skin. Inject the dose by pressing the push-button all the way in until the 0 lines up with the pointer (see diagram I). Be careful only to push the button when injecting. Turning the dose selector will not inject insulin.

Keep the needle in the skin for at least 6 seconds, and keep the push-button pressed all the way in until the needle has been pulled out from the skin (see diagram J). This will make sure that the full dose has been given. You may see a drop of insulin at the needle tip. This is normal and has no effect on the dose you just received. If blood appears after you take the needle out of your skin, press the injection site lightly with an alcohol swab. Do not rub the area.

After the injection

Do not recap the needle. Recapping can lead to a needle stick injury. Remove the needle from the KIRSTY Prefilled Pen after each injection and dispose of it. This helps to prevent infection, leakage of insulin, and will help to make sure you inject the right dose of insulin.

If you do not have a sharps container, carefully slip the needle into the outer needle cap. Safely remove the needle and throw it away as soon as you can.

• Put your used needles in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash.
• If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
  • made of a heavy-duty plastic,
  • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
  • upright and stable during use,
  • leak-resistant, and
  • properly labeled to warn of hazardous waste inside the container
• When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: https://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
• When there is not enough medicine left in your KIRSTY Prefilled Pen for your prescribed dose, the KIRSTY Prefilled Pen may be thrown away in your household trash after you have removed the

The KIRSTY Prefilled Pen prevents the cartridge from being completely emptied. It is designed to deliver 300 units.

Put the pen cap on the KIRSTY Prefilled Pen and store the KIRSTY Prefilled Pen without the needle attached (see diagram K). Storing without the needle attached helps prevent leaking, blocking of the needle, and air from entering the Pen.

How should I store KIRSTY Prefilled Pen?

• Do not freeze Do not use KIRSTY if it has been frozen.
• Keep KIRSTY away from heat or
• Store the KIRSTY Prefilled Pen without the needle

Until first use:

• Store unused KIRSTY Prefilled Pen in the refrigerator at 36°F to 46°F (2°C to 8°C).
• Unused KIRSTY Prefilled Pen may be used until the expiration date printed on the label, if kept in the
• Unused KIRSTY Prefilled Pen stored at room temperature up to 86°F (30°C) should be thrown away after 28 days.

In-use:

• Store the KIRSTY Prefilled Pen you are currently using out of the refrigerator at room temperature up to 86°F (30°C) for up to 28 days.
• The KIRSTY Prefilled Pen you are using should be thrown away after 28 days, even if it still has insulin left in it.

Maintenance

For the safe and proper use of your Prefilled Pen be sure to handle it with care. Avoid dropping your Prefilled Pen as it may damage it. If you are concerned that your Prefilled Pen is damaged, use a new one. You can clean the outside of your Prefilled Pen by wiping it with a damp cloth. Do not soak or wash your Prefilled Pen as it may damage it. Do not refill your Prefilled Pen.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. KIRSTY™ is a trademark of Biosimilars New Co Ltd; a Biocon Biologics company.
Copyright © 2023 Biocon Biologics Inc. All rights reserved.

Manufactured by:
Biocon Biologics Inc.
245 Main st, 2nd Floor
Cambridge, MA 02142, U.S.A.
U.S License No. 2324
Product of Malaysia
Approved: 07/2025

INSTRUCTIONS FOR USE

KIRSTY™ [kir-stee]
(insulin aspart-xjhz)
injection, for subcutaneous use
10 mL multiple-dose vial: 100 units/mL (U-100)

Read this Instructions for Use before you start taking KIRSTY and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Supplies you will need to give your KIRSTY injection:

• 10 mL KIRSTY vial
• insulin syringe and needle
• alcohol swabs

Preparing your KIRSTY dose:

• Wash your hands with soap and
• Before you start to prepare your injection, check the KIRSTY label to make sure that you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin.
• KIRSTY should look clear and Do not use KIRSTY if it is thick, cloudy, or is colored.
• Do not use KIRSTY past the expiration date printed on the

Step 1: Pull off the tamper resistant cap (See Figure A). Step 2: Wipe the rubber stopper with an alcohol swab (See Figure B).
Step 3: Hold the syringe with the needle pointing up. Pull down on the plunger until the black tip reaches the line for the number of units for your prescribed dose (See Figure C).
Step 4: Push the needle through the rubber stopper of the KIRSTY vial (See Figure D).
Step 5: Push the plunger all the way in. This puts air into the KIRSTY vial (See Figure E).
Step 6: Turn the KIRSTY vial and syringe upside down and slowly pull the plunger down until the black tip is a few units past the line for your dose (See Figure F). If there are air bubbles, tap the syringe gently a few times to let any air bubbles rise to the top (See Figure G).
Step 7: Slowly push the plunger up until the black tip reaches the line for your KIRSTY dose (See Figure H).
Step 8: Check the syringe to make sure you have the right dose of KIRSTY.
Step 9: Pull the syringe out of the vial’s rubber stopper (See Figure I).

Giving your injection:

• Inject your KIRSTY exactly as your healthcare provider has shown Your healthcare provider should tell you if you need to pinch the skin before injecting.
• KIRSTY can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms, infused in an insulin pump (continuous subcutaneous infusion into an area of your body recommended in the instructions that come with your insulin pump), or given through a needle in your arm (intravenously) by your healthcare provider.
• If you inject KIRSTY, change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.
• If you use KIRSTY in an insulin pump, you should change your infusion set and insertion site according to the manufacturer’s user manual. KIRSTY can be used with the continuous subcutaneous insulin infusion pumps labeled for use with KIRSTY or Read the insulin pump user manual to see if KIRSTY or NOVOLOG can be used. KIRSTY should be given into an area of your body recommended in the instructions that come with your insulin pump. Change (rotate) your insertion sites within the area you choose for each insertion to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the insertion sites. Do not insert into the exact same spot for each insertion. Do not insert where the skin has pits, is thickened, or has lumps. Do not insert where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. The insulin in the reservoir should be changed at least every 7 days or according to the pump user manual, whichever is shorter, even if you have not used all of the insulin.
• If you use KIRSTY in an insulin pump, see your insulin pump manual for instructions or talk to your healthcare provider.
• NPH insulin is the only type of insulin that can be mixed with Do not mix KIRSTY with any other type of insulin.
• KIRSTY should only be mixed with NPH insulin if it is going to be injected right away under your skin (subcutaneously).
• KIRSTY should be drawn up into the syringe before you draw up your NPH insulin.
• Talk to your healthcare provider if you are not sure about the right way to mix KIRSTY and NPH insulin.

Step 10: Choose your injection site (stomach area, buttocks, upper legs or upper arms) and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure J).
Step 11: Insert the needle into your skin. Push down on the plunger to inject your dose (See Figure K). The needle should remain in the skin for at least 6 seconds to make sure you have injected all the insulin.
Step 12: Pull the needle out of your skin. After that, you may see a drop of KIRSTY at the needle tip. This is normal and does not affect the dose you just received (See Figure L). If you see blood after you take the needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area.

After your injection:

• Do not recap the Recapping the needle can lead to a needle stick injury.
• Put the empty insulin vials, used needles and syringes in a FDA-cleared sharps disposal container right away after Do not throw away (dispose of) loose needles and syringes in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
  • made of a heavy-duty plastic,
  • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
  • upright and stable during use,
  • leak-resistant, and properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: https://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

How should I store KIRSTY?

• Do not freeze Do not use KIRSTY if it has been frozen.
• Keep KIRSTY away from heat or light.
• All unopened vials:
  • Store unopened KIRSTY vials in the refrigerator at 36°F to 46°F (2°C to 8°C).
  • Unopened vials may be used until the expiration date printed on the label, if they have been stored in the refrigerator.
  • Unopened vials should be thrown away after 28 days, if they are stored at room temperature up to 86°F (30°C).
• After vials have been opened:
  • Opened KIRSTY vials can be stored in the refrigerator at 36°F to 46°F (2°C to 8°C) or at room temperature up to 86°F (30°C).
  • Throw away all opened KIRSTY vials after 28 days, even if they still have insulin left in them.
  • If using KIRSTY in a pump, throw away all opened KIRSTY vials after 19 days.

General information about the safe and effective use of KIRSTY

• Always use a new syringe and needle for each injection.
• Do not share syringes or needles.
• Keep KIRSTY vials, syringes, and needles out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.
KIRSTY™ is a trademark of Biosimilars New Co Ltd; a Biocon Biologics company. Copyright © 2023 Biocon Biologics Inc. All rights reserved.

Manufactured by:
Biocon Biologics Inc.
245 Main st, 2nd Floor
Cambridge, MA 02142, U.S.A.
U.S License No. 2324
Product of Malaysia
Approved: 07/2025