2.1 Important Dosage Information

The following are important dosing information for SOLIQUA 100/33, a combination of insulin glargine and lixisenatide:

• Discontinue therapy with lixisenatide or basal insulin prior to initiation of SOLIQUA 100/33.
• In patients inadequately controlled on less than 30 units of basal insulin or on lixisenatide, the recommended starting dosage of SOLIQUA 100/33 is 15 units (15 units insulin glargine/5 mcg lixisenatide) given subcutaneously once daily.
• In patients inadequately controlled on 30 to 60 units of basal insulin, the recommended starting dosage of SOLIQUA 100/33 is 30 units (30 units insulin glargine/10 mcg lixisenatide) given subcutaneously once daily.
• Administer SOLIQUA 100/33 subcutaneously once a day within the hour prior to the first meal of the day.
• The maximum dosage of SOLIQUA 100/33 is 60 units (60 units insulin glargine/20 mcg lixisenatide) [see Warnings and Precautions (5.5)].
• The SOLIQUA 100/33 Pen delivers doses from 15 to 60 units in a single injection (see Table 1) [see Dosage and Administration (2.2)].
• Use alternative antidiabetic products if patients require a SOLIQUA 100/33 daily dosage:

  –

  below 15 units, or

  –

  over 60 units

Table 1 presents the units insulin glargine and the micrograms of lixisenatide in each dosage of SOLIQUA 100/33.

2.2 Titration of SOLIQUA 100/33

• After starting with the recommended dosage of SOLIQUA 100/33, based upon prior insulin dose or lixisenatide use [see Dosage and Administration 2.1], 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. The dosage of SOLIQUA 100/33 is between 15 to 60 units (see Table 1).
• 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)].

2.3 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.

2.4 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 [see Adverse Reactions (6.1)].
• Do not administer intravenously, intramuscularly, or via an insulin pump.
• 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, a component of SOLIQUA 100/33, 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 allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock can occur with insulins, including insulin glargine, a component of 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 lixisenatide. SOLIQUA 100/33 is contraindicated in patients with known 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, a component of SOLIQUA 100/33, 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 SOLIQUA 100/33 regimen may affect glycemic control and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously and only under close medical supervision, and the frequency of blood glucose monitoring should be increased. Adjustments in concomitant oral antidiabetic treatment may be needed. When converting from basal insulin therapy or lixisenatide to SOLIQUA 100/33 follow dosing recommendations [see Dosage and Administration (2.1, 2.2)].

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 (an insulin containing product) 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 postmarketing in patients treated with GLP-1 receptor agonists, such as lixisenatide, a component of 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, components of SOLIQUA 100/33, 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

Thiazolidinediones (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 insulin containing products, including 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 Macrovascular Outcomes

There have been no clinical studies establishing macrovascular risk reduction with SOLIQUA 100/33 or any other antidiabetic drug.