Insulin Glargine Solostar

1 INDICATIONS AND USAGE Insulin glargine is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Insulin glargine is a long-acting human insulin analog indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use Not recommended for treating diabetic ketoacidosis. ( 1 ) Limitations of Use Insulin glargine is not recommended for the treatment of diabetic ketoacidosis.

2 DOSAGE AND ADMINISTRATION Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, and prior insulin use. ( 2.1 , 2.3 , 2.4 ) Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time of day, but at the same time every day. ( 2.1 ) Do not dilute or mix with any other insulin or solution. ( 2.1 ) Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.2 ) Closely monitor glucose when changing to Insulin glargine and during initial weeks thereafter. ( 2.4 ) 2.1 Important Administration Instructions Administer Insulin glargine subcutaneously once daily at any time of day but at the same time every day. Prior to initiation of Insulin glargine, train patients on proper use and injection technique. Patient should follow the Instructions for Use to correctly administer Insulin glargine. Administer Insulin glargine subcutaneously into the abdominal area, thigh, or deltoid, and 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) , Adverse Reactions (6) ] . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2) ] . Visually inspect Insulin glargine vials and SoloStar prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles. The Insulin glargine SoloStar prefilled pen dials in 1-unit increments. Use Insulin glargine SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. Refrigerate unused (unopened) Insulin glargine vials and SoloStar ® prefilled pens. Do not administer intravenously or via an insulin pump. Do not dilute or mix Insulin glargine with any other insulin or solution. The SoloStar prefilled pen is for single patient use only [see Warnings and Precautions (5.1) ] . 2.2 General Dosing Instructions Individualize and adjust the dosage of Insulin glargine based on the individual'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), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.2) ] . 2.3 Initiation of Insulin Glargine Therapy Type 1 Diabetes In patients with type 1 diabetes, Insulin glargine must be used concomitantly with short-acting insulin. The recommended starting dose of Insulin glargine in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements. Short-acting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements. Type 2 Diabetes The recommended starting dose of Insulin glargine in patients with type 2 diabetes who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily. One may need to adjust the amount and timing of short- or rapid-acting insulins and dosages of any oral antidiabetic drugs. 2.4 Changing to Insulin Glargine from Other Insulin Therapies If changing patients from once-daily TOUJEO (insulin glargine) 300 units/mL to once-daily Insulin glargine, the recommended initial Insulin glargine dose is 80% of the TOUJEO dose that is being discontinued. This dose reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3) ]. If changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Insulin glargine, a change in the dose of the basal insulin may be required and the amount and timing of the shorter-acting insulins and doses of any oral antidiabetic drugs may need to be adjusted. If changing patients from once-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dose is the same as the dose of NPH that is being discontinued. If changing patients from twice-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dosage is 80% of the total NPH dose that is being discontinued. This dosage reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3) ].

4 CONTRAINDICATIONS Insulin glargine is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions (5.3) ] in patients with hypersensitivity to Insulin glargine or one of its excipients [see Warnings and Precautions (5.5) ] During episodes of hypoglycemia ( 4 ) Hypersensitivity to Insulin glargine or one of its excipients ( 4 )

5 WARNINGS AND PRECAUTIONS Never share an Insulin glargine SoloStar prefilled pen 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, coadministered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. ( 5.3 , 6.1 ) Medication Errors : Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. ( 5.4 , 6.3 ) Hypersensitivity reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Insulin glargine. Monitor and treat if indicated. ( 5.5 , 6.1 ) 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 of TZD if heart failure occurs. ( 5.7 ) 5.1 Never Share an Insulin Glargine SoloStar Prefilled Pen, Syringe, or Needle Between Patients Insulin glargine SoloStar prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin glargine vials must never re-use or 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 unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6) ] . 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 oral and antidiabetic products may be needed. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulin, including Insulin glargine. Severe hypoglycemia can cause seizures, 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 insulin preparations, the glucose lowering effect time course of Insulin glargine 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 coadministered medication [see Drug Interactions (7) ] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6 , 8.7) ] . Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. The long-acting effect of Insulin glargine may delay recovery from hypoglycemia. 5.4 Medication Errors Accidental mix-ups among insulin products, particularly between long-acting insulins and rapid-acting insulins, have been reported. To avoid medication errors between Insulin glargine and other insulins, instruct patients to always check the insulin label before each injection [see Adverse Reactions (6.3) ] . 5.5 Hypersensitivity and Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Insulin glargine. If hypersensitivity reactions occur, discontinue Insulin glargine; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1) ] . Insulin glargine is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or one of the excipients [see Contraindications (4) ] . 5.6 Hypokalemia All insulin products, including Insulin glargine, 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 concentrations). 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 Insulin glargine, 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.

7 DRUG INTERACTIONS Table 8 includes clinically significant drug interactions with Insulin glargine. Table 8: Clinically Significant Drug Interactions with Insulin Glargine 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 analogs (e.g., octreotide), and sulfonamide antibiotics. Intervention : Dose reductions and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Glargine 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 increases and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Glargine Drugs : Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention : Dose adjustment and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs : Beta-blockers, clonidine, guanethidine, and reserpine. Intervention : Increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that affect glucose metabolism : Adjustment of insulin dosage may be needed; closely monitor blood glucose. ( 7 ) Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 7 )

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions (5.3) ] Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5) ] Hypokalemia [see Warnings and Precautions (5.6) ] Adverse reactions commonly associated with Insulin glargine include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 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 conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The data in Table 1 reflect the exposure of 2327 patients with type 1 diabetes to Insulin glargine or NPH. The type 1 diabetes population had the following characteristics: Mean age was 38.5 years. Fifty-four percent were male, 96.9% were Caucasian, 1.8% were Black or African American and 2.7% were Hispanic. The mean BMI was 25.1 kg/m 2 . The data in Table 2 reflect the exposure of 1563 patients with type 2 diabetes to Insulin glargine or NPH. The type 2 diabetes population had the following characteristics: Mean age was 59.3 years. Fifty-eight percent were male, 86.7% were Caucasian, 7.8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m 2 . The frequencies of adverse events during Insulin glargine clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. Table 1: Adverse Events in Pooled Clinical Trials up to 28 Weeks Duration in Adults with Type 1 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=1257) NPH, % (n=1070) Upper respiratory tract infection 22.4 23.1 Infection Body system not specified 9.4 10.3 Accidental injury 5.7 6.4 Headache 5.5 4.7 Table 2: Adverse Events in Pooled Clinical Trials up to 1 Year Duration in Adults with Type 2 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=849) NPH, % (n=714) Upper respiratory tract infection 11.4 13.3 Infection Body system not specified 10.4 11.6 Retinal vascular disorder 5.8 7.4 Table 3: Adverse Events in a 5-Year Trial of Adults with Type 2 Diabetes (adverse events with frequency ≥10%) Insulin glargine, % (n=514) NPH, % (n=503) Upper respiratory tract infection 29.0 33.6 Edema peripheral 20.0 22.7 Hypertension 19.6 18.9 Influenza 18.7 19.5 Sinusitis 18.5 17.9 Cataract 18.1 15.9 Bronchitis 15.2 14.1 Arthralgia 14.2 16.1 Pain in extremity 13.0 13.1 Back pain 12.8 12.3 Cough 12.1 7.4 Urinary tract infection 10.7 10.1 Diarrhea 10.7 10.3 Depression 10.5 9.7 Headache 10.3 9.3 Table 4: Adverse Events in a 28-Week Clinical Trial of Children and Adolescents with Type 1 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=174) NPH, % (n=175) Infection Body system not specified 13.8 17.7 Upper respiratory tract infection 13.8 16.0 Pharyngitis 7.5 8.6 Rhinitis 5.2 5.1 Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Insulin glargine [see Warnings and Precautions (5.3) ] . Tables 5, 6, and 7 summarize the incidence of severe hypoglycemia in the Insulin glargine individual clinical trials. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (≤56 mg/dL in the 5-year trial and ≤36 mg/dL in the ORIGIN trial) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration. Percentages of Insulin glargine–treated adult patients experiencing severe symptomatic hypoglycemia in the Insulin glargine clinical trials [see Clinical Studies (14) ] were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables 5 and 6 ). In the pediatric phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type 1 diabetes. Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study B Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study C Type 1 Diabetes Adults 16 weeks In combination with insulin lispro Study D Type 1 Diabetes Pediatrics 26 weeks In combination with regular insulin Insulin glargine N=292 NPH N=293 Insulin glargine N=264 NPH N=270 Insulin glargine N=310 NPH N=309 Insulin glargine N=174 NPH N=175 Percent of patients 10.6 15.0 8.7 10.4 6.5 5.2 23.0 28.6 Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes Study E Type 2 Diabetes Adults 52 weeks In combination with oral agents Study F Type 2 Diabetes Adults 28 weeks In combination with regular insulin Study G Type 2 Diabetes Adults 5 years In combination with regular insulin Insulin glargine N=289 NPH N=281 Insulin glargine N=259 NPH N=259 Insulin glargine N=513 NPH N=504 Percent of patients 1.7 1.1 0.4 2.3 7.8 11.9 Table 7 displays the proportion of patients experiencing severe symptomatic hypoglycemia in the Insulin glargine and Standard Care groups in the ORIGIN Trial [see Clinical Studies (14) ] . Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN Trial ORIGIN Trial Median duration of follow-up: 6.2 years Insulin glargine N=6231 Standard Care N=6273 Percent of patients 5.6 1.8 Peripheral Edema Some patients taking Insulin glargine have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy Administration of insulin subcutaneously, including Insulin glargine, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration (2.2) ] . Insulin Initiation and Intensification of Glucose Control 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. Weight Gain Weight gain has occurred with some insulin therapies including Insulin glargine and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Allergic Reactions Local allergy As with any insulin therapy, patients taking Insulin glargine may experience injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of treatment-emergent injection site pain in Insulin glargine–treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site did not result in discontinuation of therapy. Systemic allergy Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Insulin glargine and may be life threatening. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of Insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and Insulin glargine treatment groups with similar incidences. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Insulin glargine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors have been reported in which other insulins, particularly rapid-acting insulins, have been accidentally administered instead of Insulin glargine [see Patient Counseling Information (17) ] . To avoid medication errors between Insulin glargine and other insulins, patients should be instructed to always verify the insulin label before each injection. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

8.1 Pregnancy Risk Summary Published studies with use of insulin glargine during pregnancy have not reported a clear association with insulin glargine and adverse developmental outcomes [see Data ] . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ] . Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dose of 0.2 units/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin [see Data ] . The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with an HbA1c >7 and has been reported to be as high as 20% to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human data Published data do not report a clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups. Animal data Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day), on a mg/kg basis. In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dose of 0.2 units/kg/day on a mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.