Limitations of Use:

• SOLIQUA 100/33 has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)]. Consider other antidiabetic therapies in patients with a history of pancreatitis.
• SOLIQUA 100/33 is not recommended for use in combination with any other product containing a GLP-1 receptor agonist [see Warnings and Precautions (5.5)].
• SOLIQUA 100/33 is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
• SOLIQUA 100/33 has not been studied in patients with gastroparesis and is not recommended in patients with gastroparesis.
• SOLIQUA 100/33 has not been studied in combination with prandial insulin.

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.

2.3 Titration of SOLIQUA 100/33

• After starting with the recommended dosage of SOLIQUA 100/33, [see Dosage and Administration (2.2)], titrate the dosage upwards or downwards by two to four units (see Table 2) every week based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal until the desired fasting plasma glucose is achieved.
• To minimize the risk of hypoglycemia or hyperglycemia, additional titration may be needed with changes in physical activity, meal patterns (i.e., macronutrient content or timing of food intake), or renal or hepatic function; during acute illness; or when used with other medications [see Warnings and Precautions (5.4) and Drug Interactions (7)].

2.4 Missed Doses

Instruct patients who miss a dose of SOLIQUA 100/33 to resume the once-daily regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose.

2.5 Important Administration Instructions

• The SOLIQUA 100/33 prefilled pen is for single-patient-use only [see Warnings and Precautions (5.3)].
• Train patients on proper use and injection technique before initiating SOLIQUA 100/33.
• Always check the SOLIQUA 100/33 label before administration [see Warnings and Precautions (5.5)].
• Visually inspect for particulate matter and discoloration prior to administration. Only use SOLIQUA 100/33 if the solution is clear and colorless to almost colorless.
• Inject SOLIQUA 100/33 subcutaneously into the abdominal area, thigh, 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), Adverse Reactions (6)].
• During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.4)].
• Do not administer intravenously or via an insulin pump.
• Use SOLIQUA 100/33 with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
• The SOLIQUA 100/33 pen dials in 1-unit increments.
• Do not dilute or mix SOLIQUA 100/33 with any other insulin or solution.
• Do not split the dose of SOLIQUA 100/33.

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 Pancreatitis

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been reported postmarketing in patients treated with GLP-1 receptor agonists. 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.

After initiation of SOLIQUA 100/33, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue SOLIQUA 100/33 and initiate appropriate management. If pancreatitis is confirmed, restarting SOLIQUA 100/33 is not recommended. Consider antidiabetic therapies other than SOLIQUA 100/33 in patients with a history of pancreatitis.

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 glucagon-like peptide-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.

5.7 Acute Kidney Injury

Acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, has been reported post marketing in patients treated with SOLIQUA 100/33. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration.

Monitor renal function when initiating or escalating doses of SOLIQUA 100/33 in patients with renal impairment and in patients reporting severe gastrointestinal reactions. Advise patients of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. SOLIQUA 100/33 is not recommended in patients with end-stage renal disease [see Use in Specific Populations (8.6)].

5.8 Immunogenicity

Patients may develop antibodies to insulin and lixisenatide following treatment. A pooled analysis of studies of lixisenatide-treated patients showed that 70% were antibody positive at Week 24. In the subset of patients (2.4%) with the highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed. A higher incidence of allergic reactions and injection-site reactions occurred in antibody positive patients [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].

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

All insulin-containing products, including SOLIQUA 100/33, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

5.10 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists

Thiazoidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin-containing products, including SOLIQUA 100/33. Fluid retention may lead to or exacerbate heart failure. Patients treated with SOLIQUA 100/33 and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

5.11 Acute Gallbladder Disease

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. 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. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

5.12 Pulmonary Aspiration During General Anesthesia or Deep Sedation

SOLIQUA 100/33 delays gastric emptying [see Clinical Pharmacology (12.1)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations.

Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking SOLIQUA 100/33, including whether modifying preoperative fasting recommendations or temporarily discontinuing SOLIQUA 100/33 could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking SOLIQUA 100/33.

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/m2. 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 m2.

6.2 Immunogenicity

6.3 Postmarketing Experience

The following additional adverse reactions have been identified during post approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Renal: acute kidney injury

Skin: Localized cutaneous amyloidosis at the injection site has occurred with insulins. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy

Gastrointestinal: ileus

Nervous system: dysgeusia

Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.

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.

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

8.2 Lactation

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)].

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of SOLIQUA 100/33 has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for SOLIQUA 100/33 in patients with hepatic impairment [see Warnings and Precautions (5.6)].

8.8 Patients with Gastroparesis

Lixisenatide slows gastric emptying. Patients with preexisting gastroparesis were excluded from clinical trials of SOLIQUA 100/33. SOLIQUA 100/33 is not recommended in patients with severe gastroparesis.

Insulin Glargine

Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.6, 5.9)]. Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed.

More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately.

Lixisenatide

During clinical studies, doses up to 30 mcg of lixisenatide twice daily (3-times the daily recommended dose) were administered to type 2 diabetic patients in a 13-week study. An increased incidence of gastrointestinal disorders was observed.

In case of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms and the SOLIQUA 100/33 dose should be reduced to the prescribed dose.

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Overview of Clinical Studies

SOLIQUA 100/33 was evaluated in two randomized clinical studies in patients with type 2 diabetes mellitus. In each of the active-controlled trials, treatment with SOLIQUA 100/33 produced statistically significant improvements in HbA1c.

14.2 Clinical Study in Patients with Type 2 Diabetes Uncontrolled on OAD Treatment

A total of 1170 patients with type 2 diabetes were randomized in an open-label, 30-week, active-controlled study (Study A: NCT05058147) to evaluate the efficacy and safety of SOLIQUA 100/33 compared to the individual components, insulin glargine 100 units/mL and lixisenatide.

Patients with type 2 diabetes, treated with metformin alone or treated with metformin and a second OAD treatment that could be a sulfonylurea or a glinide or a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a dipeptidyl peptidase-4 (DPP-4) inhibitor, and who were not adequately controlled with this treatment (HbA1c range 7.5% to 10% for patients previously treated with metformin alone and 7% to 9% for patients previously treated with metformin and a second OAD treatment) entered a run-in period for 4 weeks. During this run-in period, metformin treatment was optimized and all other OADs were discontinued. At the end of the run-in period, patients who remained inadequately controlled (HbA1c between 7% and 10%) were randomized to either SOLIQUA 100/33 (n=469), insulin glargine 100 units/mL (n=467), or lixisenatide (n=234).

The type 2 diabetes population had the following characteristics: mean age was 58.4 years, 50.6% were male, 90.1% were Caucasian, 6.7% were Black or African American, and 19.1% were Hispanic. At screening, the mean duration of diabetes was approximately 9 years, the mean BMI was approximately 31.7 kg/m2, and mean eGFR was 84.8 mL/min/1.73 m2.

SOLIQUA 100/33 and insulin glargine were to be titrated weekly to target a fasting plasma glucose goal of <100 mg/dL. Patients could not increase their dose by more than 4 units per week and the prespecified maximum dose of insulin glargine was limited to 60 units. The targeted fasting plasma glucose goal was achieved in 35% of patients in both groups at 30 weeks.

At Week 30, SOLIQUA 100/33 provided statistically significant improvement in HbA1c (p-value <0.0001) compared to insulin glargine 100 units/mL and lixisenatide-treated patients (-1.6%, -1.3%, and -0.9%). In a prespecified analysis of this primary endpoint, the differences observed were consistent with regard to baseline OAD use (metformin alone or metformin plus second OAD).

The mean difference (95% CI) in HbA1c reduction between SOLIQUA 100/33 and insulin glargine was -0.3% (-0.4, -0.2) and -0.7% (-0.8, -0.6) compared to lixisenatide.

See Table 5 for the other endpoints in the study. The difference in the glucose lowering effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where insulin glargine dosage can be different than that used in the trial.

Figure 1: Mean HbA1c (%) Over Time – Randomized and Treated Population

S = Screening (Week 6), R = Run-in (Week 1), B = Baseline, MI = Multiple imputation.
INS/LIXI = fixed ratio combination, INS = Insulin Glargine, LIXI = Lixisenatide
Note: The plot included all scheduled measurements obtained during the study, including those obtained after IMP discontinuation or introduction of rescue medication.
30MI: Missing HbA1c values at Week 30 in each group were imputed using their baseline HbA1c values plus an error. The error is normally distributed with mean zero and a standard deviation set equal to the estimated pooled standard deviation.

14.3 Clinical Studies in Patients with Type 2 Diabetes Uncontrolled on Basal Insulin

A total of 736 patients with type 2 diabetes participated in a randomized, 30-week, active-controlled, open-label, 2-treatment arm, parallel-group, multicenter study (Study B: NCT02058160) to evaluate the efficacy and safety of SOLIQUA 100/33 compared to insulin glargine 100 units/mL.

Patients screened had type 2 diabetes were treated with basal insulin for at least 6 months, receiving a stable daily dose of between 15 and 40 units alone or combined with 1 or 2 OADs (metformin, sulfonylurea, glinide, SGLT-2 inhibitor or a DPP-4 inhibitor), had an HbA1c between 7.5% and 10% and a FPG less than or equal to 180 mg/dL or 200 mg/dL depending on their previous antidiabetic treatment.

This type 2 diabetes population had the following characteristics: Mean age was 60 years, 46.7% were male, 91.7% were Caucasian, 5.2% were Black or African American and 17.9% were Hispanic. At screening, the mean duration of diabetes was approximately 12 years, the mean BMI was approximately 31 kg/m2, mean eGFR was 80.6 mL/min/1.73 m2 and 86.1% of patients had an eGFR ≥60 mL/min.

After screening, eligible patients (n=1018) entered a 6-week run-in phase where patients remained on or were switched to insulin glargine 100 units/mL, if they were treated with another basal insulin, and had their insulin glargine dose titrated/stabilized while continuing metformin (if previously taken). The mean HbA1c decreased during run-in period from 8.5% to 8.1%. Any other OADs were discontinued.

At the end of the run-in period, patients with an HbA1c between 7% and 10%, FPG ≤140 mg/dL and insulin glargine daily dose of 20 to 50 units (mean of 35 units), were randomized to either SOLIQUA 100/33 (n=367) or insulin glargine 100 units/mL (n=369).

SOLIQUA 100/33 and insulin glargine were to be titrated weekly to target a fasting plasma glucose goal of <100 mg/dL. The mean dose of insulin glargine at baseline was 35 units. The maximum dose of insulin glargine allowed in the trial was 60 units (insulin dose cap) in both groups. The targeted fasting plasma glucose goal was achieved in 33% of patients in both groups at 30 weeks.

At Week 30, there was a reduction in HbA1c from baseline of -1.1% for SOLIQUA 100/33 and -0.6% for insulin glargine 100 units/mL. The mean difference (95% CI) in HbA1c reduction between SOLIQUA 100/33 and insulin glargine was -0.5 [-0.6, -0.4] and statistically significant. The trial was designed to show the contribution of the GLP-1 component to glycemic lowering and the insulin glargine dose and the dosing algorithm was selected to isolate the effect of the GLP-1 component. At the end of the trial, the doses of insulin glargine were equivalent between treatment groups. The mean final dose of SOLIQUA 100/33 and insulin glargine at week 30 was 46.7 units (for SOLIQUA 100/33: 46.7 units insulin glargine/15.6 mcg lixisenatide). The difference in effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where alternative insulin glargine dosage can be used. See Table 6 for the other endpoints in the study.

16.1 How Supplied

SOLIQUA 100/33 (insulin glargine and lixisenatide) injection is a clear, colorless to almost colorless solution in a 3 mL prefilled, disposable, single-patient-use pen:

Needles are not included. Only use needles that are compatible for use with SOLIQUA 100/33 prefilled pen.

16.2 Storage

Dispense in the original sealed carton with the enclosed Instructions for Use.

Prior to first use, SOLIQUA 100/33 pen should be stored in a refrigerator, 36°F–46°F (2°C–8°C). Do not freeze. Discard SOLIQUA 100/33 if it has been frozen. Protect from light.

After first use, store at room temperature up to 77°F (25°C). Replace the pen cap after each use to protect from light.

Discard pen 28 days after first use.

Remove the needle after each injection and store the SOLIQUA 100/33 pen without a needle attached.

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, including anaphylaxis, have been reported with SOLIQUA 100/33. If symptoms of hypersensitivity reactions occur, instruct patients to stop taking SOLIQUA 100/33 and seek medical advice promptly [see Warnings and Precautions (5.1)].

Risk of Pancreatitis

Inform patients that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting is the hallmark symptom of acute pancreatitis. Instruct patients to promptly discontinue SOLIQUA 100/33 and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].

Never Share a SOLIQUA 100/33 Pen

Advise patients that they must never share a SOLIQUA 100/33 prefilled pen with another person, even if the needle is changed because doing so carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.3)].

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin-containing products. Inform patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia [see Warnings and Precautions (5.6)]. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.

Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.4)].

Dehydration and Renal Failure

Advise patients treated with SOLIQUA 100/33 of the potential risk of dehydration due to gastrointestinal adverse reactions and to take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function, which in some cases may require dialysis [see Warnings and Precautions (5.7)].

Overdose due to Medication Errors

Inform patients that SOLIQUA 100/33 contains two drugs: insulin glargine and lixisenatide. Accidental mix-ups between insulin products have been reported. To avoid medication errors between SOLIQUA 100/33 and other insulin products, instruct patients to always check the label before each injection. Advise patients that the administration of more than 60 units of SOLIQUA 100/33 daily can result in overdose of the lixisenatide component. Instruct patients not to administer concurrently with other glucagon-like peptide-1 receptor agonists [see Warnings and Precautions (5.5)].

Acute Gallbladder Disease

Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.11)].

Pulmonary Aspiration During General Anesthesia or Deep Sedation

Inform patients that SOLIQUA 100/33 may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking SOLIQUA 100/33 [see Warnings and Precautions (5.12)].

Use in Pregnancy

Advise patients to inform their physicians if they are pregnant or intend to become pregnant [see Use in Specific Populations (8.1)].