ADVERSE REACTIONS SECTION.

6 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)] 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 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 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 months duration, conducted in patients with type diabetes or type diabetes [see Clinical Studies (14)]. The data in Table reflect the exposure of 596 patients with type diabetes to insulin aspart in one clinical trial with 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 reflect the exposure of 91 patients with type diabetes to insulin aspart in one clinical trial with 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 diabetes mellitus and type diabetes mellitus (other than hypoglycemia) are listed in Table and Table 2, respectively.Table 1: Adverse reactions that occurred in >=5% of Type Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparatorInsulin aspart NPH (%) (n= 596)Regular Human Insulin NPH (%) (n= 286)Headache1210Injury accidental1110Nausea75Diarrhea53Table 2: Adverse reactions that occurred in >=5% of Type Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparatorInsulin aspart NPH (%) (n= 91)Human Regular Insulin NPH (%) (n= 91)Hyporeflexia117Onychomycosis105Sensory disturbance97Urinary tract infection87Chest pain53Headache53Skin disorder52Abdominal pain51Sinusitis51. Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin aspart products [see Warnings and Precautions (5.3)]. 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 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 diabetes mellitus who received subcutaneous insulin aspart was 10% at 24 weeks.. Adult and pediatric patients with type 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 diabetes mellitus who received subcutaneous insulin aspart was 10% at 24 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 IntensificationIntensification or rapid improvement in glucose control has been associated with 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.. LipodystrophyAdministration of insulin, including insulin aspart products subcutaneously, 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 GainWeight 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 6-month study with 6-month extension in adult subjects with type 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. 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 phase type diabetes clinical trial of insulin aspart, initial increase in titers of antibodies to insulin, followed by 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 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of insulin aspart products. Because these adverse reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish 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 sudden change to an unaffected injection site.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 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.. 12.2 Pharmacodynamics. Pharmacodynamics of Insulin Aspart After Subcutaneous AdministrationThe pharmacodynamic profile of insulin aspart given subcutaneously in 22 patients with type diabetes is shown in Figure 1. The maximum glucose-lowering effect of insulin aspart occurred between and hours after subcutaneous injection (0.15 units/kg). The duration of action for insulin aspart is to 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 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 1. Serial mean serum glucose collected up to hours following single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before meal in 22 patients with type diabetes. Figure 1. 12.3 Pharmacokinetics. Pharmacokinetics of subcutaneous administration of insulin aspart is presented below.. Absorption and BioavailabilityIn studies in healthy volunteers (total n=107) and patients with type 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 similar extent. In clinical trial in patients with type diabetes, insulin aspart and regular human insulin, both administered subcutaneously at dose of 0.15 units/kg body weight, reached mean maximum concentrations of 82 and 36 mU/L, respectively.. DistributionInsulin aspart has low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.Figure 2. Serial mean serum free insulin concentration collected up to hours following single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before meal in 22 patients with type diabetes. Figure 2. Metabolism and EliminationAfter 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 single dose study in 18 pediatric patients with type diabetes in 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 diabetes in both age groups between insulin aspart and regular human insulin were similar to those in healthy adult subjects and adults with type diabetes. Geriatric Patients: The pharmacokinetic and pharmacodynamic properties of insulin aspart and regular human insulin were investigated in single dose study in 18 subjects with type diabetes who were >=65 years of age. The relative differences in pharmacokinetics and pharmacodynamics in geriatric patients with type diabetes between insulin aspart and regular human insulin were similar to those in younger adults. Male and Female Patients: In healthy volunteers given 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 Cmax.. Obese Patients: single subcutaneous dose of 0.1 units/kg insulin aspart was administered in study of 23 patients with type diabetes and wide range of body mass index (BMI, 22-39 kg/m2). The pharmacokinetic parameters, AUC and Cmax, 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: single subcutaneous dose of 0.08 units/kg insulin aspart was administered in 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 Cmax of insulin aspart. Patients with Hepatic Impairment: 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 (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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Overview of Clinical Studies The safety and effectiveness of subcutaneous insulin aspart were compared to regular human insulin in 596 type diabetes adult, 187 pediatric type diabetes, and 91 adult type diabetes patients using NPH as basal insulin (see Tables 3, 4, 5). The reduction in glycated hemoglobin (HbA1c) was similar to regular human insulin. 14.2Clinical Studies in Adult and Pediatric Patients with Type Diabetes with Subcutaneous Injections Type Diabetes Adults (see Table 3)Two 24-week, open-label, active-controlled studies were conducted to compare the safety and efficacy of insulin aspart to regular human insulin injection in adult patients with type diabetes. Because the two study designs and results were similar, data are shown for only one study (see Table 3). The mean age of the trial population was 39 years and mean duration of diabetes was 15.7 years. Fifty-one percent were male. Ninety-four percent were Caucasian, 2% were Black and 4% were Other. The mean BMI was approximately 25.6 kg/m2.Insulin aspart was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbA1c were comparable for the two treatment regimens in this study (Table 3). Table 3. Type Diabetes Mellitus Adult (insulin aspart plus NPH insulin vs. regular human insulin plus NPH insulin)Insulin aspart NPH (n=596)Regular Human Insulin NPH (n=286)Baseline HbA1c (%)Values are Mean +- SD 7.9 +- 1.18.0 +- 1.2Change from Baseline HbA1c (%)-0.1 +- 0.80.0 +- 0.8Treatment Difference in HbA1c, Mean (95% confidence interval)-0.2 (-0.3, -0.1). Type Diabetes Pediatric (see Table 4) The efficacy of insulin aspart to improve glycemic control in pediatric patients with type diabetes mellitus is based on an adequate and well-controlled trial of regular human insulin in pediatric patients with type diabetes mellitus (Table 4). This 24-week, parallel-group study of pediatric patients with type diabetes (n=283), aged to 18 years, compared two subcutaneous multiple-dose treatment regimens: insulin aspart (n=187) or regular human insulin (n=96). NPH insulin was administered as the basal insulin. Similar effects on HbA1c were observed in both treatment groups (Table 4).Subcutaneous administration of insulin aspart and regular human insulin have also been compared in pediatric patients with type diabetes (n=26) aged to years with similar effects on HbA1c.Table 4. Pediatric Subcutaneous Administration of Insulin Aspart in Type Diabetes (24 weeks; n=283)Insulin aspart NPH (n=187)Regular Human Insulin NPH (n=96)Baseline HbA1c (%)Values are Mean +- SD 8.3 +- 1.28.3 +- 1.3Change from Baseline HbA1c (%)0.1 +- 1.00.1 +- 1.1Treatment Difference in HbA1c, Mean (95% confidence interval)-0.2 (-0.5, 0.1). 14.3Clinical Studies in Adults with Type Diabetes with Subcutaneous Injections Type Diabetes Adults (see Table 5)One six-month, open-label, active-controlled study was conducted to compare the safety and efficacy of insulin aspart to regular human insulin in patients with type diabetes (Table 5). The mean age of the trial population was 56.6 years and mean duration of diabetes was 12.7 years. Sixty-three percent were male. Seventy-six percent were Caucasian, 9% were Black and 15% were Other. The mean BMI was approximately 29.7 kg/m2.Insulin aspart was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbA1c were comparable for the two treatment regimens.Table 5. Subcutaneous Insulin Aspart Administration in Type Diabetes (6 months; n=176)Insulin aspart NPH (n=90)Regular Human Insulin NPH (n=86)Baseline HbA1c (%)Values are Mean +- SD 8.1 +- 1.27.8 +- 1.1Change from Baseline HbA1c (%)-0.3 +- 1.0-0.1 +- 0.8Treatment Difference in HbA1c, Mean (95% confidence interval)-0.1 (-0.4, 0.1).

CLINICAL TRIALS EXPERIENCE SECTION.

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 months duration, conducted in patients with type diabetes or type diabetes [see Clinical Studies (14)]. The data in Table reflect the exposure of 596 patients with type diabetes to insulin aspart in one clinical trial with 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 reflect the exposure of 91 patients with type diabetes to insulin aspart in one clinical trial with 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 diabetes mellitus and type diabetes mellitus (other than hypoglycemia) are listed in Table and Table 2, respectively.Table 1: Adverse reactions that occurred in >=5% of Type Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparatorInsulin aspart NPH (%) (n= 596)Regular Human Insulin NPH (%) (n= 286)Headache1210Injury accidental1110Nausea75Diarrhea53Table 2: Adverse reactions that occurred in >=5% of Type Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparatorInsulin aspart NPH (%) (n= 91)Human Regular Insulin NPH (%) (n= 91)Hyporeflexia117Onychomycosis105Sensory disturbance97Urinary tract infection87Chest pain53Headache53Skin disorder52Abdominal pain51Sinusitis51. Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin aspart products [see Warnings and Precautions (5.3)]. 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 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 diabetes mellitus who received subcutaneous insulin aspart was 10% at 24 weeks.. Adult and pediatric patients with type 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 diabetes mellitus who received subcutaneous insulin aspart was 10% at 24 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 IntensificationIntensification or rapid improvement in glucose control has been associated with 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.. LipodystrophyAdministration of insulin, including insulin aspart products subcutaneously, 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 GainWeight gain has occurred with insulins, including insulin aspart products, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

DOSAGE & ADMINISTRATION SECTION.

2 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 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.Individualize and adjust the dosage of MERILOG based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal (2.3).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 (2.3).. Subcutaneous injection (2.2):Inject subcutaneously within 5-10 minutes before 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.. Inject subcutaneously within 5-10 minutes before 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.. Individualize and adjust the dosage of MERILOG based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal (2.3).. 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 (2.3).. 2.1Important Preparation and Administration Instructions Always check insulin labels before administration [see Warnings and Precautions (5.4)]. Inspect MERILOG visually before use. It should appear clear and colorless. Do not use MERILOG if particulate matter or coloration is seen.Use MERILOG SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.. Always check insulin labels before administration [see Warnings and Precautions (5.4)]. Inspect MERILOG visually before use. It should appear clear and colorless. Do not use MERILOG if particulate matter or coloration is seen.. Use MERILOG SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.. 2.2Preparation and Administration Instructions for the Approved Routes of Administration. Subcutaneous Injection Inject MERILOG subcutaneously within 5-10 minutes before 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)]. The MERILOG SoloStar prefilled pen dials in 1-unit increments. Generally use MERILOG (administered by subcutaneous injection) in regimens with an intermediate- or long-acting insulin.. Inject MERILOG subcutaneously within 5-10 minutes before 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)]. The MERILOG SoloStar prefilled pen dials in 1-unit increments. Generally use MERILOG (administered by subcutaneous injection) in regimens with an intermediate- or long-acting insulin.. 2.3Dosage Recommendations Individualize the dosage of MERILOG based on the patients 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 MERILOG, different dosage of MERILOG may be needed [see Warnings and Precautions (5.2)]. During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].. Individualize the dosage of MERILOG based on the patients 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 MERILOG, different dosage of MERILOG may be needed [see Warnings and Precautions (5.2)]. During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].. 2.4Dosage Modifications for Drug Interactions Dosage modification may be needed when MERILOG is used concomitantly with certain drugs [see Drug Interactions (7)].. Dosage modification may be needed when MERILOG is used concomitantly with certain drugs [see Drug Interactions (7)].. 2.5Instructions for Mixing MERILOG with Other Insulins Do not mix MERILOG with any other insulin.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. The table below presents clinically significant drug interactions with MERILOG.Drugs That May Increase the Risk of HypoglycemiaDrugs: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 MERILOG is concomitantly administered with these drugs.Drugs That May Decrease the Blood Glucose Lowering Effect of MERILOGDrugs: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 MERILOG is concomitantly administered with these drugs.Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of MERILOGDrugs:Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.Intervention:Dose adjustment and increased frequency of glucose monitoring may be required when MERILOG is concomitantly administered with these drugs.Drugs That May Blunt Signs and Symptoms of HypoglycemiaDrugs:Beta-blockers, clonidine, guanethidine and reserpineIntervention:Increased frequency of glucose monitoring may be required when MERILOG 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).. 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).

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEMERILOG(TM) [mer-ih-lawg](insulin aspart-szjj)injection, for subcutaneous use 10 mL multiple-dose vial: 100 units/mL (U-100). This Instructions for Use contains information on how to inject MERILOG.Read this Instructions for Use before you start taking MERILOG and each time you get new MERILOG vial. 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.Do not share your MERILOG syringes with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.Supplies needed to give your injectiona MERILOG 10 mL viala U-100 insulin syringe and needle2 alcohol swabs1 sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.Preparing your MERILOG doseWash your hands with soap and water or with alcohol.Check the MERILOG label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.Check that the insulin is clear and colorless. Do not use the vial if the insulin looks cloudy, colored or contains particles.Do not use MERILOG after the expiration date stamped on the label or 28 days after you first use it.Always use syringe that is marked for U-100 insulin. If you use syringe other than U-100 insulin syringe, you may get the wrong dose of insulin.Always use new syringe or needle for each injection to help maintain sterility and prevent blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.Need helpIf you have any questions about your vial or about diabetes, ask your healthcare provider, or call sanofi-aventis at 1-800-633-1610.Step 1:If you are using new vial, remove the protective cap. Do not remove the stopper (see Figure A). (Figure A) Step 2:Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of MERILOG before use (see Figure B). (Figure B)Step 3:Draw air into the syringe equal to your insulin dose (see Figure C). Put the needle through the rubber top of the vial and push the plunger to inject the air into the vial (see Figure D). (Figure C) (Figure D)Step 4:Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly in one hand. Make sure the tip of the needle is in the insulin. With your free hand, pull the plunger to withdraw the correct dose into the syringe (see Figure E). (Figure E)Step 5:Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the top. Push the bubbles out with the plunger and draw insulin back in until you have the correct dose (see Figure F). (Figure F)Step 6:Remove the needle from the vial. Do not let the needle touch anything. You are now ready to inject.Giving your MERILOG injection with syringeInject your insulin exactly as your healthcare provider has shown you.MERILOG starts acting fast. You should eat meal within to 10 minutes after you take your dose of MERILOG.Step 7:Choose your injection site: MERILOG is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs (thighs) or upper arms (see Figure G).Do not use the exact same spot for each injection. Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting pits in the skin or thickened skin (lipodystrophy) and skin with lumps (localized cutaneous amyloidosis) at the injection sites.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. (Figure G) Wipe the skin with an alcohol swab to clean the injection site. Let the injection site dry before you inject your dose (see Figure H). (Figure H) Step 8:Pinch the skin.Insert the needle in the way your healthcare provider showed you.Release the skin.Slowly push in the plunger of the syringe all the way, making sure you have injected all the insulin.Leave the needle in the skin for about 10 seconds (see Figure I). (Figure I) Step 9:Pull the needle straight out of your skin.Gently press the injection site for several seconds. Do not rub the area.Do not recap the used needle. Recapping the needle can lead to needle-stick injury.Disposing of used needles and syringesPut your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.If you do not have FDA-cleared sharps container, you may use household container that is: made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak resistant, andproperly 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 container. 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 FDAs website at: http://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 store MERILOGUnopened (not in-use) MERILOG vialsStore unused MERILOG vials in the refrigerator between 36F to 46F (2C to 8C).Do not freeze MERILOG.Keep MERILOG away from direct heat and light.If vial has been frozen or overheated, throw it away.Unopened vials can be used until the expiration date on the carton and 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.After MERILOG vials have been opened (in-use)Store in-use (opened) MERILOG vials in refrigerator between 36F to 46F (2C to 8C) or at room temperature below 86F (30C) for up to 28 days.Do not freeze MERILOG.Do not expose MERILOG to excessive heat or light.If vial has been frozen, throw it away.The MERILOG vial you are using should be thrown away after 28 days, even if it still has insulin left in it.Manufactured by:sanofi-aventis U.S. LLCMorristown, NJ 07960A SANOFI COMPANYU.S. License No. 1752(C)2025 Sanofi. All rights reserved.All trademarks mentioned in this document are the property of the Sanofi group.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Approved: May 2025. MERILOG 10 mL vial. U-100 insulin syringe and needle. alcohol swabs. sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.. Wash your hands with soap and water or with alcohol.. Check the MERILOG label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.. Check that the insulin is clear and colorless. Do not use the vial if the insulin looks cloudy, colored or contains particles.. Do not use MERILOG after the expiration date stamped on the label or 28 days after you first use it.. Always use syringe that is marked for U-100 insulin. If you use syringe other than U-100 insulin syringe, you may get the wrong dose of insulin.. Always use new syringe or needle for each injection to help maintain sterility and prevent blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.. Inject your insulin exactly as your healthcare provider has shown you.. MERILOG starts acting fast. You should eat meal within to 10 minutes after you take your dose of MERILOG.. Choose your injection site: MERILOG is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs (thighs) or upper arms (see Figure G).. Do not use the exact same spot for each injection. Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting pits in the skin or thickened skin (lipodystrophy) and skin with lumps (localized cutaneous amyloidosis) at the injection sites.. 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. (Figure G) Wipe the skin with an alcohol swab to clean the injection site. Let the injection site dry before you inject your dose (see Figure H). (Figure H) Pinch the skin.. Insert the needle in the way your healthcare provider showed you.. Release the skin.. Slowly push in the plunger of the syringe all the way, making sure you have injected all the insulin.. Leave the needle in the skin for about 10 seconds (see Figure I). (Figure I) Pull the needle straight out of your skin.. Gently press the injection site for several seconds. Do not rub the area.. Do not recap the used needle. Recapping the needle can lead to needle-stick injury.. Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.. If you do not have FDA-cleared sharps container, you may use household container that is: made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with 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 container. 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 FDAs website at: http://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.. Store unused MERILOG vials in the refrigerator between 36F to 46F (2C to 8C).. Do not freeze MERILOG.. Keep MERILOG away from direct heat and light.. If vial has been frozen or overheated, throw it away.. Unopened vials can be used until the expiration date on the carton and 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.. Store in-use (opened) MERILOG vials in refrigerator between 36F to 46F (2C to 8C) or at room temperature below 86F (30C) for up to 28 days.. Do not freeze MERILOG.. Do not expose MERILOG to excessive heat or light.. If vial has been frozen, throw it away.. The MERILOG vial you are using should be thrown away after 28 days, even if it still has insulin left in it.. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetics of subcutaneous administration of insulin aspart is presented below.. Absorption and BioavailabilityIn studies in healthy volunteers (total n=107) and patients with type 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 similar extent. In clinical trial in patients with type diabetes, insulin aspart and regular human insulin, both administered subcutaneously at dose of 0.15 units/kg body weight, reached mean maximum concentrations of 82 and 36 mU/L, respectively.. DistributionInsulin aspart has low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.Figure 2. Serial mean serum free insulin concentration collected up to hours following single 0.15 units/kg pre-meal dose of insulin aspart (solid curve) or regular human insulin (hatched curve) injected immediately before meal in 22 patients with type diabetes. Figure 2. Metabolism and EliminationAfter 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 single dose study in 18 pediatric patients with type diabetes in 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 diabetes in both age groups between insulin aspart and regular human insulin were similar to those in healthy adult subjects and adults with type diabetes. Geriatric Patients: The pharmacokinetic and pharmacodynamic properties of insulin aspart and regular human insulin were investigated in single dose study in 18 subjects with type diabetes who were >=65 years of age. The relative differences in pharmacokinetics and pharmacodynamics in geriatric patients with type diabetes between insulin aspart and regular human insulin were similar to those in younger adults. Male and Female Patients: In healthy volunteers given 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 Cmax.. Obese Patients: single subcutaneous dose of 0.1 units/kg insulin aspart was administered in study of 23 patients with type diabetes and wide range of body mass index (BMI, 22-39 kg/m2). The pharmacokinetic parameters, AUC and Cmax, 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: single subcutaneous dose of 0.08 units/kg insulin aspart was administered in 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 Cmax of insulin aspart. Patients with Hepatic Impairment: 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 (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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Available information from published randomized controlled trials with insulin aspart products use during the second trimester of pregnancy have not reported an association with insulin aspart products and major birth defects or adverse maternal or fetal outcomes [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8-times and equal to the human subcutaneous dose of unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin [see Data].In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with periconceptual HbA1c >7% and has been reported to be as high as 20 to 25% in women with periconceptual HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown.. 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 DataPublished data from randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart products during the late 2nd trimester of pregnancy did not identify an association of insulin aspart products with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including variable duration of treatment and small size of the majority of the trials. Animal DataFertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of unit/kg/day, based on human exposure equivalents) and in rabbits at dose of 10 units/kg/day (approximately three times the human subcutaneous dose of unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at dose of 50 units/kg/day and in rabbits at dose of units/kg/day. These doses are approximately times the human subcutaneous dose of unit/kg/day for rats and equal to the human subcutaneous dose of unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION MERILOG(TM) [mer-ih-lawg](insulin aspart-szjj) injection, for subcutaneous use100 units/mL (U-100)This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: May 2025Do not share your MERILOG SoloStar prefilled pen with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.What is MERILOGMERILOG is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.Who should not take MERILOG Do not take MERILOG if you: are having an episode of low blood sugar (hypoglycemia). have an allergy to insulin aspart products or any of the ingredients in MERILOG.Before taking MERILOG, tell your healthcare provider about all your medical conditions including, if you are:pregnant, planning to become pregnant, or are breastfeeding. taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.Before you start taking MERILOG, talk to your healthcare provider about low blood sugar and how to manage it.How should take MERILOGRead the Instructions for Use that come with your MERILOG. Take MERILOG exactly as your healthcare provider tells you to. MERILOG starts acting fast. You should eat meal within to 10 minutes after you take your dose of MERILOG. Know the type and strength of insulin you take. Do not change the type of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. Do not reuse or share your needles with other people. You may give other people serious infection or get serious infection from them. MERILOG can be injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs (thighs), or upper arms. Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting pits in skin or thickened skin (lipodystrophy) and skin with lumps (localized cutaneous amyloidosis) at the injection sites. Do not use the exact same spot 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. What should avoid while taking MERILOG While taking MERILOG do not:Drive or operate heavy machinery, until you know how MERILOG affects you. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.What are the possible side effects of MERILOG MERILOG can cause serious side effects that can lead to death, including: Low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: dizziness or light-headedness sweatingconfusionfast heart beatblurred visionslurred speechshakinessanxiety, irritability, or mood changeshungerheadacheYour insulin dose may need to change because of:change in level of physical activity or exerciseweight gain or lossincreased stressillnesschange in dietOther common side effects of MERILOG may include:low potassium in your blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet.Get emergency medical help if you have:trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. These are not all the possible side effects of MERILOG. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of MERILOG.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about MERILOG that is written for health professionals. Do not use MERILOG for condition for which it was not prescribed. Do not give MERILOG to other people, even if they have the same symptoms that you have. It may harm them.What are the ingredients in MERILOG Active Ingredient: insulin aspart-szjj Inactive Ingredients: metacresol, phenol, polysorbate 20, sodium chloride, zinc chloride and Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. Manufactured by: sanofi-aventis U.S. LLC, Morristown, NJ 07960, SANOFI COMPANY. U.S. License No. 1752For more information, go to www.sanofi.com or call 1-800-633-1610. (C)2025 Sanofi. All rights reserved.All trademarks mentioned in this document are the property of the Sanofi group. MERILOG is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.. are having an episode of low blood sugar (hypoglycemia). have an allergy to insulin aspart products or any of the ingredients in MERILOG.. pregnant, planning to become pregnant, or are breastfeeding. taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.. Read the Instructions for Use that come with your MERILOG. Take MERILOG exactly as your healthcare provider tells you to. MERILOG starts acting fast. You should eat meal within to 10 minutes after you take your dose of MERILOG. Know the type and strength of insulin you take. Do not change the type of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. Do not reuse or share your needles with other people. You may give other people serious infection or get serious infection from them. MERILOG can be injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs (thighs), or upper arms. Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting pits in skin or thickened skin (lipodystrophy) and skin with lumps (localized cutaneous amyloidosis) at the injection sites. Do not use the exact same spot 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. Do not use the exact same spot 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.. Drive or operate heavy machinery, until you know how MERILOG affects you. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.. dizziness or light-headedness sweating. confusion. fast heart beat. blurred vision. slurred speech. shakiness. anxiety, irritability, or mood changes. hunger. headache. change in level of physical activity or exercise. weight gain or loss. increased stress. illness. change in diet. low potassium in your blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet.. trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary Available information from published randomized controlled trials with insulin aspart products use during the second trimester of pregnancy have not reported an association with insulin aspart products and major birth defects or adverse maternal or fetal outcomes [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8-times and equal to the human subcutaneous dose of unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin [see Data].In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with periconceptual HbA1c >7% and has been reported to be as high as 20 to 25% in women with periconceptual HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown.. 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 DataPublished data from randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart products during the late 2nd trimester of pregnancy did not identify an association of insulin aspart products with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including variable duration of treatment and small size of the majority of the trials. Animal DataFertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of unit/kg/day, based on human exposure equivalents) and in rabbits at dose of 10 units/kg/day (approximately three times the human subcutaneous dose of unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at dose of 50 units/kg/day and in rabbits at dose of units/kg/day. These doses are approximately times the human subcutaneous dose of unit/kg/day for rats and equal to the human subcutaneous dose of unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.. 8.2 Lactation. Risk SummaryThere are no data on the presence of insulin aspart products in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin, including insulin aspart, was present in human milk. However, there is insufficient information to determine the effects of insulin aspart products on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for MERILOG, and any potential adverse effects on the breastfed infant from MERILOG, or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of MERILOG to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of MERILOG for this indication is supported by evidence from an adequate and well-controlled study of insulin aspart in 283 pediatric patients with type diabetes mellitus aged to 18 years and from studies in adults with diabetes mellitus [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].. 8.5 Geriatric Use. Of the total number of patients (n=1,375) treated with insulin aspart in controlled clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type diabetes (18/1285) and the other half had type diabetes (18/90). The HbA1c response to insulin aspart, as compared to regular human insulin, did not differ by age.. 8.6 Renal Impairment. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent MERILOG dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent MERILOG dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Never share MERILOG SoloStar prefilled pen between patients, even if the needle is changed (5.1).Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients 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 MERILOG, 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).. Never share MERILOG SoloStar prefilled pen between patients, even if the needle is changed (5.1).. Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients 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 MERILOG, 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).. 5.1Never Share MERILOG SoloStar Prefilled Pen Between Patients MERILOG SoloStar prefilled pen should never be shared between patients, even if the needle is changed. Patients using MERILOG vials must never share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens.. 5.2Hyperglycemia 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 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 patients 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 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.. 5.3Hypoglycemia 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.. 5.4Hypoglycemia Due to Medication Errors Accidental mix-ups between insulin products have been reported. To avoid medication errors between MERILOG and other insulins, instruct patients to always check the insulin label before each injection.. 5.5Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including insulin aspart products. If hypersensitivity reactions occur, discontinue MERILOG; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. MERILOG is contraindicated in patients who have had hypersensitivity reactions to insulin aspart products or any of the excipients in MERILOG [see Contraindications (4)].. 5.6Hypokalemia. All insulins, including insulin aspart products, can cause 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).. 5.7Fluid 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 MERILOG, and 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.