Soliqua 100 / 33

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose can cause life-threatening hypoglycemia or hypokalemia (low levels of potassium in your blood).

Overdose symptoms include severe nausea and vomiting.

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.

Table 1: Units of Insulin Glargine and Micrograms of Lixisenatide in Each Dosage of Soliqua 100/33

Soliqua 100/33 (dose window display)*	Insulin glargine component dose	Lixisenatide component dose	Comment
* The dose window on the Soliqua 100/33 pen displays numbers for the even units and displays lines for the odd units.
2	---	---	Safety test dose – not for injection
15	15 units	5 mcg	Recommended starting dosage for patients previously treated with lixisenatide or less than 30 units of basal insulin
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 previously treated with 30 to 60 units of basal insulin
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
60	60 units	20 mcg	Maximum daily dosage [see Warnings and Precautions (5.5)]

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)].

Table 2: Recommended Titration of Soliqua 100/33 (Every Week)*

Self-Monitored Fasting Plasma Glucose	Soliqua 100/33 Dosage Adjustment
* The recommended Soliqua 100/33 dosage is between 15 to 60 units (see Table 1)
Above target range	+2 units (2 units of insulin glargine and 0.66 mcg of lixisenatide) to +4 units (4 units insulin glargine and 1.32 mcg 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 lixisenatide)

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.

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.

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 are 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 pre-gestational diabetes with an 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, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data

Human data

Insulin glargine

Published data do not report a clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups.

Animal data

Animal reproduction studies were not conducted with the combined products in Soliqua 100/33. The following data are based on studies conducted with the individual components of Soliqua 100/33.

Lixisenatide

In pregnant rats receiving twice daily subcutaneous doses of 2.5, 35, or 500 mcg/kg during organogenesis (gestation day 6 to 17), fetuses were present with visceral closure defects (e.g., microphthalmia, bilateral anophthalmia, diaphragmatic hernia) and stunted growth. Impaired ossification associated with skeletal malformations (e.g., bent limbs, scapula, clavicle, and pelvis) were observed at ≥2.5 mcg/kg/dose, resulting in systemic exposure that is 1-time the 20 mcg/day clinical dose, based on plasma AUC. Decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the adverse fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. Placental transfer of lixisenatide to developing rat fetuses is low with a concentration ratio in fetal/maternal plasma of 0.1%.

In pregnant rabbits receiving twice daily subcutaneous doses of 2.5, 25, 250 mcg/kg during organogenesis (gestation day 6 to 18), fetuses were present with multiple visceral and skeletal malformations, including closure defects, at ≥5 mcg/kg/day or systemic exposures that are 6-times the 20 mcg/day highest clinical dose, based on plasma AUC. Decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. Placental transfer of lixisenatide to developing rabbit fetuses is low with a concentration ratio in fetal/maternal plasma of ≤0.3%. In a second study in pregnant rabbits, no drug-related malformations were observed from twice daily subcutaneous doses of 0.15, 1.0, and 2.5 mcg/kg administered during organogenesis, resulting in systemic exposures up to 9-times the clinical exposure at 20 mcg/day, based on plasma AUC.

In pregnant rats given twice daily subcutaneous doses of 2, 20, or 200 mcg/kg from gestation day 6 through lactation, decreases in maternal body weight, food consumption, and motor activity were observed at all doses. Skeletal malformations and increased pup mortality were observed at 400 mcg/kg/day, which is approximately 200-times the 20 mcg/day clinical dose based on mcg/m2.

Insulin glargine

Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 2-times the recommended human subcutaneous high dose of 60 units/day (0.0364 mg/kg/day), based on mg/m2. In rabbits, doses up to 0.072 mg/kg/day, which is approximately 1-times 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.

Lactation

Risk Summary

There is no information regarding the presence of lixisenatide and insulin glargine in human milk, the effects on the breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. Lixisenatide is present in rat milk [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Soliqua 100/33 and any potential adverse effects on the breastfed child from Soliqua 100/33 or from the underlying maternal condition.

Data

Lixisenatide

A study in lactating rats showed low (9.4%) transfer of lixisenatide and its metabolites into milk and negligible (0.01%) levels of unchanged lixisenatide peptide in the gastric contents of weaning offspring.

Pediatric Use

Safety and effectiveness of Soliqua 100/33 have not been established in pediatric patients below 18 years of age.

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.

Renal Impairment

Frequent glucose monitoring and dose adjustment may be necessary for Soliqua 100/33 in patients with renal impairment [see Warnings and Precautions (5.7)].

Insulin Glargine

Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure.

Lixisenatide

In patients with mild and moderate renal impairment no dose adjustment is required but close monitoring for lixisenatide related adverse reactions and for changes in renal function is recommended because of higher incidences of hypoglycemia, nausea and vomiting that were observed in these patients. Increased gastrointestinal adverse reactions may lead to dehydration and acute renal failure and worsening of chronic failure in these patients.

Clinical experience in patients with severe renal impairment is limited as there were only 5 patients with severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) exposed to lixisenatide in all controlled studies. Lixisenatide exposure was higher in these patients [see Clinical Pharmacology (12.3)]. Patients with severe renal impairment exposed to lixisenatide should be closely monitored for occurrence of gastrointestinal adverse reactions and for changes in renal function.

There is no therapeutic experience in patients with end-stage renal disease (eGFR <15 mL/min/1.73 m2), and it is not recommended to use Soliqua 100/33 in this population.

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)].

Patients with Gastroparesis

Lixisenatide, one of the components of Soliqua 100/33, 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.

How supplied

Soliqua 100/33 is an injection supplied as a sterile, clear, colorless to almost colorless solution in a 3 mL prefilled, disposable, single-patient use pen injector:

Dosage Unit/Strength	Package size	NDC #
3 mL Soliqua 100/33 disposable prefilled pen 100 units/mL insulin glargine and 33 mcg/mL lixisenatide	Package of 5	0024-5761-05

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

Storage

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. Protect from light. Discard after the expiration date printed on the label.

Soliqua 100/33 should not be stored in the freezer and should not be allowed to freeze. Discard Soliqua 100/33 if it has been frozen.

After first use, store at room temperature below 86°F (30°C). Replace the pen cap after each use to protect from light.

Discard pen 14 days after first use.

Always remove the needle after each injection and store the Soliqua 100/33 pen without a needle attached. This prevents contamination and/or infection, or leakage of the Soliqua 100/33 pen, and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination.

Read these instructions carefully before using your Soliqua 100/33 pen.

Do not share your Soliqua 100/33 pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.

Soliqua 100/33 is an injectable prescription medicine that contains 2 diabetes medicines, insulin glargine and lixisenatide in a SoloStar pen. The drug combination in this pen is only for the daily injection of 15 to 60 units of Soliqua 100/33. Each unit dialed contains 1 unit insulin glargine and 0.33 mcg lixisenatide.

Important information

• Check the label on the Soliqua 100/33 pen each time you give your injection to make sure you are using the correct medicine.
• Do not use your pen if it is damaged or if you are not sure that it is working correctly.
• Perform a safety test before each injection (see "Step 3: Do a safety test").
• Always carry a spare pen and spare needles in case they are lost or stop working.
• Do not reuse needles. Always use a new sterile needle for each injection. This helps stop blocked needles, contamination and infection. If you reuse needles, you might not get your dose (underdosing) or get too much (overdosing).
• Do not use Soliqua 100/33 in an insulin pump or inject Soliqua 100/33 into your vein (intravenously) or muscle (intramuscularly).
• Do not mix Soliqua 100/33 in any other type of insulin or liquid medicine prior to injection.
• Change (rotate) your injection sites within the area you chose with each dose. Do not use the same spot for each injection, to avoid skin thickening or pits at the injection site (lipodystrophy).

Learn to inject

• Talk with your healthcare provider about how to use the Soliqua 100/33 pen and how to inject correctly before using your pen.
• Ask for help if you have problems handling the pen, for example if you have vision problems.
• Read all of these instructions before using your pen. You may get too much or too little medicine if you do not follow the instructions correctly.

Need help?

If you have any questions about your pen or about diabetes, ask your healthcare provider, go to www.soliqua100-33.com or call sanofi-aventis at 1-800-633-1610.

Supplies you will need:

• 1 Soliqua 100/33 pen
• 1 new sterile needle (see Step 2 "Attach a new needle")
• 1 alcohol swab
• a puncture-resistant container for used needles and pens (see "Throwing your pen away" at the end of this Instructions for Use)

Places to inject

Get to know your pen

Step 1: Check your pen

Take a new pen out of the refrigerator at least 1 hour before you inject. Cold medicine is more painful to inject.

1A Check the name and expiration date on the label of your pen.

• Make sure you have the correct medicine. This pen is colored light green with an orange injection button (see the "Get to know your pen" diagram).
• Do not use your pen after the expiration date on the pen label.

1B Pull off the pen cap. 1C Check that the medicine is clear and to almost colorless.

• If you see small particles, return it to your pharmacy for a replacement.

1D Wipe the rubber seal with an alcohol swab.

If you have other injector pens

• Making sure you have the correct medicine is especially important if you have other injector pens.

Step 2: Attach a new needle

• Do not reuse needles. Always use a new sterile needle for each injection. This helps stop blocked needles, contamination and infection.
• Only use needles that are meant to be used with Soliqua 100/33. Needles are supplied separately. If you do not know what needles to use, ask your healthcare provider or pharmacist.

2A Take a new needle and peel off the protective seal. 2B Keep the needle straight and screw it onto the pen until fixed. Do not over-tighten. 2C Pull off the outer needle cap. Keep this for later. 2D Pull off the inner needle cap and throw it away.

Handling needles

• Take care when handling needles to prevent needle-stick injury and cross-infection.

Step 3: Do a safety test

Perform a safety test before each injection to:

• Check your pen and the needle to make sure they are working properly.
• Make sure that you get the correct dose.

3A Select 2 units by turning the dose selector until the dose pointer is at the 2 mark. 3B Press the injection button all the way in.

• When the medicine comes out of the needle tip, your pen is working correctly.

If no liquid appears:

• You may need to repeat this step up to 3 times before seeing the medicine.
• If no medicine comes out after the third time, the needle may be blocked. If this happens:
  • change the needle (see Step 6 to remove the needle and Step 2 to attach a new needle),
  • then repeat the safety test (see Step 3A).
• Do not use your pen if still no medicine comes out of the needle tip. Use a new pen.
• Do not use a syringe to remove medicine from your pen.

If you see air bubbles

• You may see air bubbles in the medicine. This is normal, they will not harm you.

Step 4: Select the dose

• Do not select a dose or press the injection button without a needle attached. This may damage your pen.
• Only use this pen to inject your daily dose from 15 to 60 units. Do not change your dose unless your healthcare provider has told you to change your dose.
• Do not use this pen if you need a single daily dose that is more than 60 units.
• Do not use the pen if your single daily dose is less than 15 units, the black area in dose window as shown in the picture.

4A Make sure a needle is attached and the dose is set to '0'. 4B Turn the dose selector until the dose pointer lines up with your dose.

• Do not dial your dose by counting the clicks, because you might dial the wrong dose. Always check the number in the dose window to make sure you dialed the correct dose.
• If you turn past your dose, you can turn back down.
• If there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left.
• If you cannot select your full prescribed dose, use a new pen.

How to read the dose window

• Each line in the dose window equals 1 unit of Soliqua 100/33.
• Even numbers are shown in line with the dose pointer, as shown in picture.

30 units selected

• Odd numbers are shown as a line between even numbers, as shown in picture.

29 units selected

Units of medicine in your pen

• This pen contains 300 units of Soliqua 100/33 and it is intended to be used for more than one dose.

STEP 5: Inject your dose

If you find it hard to press the injection button in, do not force it as this may break your pen. See the section after Step 5E below for help.

5A Choose a place to inject as shown in the picture labeled "Places to inject." 5B Push the needle into your skin as shown by your healthcare provider.

• Do not touch the injection button yet.

5C Place your thumb on the injection button. Then press all the way in and hold.

• Do not press injection button at an angle. Your thumb could block the dose selector from turning.

5D Keep the injection button held in and when you see "0" in the dose window, slowly count to 10.

• This will make sure you get your full dose.

5E After holding and slowly counting to 10, release the injection button. Then remove the needle from your skin.

If you find it hard to press the injection button in:

• Change the needle (see Step 6 to remove the needle and Step 2 to attach a new needle) then do a safety test (see Step 3).
• If you still find it hard to press in, get a new pen.
• Do not use a syringe to remove medicine from your pen.

STEP 6: Remove the needle

• Take care when handling needles to prevent needle-stick injury and cross-infection.
• Do not put the inner needle cap back on.

6A Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap back. Then push firmly on.

• The needle can puncture the cap if it is recapped at an angle.

6B Grip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle.

• Try again if the needle does not come off the first time.

6C Throw away the used needle in a puncture-resistant container (see "Throwing your pen away" at the end of this Instructions for Use). 6D Put your pen cap back on.

• Do not put the pen back in the refrigerator.

Use by

• Only use your pen for up to 14 days after its first use.

How to store your pen

Before first use

• Keep new pens in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Do not freeze. If you accidently freeze your pen, throw it away.

After first use

• Keep your pen at room temperature, below 86°F (30°C).
• Do not put your pen back in the refrigerator.
• Do not store your pen with the needle attached.
• Store the pen with your pen cap on.

Keep this pen out of the sight and reach of children.

How to care for your pen

Handle your pen with care

• Do not drop your pen or knock it against hard surfaces.
• If you think that your pen may be damaged, do not try to fix it. Use a new one.

Protect your pen from dust and dirt

• You can clean the outside of your pen by wiping it with a damp cloth (water only). Do not soak, wash or lubricate the pen. This may damage it.

Throwing your pen away

• Put the used Soliqua 100/33 pen in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the Soliqua 100/33 pen in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
  • made of a heavy-duty plastic,
  • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
  • upright and stable during use,
  • leak-resistant, and
  • properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

sanofi-aventis U.S. LLC; Bridgewater, NJ 08807
A SANOFI COMPANY

©2017 sanofi-aventis U.S. LLC

SOLIQUA and SoloStar are trademarks of sanofi-aventis U.S. LLC.

Approved: August 2017