Soliqua 100/33

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Inject subcutaneously once a day within the hour prior to the first meal of the day. ( 2.1 ) SOLIQUA 100/33 pen delivers 15 units to 60 units per injection. ( 2.1 , 2.2 ) Maximum daily dosage is 60 units (60 units of insulin glargine and 20 mcg of lixisenatide). ( 2.1 ) Discontinue basal insulin or GLP-1 receptor agonist prior to initiation. ( 2.2 ) In patients naive to basal insulin or to a GLP-1 receptor agonist, currently on less than 30 units of basal insulin, or on a GLP-1 receptor agonist, the recommended starting dosage is 15 units subcutaneously once daily. ( 2.2 ) In patients inadequately controlled on 30 to 60 units of basal insulin, the starting dosage is 30 units subcutaneously once daily. ( 2.2 ) See Full Prescribing Information for titration recommendations. ( 2.3 ) Inject subcutaneously in abdominal area, thigh, or upper arm and rotate injection sites within the same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.5 ) Do not administer intravenously, or via an infusion pump. ( 2.5 ) Do not dilute or mix with any other insulin products or solutions. ( 2.5 ) 2.1 Important Dosage Information SOLIQUA 100/33 is a combination of insulin glargine and lixisenatide. Administer SOLIQUA 100/33 subcutaneously once a day within the hour prior to the first meal of the day. The SOLIQUA 100/33 pen delivers doses from 15 to 60 units in a single injection. Table 1 presents the units of insulin glargine and the micrograms of lixisenatide in each dosage of SOLIQUA 100/33 [see Dosage and Administration (2.2) ] . The maximum dose of SOLIQUA 100/33 is 60 units daily (60 units insulin glargine and 20 mcg lixisenatide) [see Warnings and Precautions (5.5) ] . 2.2 Recommended Starting Dose In patients naive to basal insulin or to a GLP-1 receptor agonist, currently on a GLP-1 receptor agonist or currently on less than 30 units of basal insulin daily: Discontinue therapy with basal insulin or a GLP-1 receptor agonist prior to initiation of SOLIQUA 100/33. The recommended starting dosage of SOLIQUA 100/33 is 15 units (15 units insulin glargine and 5 mcg lixisenatide) given subcutaneously once daily. In patients currently on 30 to 60 units of basal insulin daily, with or without a GLP-1 receptor agonist: Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of SOLIQUA 100/33. The recommended starting dosage of SOLIQUA 100/33 is 30 units (30 units insulin glargine and 10 mcg lixisenatide) given subcutaneously once daily. Table 1: Units of Insulin Glargine and Micrograms of Lixisenatide in Each Dosage of SOLIQUA 100/33 SOLIQUA 100/33 (dose window display) The dose window on the SOLIQUA 100/33 pen displays numbers for the even units and displays lines for the odd units. Insulin glargine component dose Lixisenatide component dose Comment 2 --- --- Safety test dose – not for injection 15 15 units 5 mcg Recommended starting dosage for patients naive to basal insulin or GLP-1 receptor agonist, currently on GLP-1 receptor agonist, or currently on less than 30 units of basal insulin daily 16 16 units 5.3 mcg 17 17 units 5.7 mcg 18 18 units 6 mcg 19 19 units 6.3 mcg 20 20 units 6.7 mcg 21 21 units 7 mcg 22 22 units 7.3 mcg 23 23 units 7.7 mcg 24 24 units 8 mcg 25 25 units 8.3 mcg 26 26 units 8.7 mcg 27 27 units 9 mcg 28 28 units 9.3 mcg 29 29 units 9.7 mcg 30 30 units 10 mcg Recommended starting dosage for patients currently on 30 to 60 units of basal insulin daily, with or without a GLP-1 receptor agonist: 31 31 units 10.3 mcg 32 32 units 10.7 mcg 33 33 units 11 mcg 34 34 units 11.3 mcg 35 35 units 11.7 mcg 36 36 units 12 mcg 37 37 units 12.3 mcg 38 38 units 12.7 mcg 39 39 units 13 mcg 40 40 units 13.3 mcg 41 41 units 13.7 mcg 42 42 units 14 mcg 43 43 units 14.3 mcg 44 44 units 14.7 mcg 45 45 units 15 mcg 46 46 units 15.3 mcg 47 47 units 15.7 mcg 48 48 units 16 mcg 49 49 units 16.3 mcg 50 50 units 16.7 mcg 51 51 units 17 mcg 52 52…

5 WARNINGS AND PRECAUTIONS 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 …

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS 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) ] .

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 …

6 ADVERSE REACTIONS 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 m…