WATER: 4,729 Adverse Event Reports & Safety Profile

DESCRIPTION Sterile Water for Irrigation, USP is a sterile, distilled, nonpyrogenic water for injection intended only for sterile irrigation, washing, rinsing and dilution purposes. pH 5.5 (5.0 to 7.0).

Sterile

Water for Irrigation, USP contains no bacteriostat, antimicrobial agent or added buffer and is intended for use only as a single-dose or short procedure irrigation. When smaller volumes are required the unused portion should be discarded.

Sterile

Water for Irrigation, USP may be classified as a sterile irrigant, wash, rinse, diluent and pharmaceutical vehicle. Water for Irrigation, USP is chemically designated H 2 O. The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. The semi-rigid container is fabricated from a specially formulated polyolefin. It is a copolymer of ethylene and propylene. The container requires no vapor barrier to maintain the proper drug concentration. The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

AND USAGE Treprostinil injection is a prostacyclin vasodilator indicated for: Treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%). ( 1.1 ) Patients who require transition from epoprostenol, to reduce the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. ( 1.2 )

1.1 Pulmonary Arterial Hypertension Treprostinil injection is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%) <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> .

1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from Epoprostenol In patients with PAH requiring transition from epoprostenol, treprostinil injection is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.

AND ADMINISTRATION PAH WHO Group 1 in patients with NYHA Class II-IV symptoms : Initial dose for patients new to prostacyclin infusion therapy: 1.25 ng/kg/min; increase based on clinical response (increments of 1.25 ng/kg/min per week for the first 4 weeks of treatment, later 2.5 ng/kg/min per week). Avoid abrupt cessation. ( 2.2 , 2.4 ) Mild to moderate hepatic insufficiency: Decrease initial dose to 0.625 ng/kg/min. Severe hepatic insufficiency: No studies performed. ( 2.5 ) Transition from Epoprostenol : Increase the treprostinil injection dose gradually as the epoprostenol dose is decreased, based on constant observation of response. ( 2.7 ) Administration : Continuous subcutaneous infusion is the preferred mode. Use intravenous (IV) infusion if subcutaneous infusion is not tolerated. ( 2.1 , 2.6 )

2.1 General Treprostinil injection can be administered with or without further dilution with Sterile Diluent for treprostinil injection or similar approved high-pH glycine diluent (e.g., Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration.

See Table

1 below for storage and administration time limits for the different diluents.

Diluted

Treprostinil has been shown to be stable at ambient temperature when stored for up to14 days using high-pH glycine diluent at concentrations as low as 0.004 mg/mL (4,000 ng/mL).

Table

1: Selection of Diluent Diluent Storage Limits Administration Limits None See Section 16 16 weeks at 40°C Sterile Diluents for Treprostinil Injection, Flolan, or Epoprostenol 14 days at room temperature 48 hours at 40°C Sterile Water for Injection0.9% Sodium Chloride for Injection 4 hours at room temperature or 24 hours refrigerated 48 hours at 40°C

2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy Treprostinil injection is indicated for subcutaneous (SC) or intravenous (IV) use only as a continuous infusion. Treprostinil injection is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated because of severe site pain or reaction. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min.

2.3 Initial Dose for Patients Transitioning to an Implantable Intravenous Infusion Pump The initial dose of treprostinil injection should be the same as the current dose the patient is receiving using the external infusion pump at the time of transition.

2.4 Dosage Adjustments The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacologic effects of treprostinil injection (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction). The infusion rate should be increased in increments of 1.25 ng/kg/min per week for the first four weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. Dosage adjustments may be undertaken more often if tolerated. Avoid abrupt cessation of infusion <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . Restarting a treprostinil injection infusion within a few hours after an interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of treprostinil injection to be re-titrated.

2.5 Patients with Hepatic Insufficiency In patients with mild or moderate hepatic insufficiency, decrease the initial dose of treprostinil injection to 0.625 ng/kg/min ideal body weight. Treprostinil injection has not been studied in patients with severe hepatic insufficiency <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ]</span> .

2.6 Administration Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, do not use.

Preparation

Treprostinil injection is administered by subcutaneous or intravenous infusion at a calculated rate based on a patient's dose (ng/kg/min), weight (kg) and the treprostinil injection concentration (mg/mL). For administration of Undiluted Treprostinil Injection the rate is calculated using the following formula: Undiluted Infusion Rate (mL/hour) = Dose (ng/kg/min) × Weight (kg) ×

0.00006 Conversion factor of 0.00006 = 60 min/hour × 0.000001 mg/ng Treprostinil Injection Vial Strength (mg/mL) For administration of Diluted Treprostinil Injection the rate and concentration is calculated using the following formulas: Step 1 Diluted Treprostinil Injection Concentration (mg/mL) Dose (ng/kg/min) × Weight (kg) × 0.00006 = Infusion Rate (mL/hour) The volume of treprostinil injection needed to make the required diluted treprostinil concentration for the given reservoir size can then be calculated using the following formula: Step 2 Volume of Treprostinil Injection (mL) = Diluted Treprostinil Concentration (mg/mL) × Total Volume of Diluted Treprostinil olution in Reservoir (mL)

Treprostinil Injection Vial

Strength (mg/mL) The calculated volume of treprostinil injection is then added to the reservoir along with the sufficient volume of diluent to achieve the desired total volume in the reservoir.

Subcutaneous Infusion

Treprostinil injection is administered subcutaneously by continuous infusion, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. The infusion pump should: (1) be adjustable to approximately 0.002 mL/hour, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better, (4) be positive pressure-driven, and (5) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with treprostinil injection. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets.

Intravenous Infusion External Intravenous Infusion

Pump:Treprostinil injection is administered intravenously by continuous infusion via a surgically placed indwelling central venous catheter using an external infusion pump designed for intravenous drug delivery. If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be used for short term administration of treprostinil injection. Use of a peripheral intravenous infusion for more than a few hours increases the risk of thrombophlebitis. The infusion pump used to administer treprostinil injection should: (1) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (2) have delivery accuracy of ±6% or better, (3) be positive pressure driven, and (4) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with treprostinil injection. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets. Infusion sets with an in-line 0.22- or 0.2- micron pore size filter should be used.

Implantable Intravenous Infusion

Pump: Use an implantable intravenous infusion pump approved for use with treprostinil injection, such as the Implantable System for treprostinil injection (ISR). Refer to the pump manufacturer's manual for specific instructions regarding preparation, programing, implantation, and refilling.

2.7 Patients Requiring Transition from Epoprostenol Transition from epoprostenol to treprostinil injection is accomplished by initiating the infusion of treprostinil injection and increasing it, while simultaneously reducing the dose of intravenous epoprostenol. The transition to treprostinil injection should take place in a hospital with constant observation of response (e.g., walk distance and signs and symptoms of disease progression). Initiate treprostinil injection at a recommended dose of 10% of the current epoprostenol dose, and then escalate as the epoprostenol dose is decreased (see Table 2 for recommended dose titrations). Patients are individually titrated to a dose that allows transition from epoprostenol therapy to treprostinil injection while balancing prostacyclin-limiting adverse events. Treat increases in the patient&apos;s symptoms of PAH first with increases in the dose of treprostinil injection. Treat side effects normally associated with prostacyclin and prostacyclin analogs first by decreasing the dose of epoprostenol.

Table

2: Recommended Transition Dose Changes Step Epoprostenol Dose Treprostinil Injection Dose 1 Unchanged 10% Starting Epoprostenol Dose 2 80% Starting Epoprostenol Dose 30% Starting Epoprostenol Dose 3 60% Starting Epoprostenol Dose 50% Starting Epoprostenol Dose 4 40% Starting Epoprostenol Dose 70% Starting Epoprostenol Dose 5 20% Starting Epoprostenol Dose 90% Starting Epoprostenol Dose 6 5% Starting Epoprostenol Dose 110% Starting Epoprostenol Dose 7 0 110% Starting Epoprostenol Dose + additional 5-10% increments as needed

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.

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

AND PRECAUTIONS

• Never share a NOVOLOG FlexPen or a NOVOLOG FlexTouch, 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, 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 NOVOLOG, 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 NOVOLOG by subcutaneous injection if pump malfunction occurs ( 5.8 ).

5.1 Never Share a NOVOLOG FlexPen, NOVOLOG FlexTouch, PenFill Cartridge, or PenFill Cartridge Device between Patients NOVOLOG FlexPen, NOVOLOG FlexTouch, PenFill cartridge, and PenFill cartridge devices should never be shared between patients, even if the needle is changed. Patients using NOVOLOG 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 <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 , 6.3 )]</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, dosage adjustments of concomitant anti-diabetic products may be needed.

5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of all insulins, including NOVOLOG. 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) <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. As with all insulins, the glucose lowering effect time course of NOVOLOG 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 NOVOLOG 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 NOVOLOG. If hypersensitivity reactions occur, discontinue NOVOLOG; treat per standard of care and monitor until symptoms and signs resolve <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span>. NOVOLOG is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>.

5.6 Hypokalemia All insulins, including NOVOLOG, 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 NOVOLOG, 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 NOVOLOG 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 How Supplied/Storage and Handling ( 16.2 ) and Patient Counseling Information ( 17 )]</span> .

PRECAUTIONS Do not use for irrigation that may result in absorption into the blood. Caution should be observed when solute-free water is used for continuous irrigation or allowed to "dwell" inside body cavities because of possible absorption into the blood stream and the production of intravascular hemolysis and circulatory overload. Aseptic technique is essential with the use of sterile preparations for irrigation of body cavities, wounds and urethral catheters or for wetting dressings that come in contact with body tissues. When used as a "pour" irrigation, no part of the contents should be allowed to contact the surface below the outer protected thread area of the semi-rigid wide mouth container. The flexible container is designed for use with nonvented irrigation sets. When used for irrigation via appropriate irrigation equipment, the administration set should be attached promptly. Unused portions should be discarded and a fresh container of appropriate size used for the start up of each cycle or repeat procedure. For repeated irrigations of urethral catheters, a separate container should be used for each patient. Do not administer unless water is clear, seal is intact and container is undamaged. Discard unused portion. Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Sterile Water for Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing

Mothers: Caution should be exercised when Sterile Water for Irrigation, USP is administered to a nursing woman. Pregnancy: Teratogenic Effects.

Pregnancy

Category C. Animal reproduction studies have not been conducted with Sterile Water for Irrigation, USP. It is also not known whether Sterile Water for Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Sterile

Water for Irrigation, USP should be given to a pregnant woman only if clearly needed.

Pediatric

Use: Safety and effectiveness in pediatric patients have not been established.

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.

Drug Facts NDC 0065-0530-01 Active Ingredient Purpose Purified Water 98.6% Eye Irrigation

Active Ingredients Purpose Purified Water 98.6% Eye Irrigation

Inactive Ingredients Benzalkonium Chloride 0.013% as preservative, Calcium Chloride Dihydrate, Magnesium Chloride Hexahydrate, Potassium Chloride, Sodium Acetate Trihydrate, Sodium Chloride, Sodium Citrate Dihydrate, Sodium Hydroxide and/or Hydrochloric Acid to adjust pH. The pH range of solution is in the physiologic range.

Inactive Ingredients Benzalkonium Chloride

0.013% as a preservative, Calcium Chloride Dihydrate, Magnesium Chloride Hexahydrate, Potassium Chloride, Sodium Acetate Trihydrate, Sodium Citrate Dihydrate, Sodium Chloride and Sodium Hydroxide and/or Hydrochloric Acid to adjust pH. The pH of the solution is in the physiological range.