Soliqua
(Insulin Glargine And Lixisenatide)Dosage & Administration
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Soliqua Prescribing Information
| Warnings and Precautions, Severe Gastrointestinal Adverse Reactions (Use of GLP-1 receptor agonists, including SOLIQUA 100/33, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.)] . SOLIQUA 100/33 is not recommended in patients with severe gastroparesis. | 5/2025 |
| Warnings and Precautions, 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. | 11/2024 |
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.
- Inject subcutaneously once a day within the hour prior to the first meal of the day. ()
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)].
- SOLIQUA 100/33 pen delivers 15 units to 60 units per injection. (,
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 DoseIn 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 1515 units5 mcgRecommended 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 daily16 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 3030 units10 mcgRecommended 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 units 17.3 mcg 53 53 units 17.7 mcg 54 54 units 18 mcg 55 55 units 18.3 mcg 56 56 units 18.7 mcg 57 57 units 19 mcg 58 58 units 19.3 mcg 59 59 units 19.7 mcg 6060 units20 mcgMaximum daily dosage[see Warnings and Precautions (5.5)] - Maximum daily dosage is 60 units (60 units of insulin glargine and 20 mcg of lixisenatide). ()
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)].
- Discontinue basal insulin or GLP-1 receptor agonist prior to initiation. ()
2.2 Recommended Starting DoseIn 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 1515 units5 mcgRecommended 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 daily16 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 3030 units10 mcgRecommended 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 units 17.3 mcg 53 53 units 17.7 mcg 54 54 units 18 mcg 55 55 units 18.3 mcg 56 56 units 18.7 mcg 57 57 units 19 mcg 58 58 units 19.3 mcg 59 59 units 19.7 mcg 6060 units20 mcgMaximum daily dosage[see Warnings and Precautions (5.5)] - 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 Recommended Starting DoseIn 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 1515 units5 mcgRecommended 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 daily16 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 3030 units10 mcgRecommended 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 units 17.3 mcg 53 53 units 17.7 mcg 54 54 units 18 mcg 55 55 units 18.3 mcg 56 56 units 18.7 mcg 57 57 units 19 mcg 58 58 units 19.3 mcg 59 59 units 19.7 mcg 6060 units20 mcgMaximum daily dosage[see Warnings and Precautions (5.5)] - In patients inadequately controlled on 30 to 60 units of basal insulin, the starting dosage is 30 units subcutaneously once daily. ()
2.2 Recommended Starting DoseIn 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 1515 units5 mcgRecommended 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 daily16 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 3030 units10 mcgRecommended 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 units 17.3 mcg 53 53 units 17.7 mcg 54 54 units 18 mcg 55 55 units 18.3 mcg 56 56 units 18.7 mcg 57 57 units 19 mcg 58 58 units 19.3 mcg 59 59 units 19.7 mcg 6060 units20 mcgMaximum daily dosage[see Warnings and Precautions (5.5)] - See Full Prescribing Information for titration recommendations. ()
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 bytwo 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)].
Table 2: Recommended Titration of SOLIQUA 100/33 (Every Week)The recommended SOLIQUA 100/33 dosage is between 15 to 60 units (see Table 1). Self-Monitored Fasting Plasma Glucose SOLIQUA 100/33 Dosage Adjustment Above target range +2 units (2 units of insulin glargine and 0.66 mcg of lixisenatide) to +4 units (4 units of insulin glargine and 1.32 mcg of lixisenatide) Within target range 0 units Below target range -2 units (2 units of insulin glargine and 0.66 mcg of lixisenatide) to -4 units (4 units of insulin glargine and 1.32 mcg of lixisenatide) - After starting with the recommended dosage of SOLIQUA 100/33,
- 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 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)].
- Donotadminister 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.
- The SOLIQUA 100/33 prefilled pen is for single-patient-use only
- Do notadminister intravenously, or via an infusion pump. ()
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)].
- Donotadminister 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.
- The SOLIQUA 100/33 prefilled pen is for single-patient-use only
- Do not dilute or mix with any other insulin products or solutions. ()
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)].
- Donotadminister 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.
- The SOLIQUA 100/33 prefilled pen is for single-patient-use only
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.
- Pregnancy: SOLIQUA 100/33 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ()
8.1 PregnancyRisk SummaryBased 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 riskPoorly 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.
DataHuman data
Insulin glarginePublished 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.
LixisenatideIn 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/m2.
Insulin glargineSubcutaneous 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/m2. 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/m2, 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.
SOLIQUA 100/33 is contraindicated:
- During episodes of hypoglycemia [see.]
5.6 HypoglycemiaHypoglycemia 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 HypoglycemiaThe 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. As with all insulin-containing preparations, the glucose lowering effect time course of SOLIQUA 100/33 may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection-site blood supply and temperature
[see Clinical Pharmacology (12.2)].Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to coadministered medication
[see Drug Interactions (7.1)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia[see Use in Specific Populations (8.6, 8.7)].Risk Mitigation Strategies for HypoglycemiaPatients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
The long-acting effect of insulin glargine may delay recovery from hypoglycemia.
- 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.and
5.1 Anaphylaxis and Serious Hypersensitivity ReactionsIn 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.]6.1 Clinical Trials ExperienceBecause 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.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 HypoglycemiaHypoglycemia 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=469SOLIQUA 100/33
Study B
N=365Severe symptomatic hypoglycemiaDefined 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 ReactionsGastrointestinal 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.
LipodystrophyAdministration 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 HypersensitivityLixisenatide
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)].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.
PancreatitisIn 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 DiseaseIn 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 ReactionsAs 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%.
Insulin Initiation and Intensification of Glucose ControlIntensification 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.
Peripheral EdemaSome patients taking insulin glargine, a component of SOLIQUA 100/33 have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
Weight GainWeight gain can occur with insulin-containing products, including SOLIQUA 100/33, and has been attributed to the anabolic effects of insulin.