Insulin Glargine and Lixisenatide

SOLIQUA 100/33 is a combination of insulin glargine and lixisenatide and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. SOLIQUA 100/33 is a combination of insulin glargine, an insulin analog, and lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use ( 1 ) : Concomitant use in combination with any other product containing a GLP-1 receptor agonist is not recommended. Not recommended for the treatment of diabetic ketoacidosis. Has not been studied in combination with prandial insulin. Limitations of Use : SOLIQUA 100/33 contains lixisenatide. Coadministration with any other product containing lixisenatide or another glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended [see Warnings and Precautions (5.5) ] . SOLIQUA 100/33 is not recommended for the treatment of diabetic ketoacidosis. SOLIQUA 100/33 has not been studied in combination with prandial insulin.

SOLIQUA 100/33 is a clear, colorless to almost colorless solution available as: Injection: 100 units of insulin glargine and 33 mcg of lixisenatide per mL in a 3 mL prefilled, disposable, single-patient-use SoloStar ® pen. Injection: 100 units insulin glargine and 33 mcg lixisenatide per mL in a 3 mL single-patient-use pen. ( 3 )

SOLIQUA 100/33 is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions (5.6) ] . In patients with serious hypersensitivity to insulin glargine, lixisenatide, or any of the excipients in SOLIQUA 100/33. Hypersensitivity reactions including anaphylaxis have occurred with both lixisenatide and insulin glargine [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . During episodes of hypoglycemia. ( 4 ) Serious hypersensitivity to insulin glargine, lixisenatide, or any of the excipients in SOLIQUA 100/33 ( 4 )

Anaphylaxis and Serious Hypersensitivity Reactions : Severe, life-threatening, and generalized allergic reactions can occur. Instruct patients to discontinue use if a reaction occurs and promptly seek medical attention. ( 5.1 ) Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including SOLIQUA 100/33. Discontinue if pancreatitis is suspected. ( 5.2 ) Never share a SOLIQUA 100/33 prefilled pen between patients, even if the needle is changed. ( 5.3 ) 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. ( 5.4 ) Overdose Due to Medication Errors : SOLIQUA 100/33 contains two drugs. Instruct patients to always check the label before each injection since accidental mix-ups with insulin products can occur. Do not exceed the maximum dose or use with other GLP-1 receptor agonists. ( 5.5 ) 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. ( 5.6 ) Acute kidney injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. SOLIQUA 100/33 is not recommended in patients with end-stage renal disease. ( 5.7 ) Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. SOLIQUA 100/33 is not recommended in patients with severe gastroparesis ( 5.8 ). Immunogenicity : Patients may develop antibodies to insulin glargine and lixisenatide. If there is worsening glycemic control or failure to achieve targeted glycemic control, significant injection-site reactions or allergic reactions, alternative antidiabetic therapy should be considered. ( 5.9 ) Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. ( 5.10 ) Fluid Retention and Heart Failure with Use of PPAR-gamma agonists : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.11 ) Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.12 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures . ( 5.13 )

5.1 Anaphylaxis and Serious Hypersensitivity Reactions In clinical trials of lixisenatide there have been cases of anaphylaxis (frequency of 0.1% or 10 cases per 10,000 patient-years) and other serious hypersensitivity reactions including angioedema. Severe, life-threatening, generalized allergic reactions, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock can occur with insulins, including insulin glargine. There have been postmarketing reports of serious hypersensitivity reactions, including anaphylactic reactions and angioedema, in patients treated with SOLIQUA 100/33 [see Adverse Reactions (6.1) ] . Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with SOLIQUA 100/33. SOLIQUA 100/33 is contraindicated in patients with known serious hypersensitivity to lixisenatide or insulin glargine [see Contraindications (4) ] . If a hypersensitivity reaction occurs, the patient should discontinue SOLIQUA 100/33 and promptly seek medical attention.

5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists [see Adverse Reactions (6) ] . After initiation of SOLIQUA 100/33, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue SOLIQUA 100/33 and initiate appropriate management.

5.3 Never Share a SOLIQUA 100/33 Prefilled Pen Between Patients SOLIQUA 100/33 prefilled pens must never be shared between patients, even if the needle is changed. Sharing of the pen poses a risk for transmission of blood-borne pathogens.

5.4 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in 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 (5.6) ] 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. Adjustments in concomitant oral antidiabetic treatment may be needed. When converting from basal insulin therapy or a GLP-1 receptor agonist to SOLIQUA 100/33 follow dosing recommendations [see Dosage and Administration (2.2 , 2.3) ] .

5.5 Overdose Due to Medication Errors SOLIQUA 100/33 contains two drugs: insulin glargine and lixisenatide. Administration of more than 60 units of SOLIQUA 100/33 daily can result in overdose of the lixisenatide component. Do not exceed the 20-mcg maximum recommended dose of lixisenatide or use with other GLP-1 receptor agonists. Accidental mix-ups between insulin products have been reported. To avoid medication errors between SOLIQUA 100/33 and other insulins, instruct patients to always check the insulin label before each injection.

5.6 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulin-containing products, including SOLIQUA 100/33 [see Adverse Reactions (6.1) ] . 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). SOLIQUA 100/33 (an insulin-containing product), or any insulin, should not be used during episodes of hypoglycemia [see Contraindications (4) ] . 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 (7.1) ] , or in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia generally increases with intensity of glycemic control. 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. […]

The following adverse reactions are discussed elsewhere: Anaphylaxis and Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Acute Pancreatitis [see Warnings and Precautions (5.2) ] Hypoglycemia [see Warnings and Precautions (5.6) ] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.7) ] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.8) ] Hypokalemia [see Warnings and Precautions (5.10) ] Acute Gallbladder Disease [see Warnings and Precautions (5.12) ] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.13) ] The most common adverse reactions, reported in ≥5% of patients treated with SOLIQUA 100/33 include hypoglycemia, nausea, nasopharyngitis, diarrhea, upper respiratory tract infection, and headache. ( 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 safety of SOLIQUA 100/33 (n=834, with a mean treatment duration of 203 days) has been evaluated in two clinical studies (30 weeks duration) in type 2 diabetes patients. The studies, Study A and B [see Clinical Studies (14) ] , had the following characteristics: mean age was approximately 59 years; approximately 50% were male, 90% were Caucasian, 6% were Black or African American, and 18% were Hispanic. The mean duration of diabetes was 10.3 years, mean HbA1c at screening for Study A was 8.2 and Study B was 8.5. The mean BMI at baseline was 32 kg/m 2 . Baseline eGFR was ≥60 mL/min in 87.2% of the pooled study population and mean baseline eGFR was 83.0 mL/min/1.73 m 2 . Table 3: Adverse Reactions Occurring in ≥5% of SOLIQUA 100/33–Treated Patients with Type 2 Diabetes Mellitus from Two Pooled Clinical Trials SOLIQUA 100/33, % (n=834) Nausea

10.0 Nasopharyngitis

7.0 Diarrhea

7.0 Upper respiratory tract infection

5.5 Headache

5.4 Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, and insulin-containing products including SOLIQUA 100/33 [see Warnings and Precautions (5.6) ] . 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 SOLIQUA 100/33 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. In the SOLIQUA 100/33 program, severe hypoglycemia was defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions and documented symptomatic hypoglycemia was defined as an event with typical symptoms of hypoglycemia accompanied by a self-monitored plasma glucose value equal to or less than 70 mg/dL (see Table 4 ). No clinically important differences in risk of severe hypoglycemia between SOLIQUA 100/33 and comparators were observed in clinical trials. Table 4: Hypoglycemic Episodes in SOLIQUA 100/33-Treated Patients with T2DM SOLIQUA 100/33 Study A N=469 SOLIQUA 100/33 Study B N=365 Severe symptomatic hypoglycemia Defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. (%) 0

1.1 Hypoglycemia (self-monitored plasma glucose <54 mg/dL) (%) 8.1

17.8 Gastrointestinal Adverse Reactions Gastrointestinal adverse reactions are the most commonly observed adverse reaction in patients using lixisenatide. Gastrointestinal adverse reactions occur more frequently at the beginning of SOLIQUA 100/33 therapy. Gastrointestinal adverse reactions including nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesophageal reflux disease, abdominal distension, and decreased appetite have been reported in patients treated with SOLIQUA 100/33. In Study A, vomiting was 6.4% in the lixisenatide-treated patients versus 3.2% in the SOLIQUA 100/33–treated patients and 1.5% in the insulin glargine–treated patients; nausea was 24% in the lixisenatide-treated patients versus 9.6% in the SOLIQUA 100/33–treated patients, and 3.6% in the insulin glargine–treated patients. Lipodystrophy Administration of insulin subcutaneously, including SOLIQUA 100/33, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration (2.5) ] . Anaphylaxis and Hypersensitivity Lixisenatide In the lixisenatide development program anaphylaxis cases were adjudicated. Anaphylaxis was defined as a skin or mucosal lesion of acute onset associated with at least 1 other organ system involvement. Symptoms such as hypotension, laryngeal edema or severe bronchospasm could be present but were not required for the case definition. More cases adjudicated as meeting the definition for anaphylaxis occurred in lixisenatide-treated patients (incidence rate of 0.2% or 16 cases per 10,000 patient years) than placebo-treated patient (incidence rate of 0.1% or 7 cases per 10,000 patient years). Allergic reactions (such as anaphylactic reaction, angioedema, and urticaria) adjudicated as possibly related to the study medication were observed more frequently in lixisenatide-treated patients (0.4%) than placebo-treated patients (0.2%) [see Warnings and Precautions (5.1) ] . A higher incidence of allergic reactions occurred in anti-lixisenatide antibody positive patients [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.6) ]. Insulin glargine Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including SOLIQUA 100/33, and may be life-threatening. Pancreatitis In clinical trials of lixisenatide there were 21 cases of pancreatitis among lixisenatide-treated patients and 14 cases in comparator-treated patients (incidence rate of 21 vs 17 per 10,000 patient-years). Lixisenatide cases were reported as acute pancreatitis (n=3), pancreatitis (n=12), chronic pancreatitis (n=5), and edematous pancreatitis (n=1). Some patients had risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Acute Gallbladder Disease In a cardiovascular outcomes trial, cholelithiasis occurred in 0.4% of lixisenatide-treated patients versus 0.2% in placebo-treated patients and acute cholecystitis in 0.3% of lixisenatide-treated patients versus 0.2% in placebo-treated patients. Injection-Site Reactions As with any insulin or GLP-1 receptor agonist–containing product, patients taking SOLIQUA 100/33 may experience injection-site reactions, including injection-site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection-site mass. In the clinical program the proportion of injection-site reactions occurring in patients treated with SOLIQUA 100/33 was 1.7%. A higher incidence of injection site reactions occurred in anti-lixisenatide antibody positive patients [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.6) ]. 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. […]

Drugs that affect glucose metabolism : Adjustment of SOLIQUA 100/33 dosage may be needed; closely monitor blood glucose. ( 7.1 ) Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Hypoglycemia signs and symptoms may be reduced. ( 7.1 ) Effects of delayed gastric emptying on oral medications : Lixisenatide delays gastric emptying which may impact absorption of concomitantly administered oral medications. Oral contraceptives and other medications such as antibiotics and acetaminophen should be taken at least 1 hour prior to SOLIQUA 100/33 administration or 11 hours after. ( 7.2 )

7.1 Medications that Can Affect Glucose Metabolism A number of medications affect glucose metabolism and may require dose adjustment of SOLIQUA 100/33 and particularly close monitoring. 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 SOLIQUA 100/33 is coadministered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of SOLIQUA 100/33 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 SOLIQUA 100/33 is coadministered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of SOLIQUA 100/33 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 SOLIQUA 100/33 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 SOLIQUA 100/33 is coadministered with these drugs.

7.2 Effects of Delayed Gastric Emptying on Oral Medications Lixisenatide-containing products, including SOLIQUA 100/33, delay gastric emptying which may reduce the rate of absorption of orally administered medications. Use caution when coadministering oral medications that have a narrow therapeutic ratio or that require careful clinical monitoring. These medications should be adequately monitored when concomitantly administered with lixisenatide. If such medications are to be administered with food, patients should be advised to take them with a meal or snack when lixisenatide is not administered. Antibiotics, acetaminophen, or other medications that are particularly dependent on threshold concentrations for efficacy or for which a delay in effect is undesirable should be administered at least 1 hour before SOLIQUA 100/33 injection [see Clinical Pharmacology (12.3) ] . Oral contraceptives should be taken at least 1 hour before SOLIQUA 100/33 administration or 11 hours after [see Clinical Pharmacology (12.3) ] .

Pregnancy : SOLIQUA 100/33 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ( 8.1 )

8.1 Pregnancy Risk Summary Based on animal reproduction studies, there may be risks to the fetus from exposure to lixisenatide, a component of SOLIQUA 100/33, during pregnancy. SOLIQUA 100/33 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The limited available data with SOLIQUA 100/33 and lixisenatide in pregnant women is not sufficient to inform a drug-associated risk of major birth defects and miscarriage. Published studies with insulin glargine use during pregnancy have not reported a clear association with insulin glargine and major birth defect or miscarriage risk [see Data ] . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ] . Lixisenatide administered to pregnant rats and rabbits during organogenesis was associated with visceral closure and skeletal defects at systemic exposures that decreased maternal food intake and weight gain during gestation, and that are 1-time and 6-times higher than the 20 mcg/day highest clinical dose, respectively, based on plasma AUC [see Data ] . The estimated background risk of major birth defects is 6%–10% in women with pregestational diabetes with a HbA1c >7 and has been reported to be as high as 20%–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%–4% and 15%–20%, respectively. Clinical considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human data Insulin glargine 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 Animal reproduction studies were not conducted with the combined products in SOLIQUA 100/33. The following data are based on studies conducted with the individual components of SOLIQUA 100/33. Lixisenatide In pregnant rats receiving twice daily subcutaneous doses of 2.5, 35, or 500 mcg/kg during organogenesis (gestation day 6 to 17), fetuses were present with visceral closure defects (e.g., microphthalmia, bilateral anophthalmia, diaphragmatic hernia) and stunted growth. Impaired ossification associated with skeletal malformations (e.g., bent limbs, scapula, clavicle, and pelvis) were observed at ≥2.5 mcg/kg/dose, resulting in systemic exposure that is 1-time the 20 mcg/day clinical dose, based on plasma AUC. Decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the adverse fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. Placental transfer of lixisenatide to developing rat fetuses is low with a concentration ratio in fetal/maternal plasma of 0.1%. In pregnant rabbits receiving twice daily subcutaneous doses of 2.5, 25, 250 mcg/kg during organogenesis (gestation day 6 to 18), fetuses were present with multiple visceral and skeletal malformations, including closure defects, at ≥5 mcg/kg/day or systemic exposures that are 6-times the 20 mcg/day highest clinical dose, based on plasma AUC. Decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. Placental transfer of lixisenatide to developing rabbit fetuses is low with a concentration ratio in fetal/maternal plasma of ≤0.3%. In a second study in pregnant rabbits, no drug-related malformations were observed from twice daily subcutaneous doses of 0.15, 1.0, and 2.5 mcg/kg administered during organogenesis, resulting in systemic exposures up to 9-times the clinical exposure at 20 mcg/day, based on plasma AUC. In pregnant rats given twice daily subcutaneous doses of 2, 20, or 200 mcg/kg from gestation day 6 through lactation, decreases in maternal body weight, food consumption, and motor activity were observed at all doses. Skeletal malformations and increased pup mortality were observed at 400 mcg/kg/day, which is approximately 200-times the 20 mcg/day clinical dose based on mcg/m 2 . Insulin glargine 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 2-times the recommended human subcutaneous high dose of 60 units/day (0.0364 mg/kg/day), based on mg/m 2 . In rabbits, doses up to 0.072 mg/kg/day, which is approximately 1-time the maximum recommended human subcutaneous dose of 60 units/day (0.0364 mg/kg/day), based on mg/m 2 , 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.

8.2 Lactation Risk Summary There is no information regarding the presence of lixisenatide and insulin glargine in human milk, the effects on the breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. Lixisenatide is present in rat milk [see Data ] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SOLIQUA 100/33 and any potential adverse effects on the breastfed child from SOLIQUA 100/33 or from the underlying maternal condition. Data Lixisenatide A study in lactating rats showed low (9.4%) transfer of lixisenatide and its metabolites into milk and negligible (0.01%) levels of unchanged lixisenatide protein in the gastric contents of weaning offspring.

8.4 Pediatric Use Safety and effectiveness of SOLIQUA 100/33 have not been established in pediatric patients.

8.5 Geriatric Use Of the total number of subjects (n=834) in controlled clinical studies of patients with type 2 diabetes, who were treated with SOLIQUA 100/33, 25.2% (n=210) were ≥65 years of age and 4% (n=33) were ≥75 years of age. No overall differences in effectiveness and safety were observed in the subgroup analyses across the age groups. Nevertheless, caution should be exercised when SOLIQUA 100/33 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.

8.6 Renal Impairment Frequent glucose monitoring and dose adjustment may be necessary for SOLIQUA 100/33 in patients with renal impairment [see Warnings and Precautions (5.7) ] . Insulin Glargine Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. […]

SOLIQUA 100/33 SOLIQUA 100/33 is a combination of insulin glargine, a basal insulin analog, and lixisenatide, a GLP-1 receptor agonist. Insulin glargine The primary activity of insulin, including insulin glargine, is 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. Lixisenatide Lixisenatide is a GLP-1 receptor agonist that increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying.