Water

INDICATIONS AND USAGE Sterile Water for Injection, USP is indicated for use only as a solvent or diluent vehicle for parenterally administered drugs or solutions and as a source of water for parenteral fluid replenishment after suitable additives are introduced. For intravenous administration, an osmolar concentration not less than two-fifths (0.4) of the normal osmolarity of the extracellular fluid (280 mOsmol/liter) is essential to avoid intravascular hemolysis.

DOSAGE 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 ): Inject 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 risk of lipodystrophy and localized cutaneous amyloidosis. Should generally be used in regimens with an intermediate- or long-acting insulin. Continuous Subcutaneous Infusion (Insulin Pump) ( 2.2 ): Refer to the insulin infusion 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. Use in accordance with the insulin pump instructions for use. Administer by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. Rotate the injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not mix with other insulins or diluents in the pump. Intravenous Administration ( 2.2 ): Dilute KIRSTY to concentrations from 0.05 unit/mL to 1 unit/mL insulin aspart-xjhz in infusion systems using polypropylene infusion bags. KIRSTY is stable in infusion fluids such as 0.9% Sodium Chloride Injection, USP. Individualize and adjust the dosage of KIRSTY 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 [see Warnings and Precautions (5.4)]. Inspect KIRSTY visually before use. It should appear clear and colorless. Do not use KIRSTY if particulate matter or coloration is seen. In patients with visual impairment who rely on audible clicks to dial their dose, use KIRSTY prefilled pen with caution. Do not mix KIRSTY 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 KIRSTY 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 KIRSTY prefilled pen in 1-unit increments. • Generally use KIRSTY (administered by subcutaneous injection) in regimens with an intermediate-or long-acting insulin. • May dilute KIRSTY with Insulin Diluting Medium for KIRSTY for subcutaneous injection. Diluting one part KIRSTY to: • Nine parts diluent will yield a concentration one-tenth that of KIRSTY (equivalent to U-10). • One part diluent will yield a concentration one-half that of KIRSTY (equivalent to U-50). Discard any unused diluent after opening the vial of Insulin Diluting Medium for KIRSTY. Continuous Subcutaneous Infusion (Insulin Pump) Can use this KIRSTY product with the 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. Use KIRSTY in accordance with the insulin pump system’s instructions for use. Train patients using continuous subcutaneous insulin fusion pump therapy to administer insulin by injection and have alternate insulin therapy available in case of pump failure. Administer KIRSTY 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 KIRSTY in the reservoir at least every 7 days or according to the pump user manual, whichever is shorter. Follow the KIRSTY-specific information for in-use time because KIRSTY-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 KIRSTY when administering by continuous subcutaneous infusion. Do not expose KIRSTY in the pump reservoir to temperatures greater than 98.6°F (37°C). Intravenous Administration Administer KIRSTY 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 KIRSTY to concentrations from 0.05 unit/mL to 1 unit/mL insulin aspart-xjhz in infusion systems using polypropylene infusion bags. KIRSTY is stable in infusion fluids such as 0.9% Sodium Chloride Injection, USP. 2.3 Dosage Recommendations Individualize the dosage of KIRSTY 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 KIRSTY, a different dosage of KIRSTY 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 KIRSTY is used concomitantly with certain drugs [see Drug Interactions (7) ]. 2.5 Instructions for Mixing KIRSTY with Other Insulins The table below includes instructions regarding mixing KIRSTY with other insulins. Subcutaneous injection route • KIRSTY may only be mixed with NPH insulin preparations. • If KIRSTY is mixed with NPH insulin, withdraw KIRSTY into the syringe first and inject immediately after mixing. Continuous subcutaneous infusion route (Insulin Pump) Do not mix KIRSTY with any other insulin.

WARNINGS AND PRECAUTIONS • Never share a KIRSTY prefilled pen, needles or syringes 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, concomitantly administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairments and hypoglycemia unawareness ( 5.3 ). • Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection ( 5.4 ). • Hypersensitivity reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, may occur. Discontinue KIRSTY, treat, and monitor if indicated ( 5.5 ). • Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia 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 KIRSTY by subcutaneous injection if pump malfunction occurs ( 5.8 ). 5.1 Never Share a KIRSTY Prefilled Pen, Needles or Syringes 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. 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 , 6.3) ]. 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. 5.3 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. 5.4 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. 5.5 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) ]. 5.6 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). 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 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. 5.8 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) ] .

CONTRAINDICATIONS Due to the potential toxicity of benzyl alcohol in neonates, solutions containing benzyl alcohol must not be used in this patient population. Parenteral preparations with benzyl alcohol should not be used for fluid replacement. Parenteral preparations containing benzyl alcohol should not be used in epidural or spinal anesthesia procedures. Bacteriostatic Water for Injection, USP must be made approximately isotonic prior to use.

DRUG INTERACTIONS 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. • 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 ). * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of KIRSTY has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.

ADVERSE REACTIONS 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) ] Adverse reactions observed with insulin aspart products include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash, and pruritus ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Biocon Biologics at 1-833-986-1468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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/m 2 . The mean duration of diabetes was 15.7 years and the mean HbA 1c 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/m 2 . The mean duration of diabetes was 12.7 years and the mean HbA 1c 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. 6.2 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. 6.3 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

CLINICAL PHARMACOLOGY Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water for distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na + ) plays a major role in maintaining physiologic equilibrium. The small volume of fluid provided by Sterile Water for Injection, USP when used only as a pharmaceutic aid for diluting or dissolving drugs for parenteral injection, is unlikely to exert a significant effect on fluid balance except possibly in neonates or very small infants.