Adlyxin

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

General

Lixisenatide is available in the following dosage form(s) and strength(s):

• Injection: 50 mcg/mL in 3 mL in green prefilled pen (for 14 pre-set doses; 10 mcg per dose).1

• Injection: 100 mcg/mL in 3 mL in burgundy prefilled pen (for 14 pre-set doses; 20 mcg per dose).1

Dosage

It is essential that the manufacturer’s labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

• Initiate at 10 mcg once daily for 14 days. On day 15, increase dosage to 20 mcg once daily. 1

• Administer once daily within one hour before the first meal of the day. 1

• Inject subcutaneously in the abdomen, thigh or upper arm.1

Specific Drugs

It is essential that the manufacturer’s labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Lixisenatide delays gastric emptying which may impact absorption of concomitantly administered oral medications. Oral medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen, should be administered 1 hour before lixisenatide. 1

• Oral contraceptives should be taken at least 1 hour before lixisenatide administration or 11 hours after the dose of lixisenatide.1

Adlyxin is contraindicated in patients with known hypersensitivity to lixisenatide or to any component of Adlyxin. Hypersensitivity reactions including anaphylaxis have occurred with Adlyxin [see Warnings and Precautions (5.1) and Adverse reactions (6.1)].

Adlyxin contains lixisenatide, which acts as a GLP-1 receptor agonist. Lixisenatide is a peptide containing 44 amino acids, which is amidated at the C-terminal amino acid (position 44). The order of the amino acids is given in the figure below. Its molecular weight is 4858.5 and its molecular formula is C215H347N61O65S. Lixisenatide has the following chemical structure:

Adlyxin injection is a sterile, clear, colorless aqueous solution for subcutaneous administration. Adlyxin is supplied in two single-patient use prefilled pens. Each green prefilled pen contains 3 mL solution and each mL contains 50 mcg lixisenatide. Each burgundy prefilled pen contains 3 mL solution, and each mL contains 100 mcg lixisenatide. Inactive ingredients for both prefilled pens are glycerol 85% (54 mg), sodium acetate trihydrate (10.5 mg), methionine (9.0 mg), metacresol (8.1 mg), and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.

Adlyxin has been studied as monotherapy, in combination with oral antidiabetic medications, and in combination with basal insulin (with or without oral antidiabetic medications). The efficacy of Adlyxin was compared with placebo, exenatide, and insulin glulisine.

In patients with type 2 diabetes, Adlyxin produced reductions from baseline in HbA1c compared to placebo.

Monotherapy

In a 12-week double blind study, 241 patients with type 2 diabetes inadequately controlled on diet and exercise were randomized to Adlyxin 20 mcg once daily or placebo. The mean age of the study population was 53.9 years, and the mean duration of type 2 diabetes mellitus was 2.5 years. 51.0% were male. 72.6% were White, 2.5% were Black or African American. 22.0% were Hispanic. 3.7% had an eGFR <60 ml/min/1.73 m2 . The mean BMI was 32 kg/m2.

Compared with placebo, treatment with Adlyxin 20 mcg once daily resulted in statistically significant reductions in HbA1c from baseline at Week 12 (see Table 3). The adjusted mean change in weight from baseline did not differ significantly between Adlyxin (-1.9 kg) and placebo (-2.0 kg).

Table 3: Placebo-Controlled Study (12-week Treatment Period Results) - Intent-To-Treat (ITT) Population

	Placebo (N=122)	Adlyxin 20 mcg (N= 119)
ITT population = all randomized patients.
10% of patients in Adlyxin and 10% in the placebo had missing HbA1c data at Week 12 in the ITT population.
* Using multiple imputation with respect to jump to placebo for missing data at Week 12 in the Adlyxin group. † Patients with missing HbA1c value at Week 12 were considered non-responders.
HbA1c (%)
Baseline (mean)	8.07	8.07
LS mean change from baseline*	-0.18	-0.83
Difference from placebo (95% CI)		-0.65 (-0.903, -0.399) (p<0.0001)
Patients (%) achieving HbA1c <7.0%†	24	44
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline (mean)	160.39	162.77
LS mean change from baseline*	1.46	-15.84
Body weight (kg)
Baseline (mean)	86.08	86.50
LS mean change from baseline*	-2.03	-1.94

Add-on Combination Therapy to Metformin (Alone or in Combination with Sulfonylurea)

In a 24-week study, 323 patients with type 2 diabetes inadequately controlled on diet exercise and metformin were randomized to Adlyxin 20 mcg once daily or placebo. The mean age of the study population was 56.7 years, and the mean duration of type 2 diabetes mellitus was 5.9 years. 44.6% were male. 90.1% were White, 0.6% were Black or African American. 27.9% were Hispanic. 1.2% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 33 kg/m2. The mean dose of metformin was 1955 mg per day.

Compared with placebo, treatment with Adlyxin 20 mcg once daily resulted in statistically significant reductions in HbA1c from baseline at Week 24 (see Table 4).

Table 4: Placebo-Controlled Study in Patients with Type 2 Diabetes Mellitus in Combination with Metformin (24-week Results) - ITT Population

Background therapy	With metformin*
	Placebo (N= 162)	Adlyxin 20 mcg (N= 161)
ITT population = all randomized patients.
* 11% of patients in Adlyxin 20 mcg and 6% in the placebo had missing HbA1c data at Week 24 in the ITT population. † Using multiple imputation with respect to jump to placebo for missing data at Week 24 in the Adlyxin group. ‡ Patients with missing HbA1c value at Week 24 were considered non-responders.
HbA1c (%)
Baseline (mean)	8.03	7.99
LS mean change from baseline†	-0.26	-0.72
Difference from placebo (95% CI)		-0.46 (-0.640, -0.279) (p<0.0001)
Patients (%) achieving HbA1c <7.0%‡	22	44
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline (mean)	170.32	172.23
LS mean change from baseline†	-7.25	-16.88
Difference from placebo (95% CI)		-9.64 (-16.306, -2.970) (p=0.0046)
Body weight (kg)
Baseline (mean)	87.87	90.21
LS mean change from baseline†	-1.71	-2.70
Difference from placebo (95% CI)		-1.00 (-1.706, -0.286) (p=0.006)

In a 24-week study, 391 Asian patients with type 2 diabetes inadequately controlled on diet exercise and metformin with or without a sulfonylurea were randomized to Adlyxin 20 mcg once daily or placebo. The mean age of the study population was 54.8 years, and mean duration of type 2 diabetes mellitus was 6.6 years. 49.1% were male. All patients were Asian. 2.8% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 27 kg/m2. The mean dose of metformin was 1368 mg per day and 44.8% of patients were on a sulfonylurea.

Compared with placebo, treatment with Adlyxin 20 mcg once daily resulted in statistically significant reductions in HbA1c from baseline at Week 24 (see Table 5).

Table 5: Placebo-Controlled Study in Asian Patients with Type 2 Diabetes Mellitus in Combination with Metformin with or without Sulfonylurea (24-week Results) – ITT Population

Background therapy	With metformin +/- sulfonylurea*
	Placebo (N= 195)	Adlyxin 20 mcg (N= 196)
ITT population = all randomized patients.
* 7% of patients in Adlyxin and 6% in the placebo had missing HbA1c data at Week 24 in the ITT population. † Using multiple imputation with respect to jump to placebo for missing data at Week 24 in the Adlyxin group. ‡ Patients with missing HbA1c value at Week 24 were considered non-responders.
HbA1c (%)
Baseline (mean)	7.85	7.95
LS mean change from baseline†	-0.57	-0.84
Difference from placebo (95% CI)		-0.27 (-0.447, -0.090) (p=0.0032)
Patients (%) achieving HbA1c <7.0%‡	37	49
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline (mean)	157.47	159.26
LS mean change from baseline†	-7.05	-13.39
Body weight (kg)
Baseline (mean)	72.74	73.18
LS mean change from baseline†	-1.12	-1.36

In a 24-week open-label study, 634 patients with type 2 diabetes inadequately controlled on diet, exercise and metformin were randomized to Adlyxin 20 mcg once daily or exenatide 10 mcg twice daily. The mean age of the study population was 57.4 years, and mean duration of type 2 diabetes mellitus was 6.8 years. 53.3% were male. 92.7% were White, 2.8% were Black or African American. 26.8% were Hispanic. 1.7% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 34 kg/m2. The mean dose of metformin was 2039 mg per day.

Adlyxin 20 mcg once daily met the pre-specified non-inferiority margin of 0.4% versus exenatide 10 mg BID for the difference in HbA1c reduction from baseline (see Table 6). However in this study, Adlyxin provided less HbA1c reduction than exenatide 10 mg BID and the difference was statistically significant (p=0.0175).

Table 6: Active-Controlled Study in Patients with Type 2 Diabetes Mellitus in Combination with Metformin (24-week Treatment Period Results) - ITT population

	Adlyxin (N=318)	Exenatide BID (N=316)
ITT population = all randomized patients.
14% of patients in Adlyxin and 14% in exenatide had missing HbA1c data at Week 24 in the ITT population
* Using multiple imputation with respect to use the baseline value for missing data at Week 24 in each group. † Patients with missing HbA1c value at Week 24 were considered non-responders
HbA1c (%)
Baseline (mean)	7.95	7.97
LS Mean change from baseline*	-0.73	-0.90
LS mean difference vs Exenatide BID*	0.17
95% CI	(0.030 to 0.314) (p=0.0175)
Patients (%) achieving HbA1c <7.0%†	43.1	45.6
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline	174.24	173.88
LS Mean change from baselinea	-19.79	-24.19
Body weight (kg)
Baseline	94.01	96.09
LS Mean change from baselinea	-2.74	-3.72

Add-on Combination Therapy to a Sulfonylurea (Alone or in Combination with Metformin)

In a 24-week study, 859 patients with type 2 diabetes inadequately controlled with diet, exercise and a sulfonylurea with or without metformin were randomized to Adlyxin 20 mcg once daily or placebo. The mean age of the study population was 57.2 years, and mean duration of type 2 diabetes mellitus was 9.3 years. 50.5% were male. 52.2% were White, 3.0% were Black or African American. 2.7% were Hispanic. 4.7% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 30 kg/m2. The two most common sulfonylureas used were glimepiride and glibenclamide and the mean dose of these drugs at baseline were 5.1 mg and 12.9 mg respectively, and 84.4% of patients were on metformin.

Compared with placebo, treatment with Adlyxin 20 mcg once daily resulted in statistically significant reductions in HbA1c from baseline at Week 24 (see Table 7).

Table 7: Placebo-Controlled Study in Patients with Type 2 Diabetes Mellitus in Combination with a Sulfonylurea (24-week results) – ITT Population

Background therapy	With sulfonylurea +/- metformin*
	Placebo (N= 286)	Adlyxin 20 mcg (N= 573)
ITT population = all randomized patients.
* 13% of patients in Adlyxin and 13% in the placebo had missing HbA1c data at Week 24 in the ITT population. † Using multiple imputation with respect to jump to placebo for missing data at Week 24 in the Adlyxin group. ‡ Patients with missing HbA1c value at Week 24 were considered non-responders.
HbA1c (%)
Baseline (mean)	8.21	8.28
LS mean change from baseline†	-0.18	-0.77
Difference from placebo (95% CI)		-0.58 (-0.715, -0.453) (p<0.0001)
Patients (%) achieving HbA1c <7.0%‡	13	33
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline (mean)	167.47	174.24
LS mean change from baseline†	-10.36	-17.09
Difference from placebo (95% CI)		-6.73 (-11.946, -1.518) (p=0.0114)
Body weight (kg)
Baseline (mean)	84.34	82.34
LS mean change from baseline†	-0.83	-1.63
Difference from placebo (95% CI)		-0.80 (-1.244, -0.349) (p=0.0005)

Add-on Treatment to Pioglitazone (Alone or in Combination with Metformin)

In a 24-week study, 484 patients with type 2 diabetes with inadequately controlled with diet, exercise and pioglitazone with or without metformin were randomized to Adlyxin 20 mcg once daily or placebo. The mean age of the study population was 55.8 years, and mean duration of type 2 diabetes mellitus was 8.1 years. 52.5% were male. 83.7% were White, 4.8% were Black or African American. 26.4% were Hispanic. 4.1% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 34 kg/m2. The mean dose of pioglitazone was 33.6 mg per day and 81.0% of patients were on metformin.

Compared with placebo, treatment with Adlyxin 20 mcg once daily resulted in statistically significant reductions in HbA1c from baseline at Week 24 (see Table 8).

Table 8: Placebo-Controlled Study in Patients with Type 2 Diabetes Mellitus in Combination with Pioglitazone (24-week results) – ITT Population

Background therapy	Pioglitazone +/- metformin*
	Placebo (N= 161)	Adlyxin 20 mcg (N= 323)
ITT population = all randomized patients.
* 9% of patients in Adlyxin and 12% in the placebo had missing HbA1c data at Week 24 in the ITT population. † Using multiple imputation with respect to jump to placebo for missing data at Week 24 in the Adlyxin group. ‡ Patients with missing HbA1c value at Week 24 were considered non-responders.
HbA1c (%)
Baseline (mean)	8.06	8.08
LS mean change from baseline†	-0.43	-0.91
Difference from placebo (95% CI)		-0.48 (-0.647, -0.318) (p<.0001)
Patients (%) achieving HbA1c <7.0%‡	25	49
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline (mean)	164.49	164.16
LS mean change from baseline†	-14.12	-24.56
Difference from placebo (95% CI)		-10.45 (-16.580, -4.315) (p=0.0008)
Body weight (kg)
Baseline (mean)	96.74	92.93
LS mean change from baseline†	0.26	-0.11

Add-on to Basal Insulin (Alone or in Combination with Oral Antidiabetics)

In a 24-week study, 496 patients with type 2 diabetes inadequately controlled on diet, exercise and basal insulin with or without metformin were randomized to Adlyxin 20 mcg once daily or placebo. The mean age of the study population was 57.2 years, and mean duration of type 2 diabetes mellitus was 12.46 years. 46.0% were male. 77.6% were White, 4.0% were Black or African American. 27.0% were Hispanic. 3.2% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 32 kg/m2. At baseline, the mean basal insulin dose was 54.9 units and 79.2% of individuals were receiving metformin.

In another 24-week study, 311 Asian patients with type 2 diabetes inadequately controlled on diet, exercise and basal insulin with or without a sulfonylurea were randomized to Adlyxin 20 mcg once daily or to placebo. The mean age of the study population was 58.4 years, and mean duration of type 2 diabetes mellitus was 13.92 years. 47.9% were male. All patients were Asian. 15.8% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 25 kg/m2. At baseline, the mean basal insulin dose was 24.2 units and 70.4% of individuals were receiving a sulfonylurea.

Compared with placebo, treatment with Adlyxin 20 mcg once daily resulted in statistically significant reductions in HbA1c from baseline at Week 24 (see Table 9) in both studies.

Table 9: Placebo-Controlled Studies in Patients with Type 2 Diabetes Mellitus in Combination with a Basal Insulin (24-week Treatment Period Results) – ITT Population

Background therapy	With basal insulin +/-metformin*		With basal insulin +/- sulfonylurea†
	Placebo (N= 167)	Adlyxin 20 mcg (N= 329)	Placebo (N= 157)	Adlyxin 20 mcg (N= 154)
ITT population = all randomized patients.
* 16% of patients in Adlyxin and 13% in the placebo had missing HbA1c data at Week 24 with basal insulin +/- metformin in the ITT population. † Conducted in an Asian population. 8 % of patients in Adlyxin and 6% of patients in placebo had missing HbA1c data at Week 24 with basal insulin +/- sulfonylurea in the ITT population. ‡ Using multiple imputation with respect to jump to placebo for missing data at Week 24 in the Adlyxin group. § Patients with missing HbA1c value at Week 24 were considered non-responders.
HbA1c (%)
Baseline (mean)	8.37	8.42	8.52	8.54
LS mean change from baseline‡	-0.34	-0.71	0.07	-0.70
Difference from placebo (95% CI)		-0.36 (-0.557, -0.170) (p=0.0002)		-0.76 (-1.005, -0.516) (p<.0001)
Patients (%) achieving HbA1c <7.0%§	11	25	6	33
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline (mean)	144.94	146.44	139.69	138.25
LS mean change from baseline‡	-13.07	-13.02	2.02	-4.38
Body weight (kg)
Baseline (mean)	88.94	87.10	65.60	65.93
LS mean change from baseline‡	-0.36	-1.55	-0.03	-0.48

In a 24-week study, 446 patients with type 2 diabetes, inadequately controlled on diet exercise and on insulin glargine and metformin with or without thiazolidinediones, were randomized to Adlyxin 20 mcg once daily or placebo. The mean age of the study population was 56.2 years, and mean duration of type 2 diabetes mellitus was 9.1 years. 49.8% were male. 74.4% were White, 4.5% were Black or African American. 22.6% were Hispanic. 3.8% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 32 kg/m2. At baseline, the mean insulin glargine dose was 44.5 units, the mean metformin dose was 2049 mg and 12.1% of individuals were receiving thiazolidinedione.

Compared with placebo, treatment with Adlyxin 20 mcg once daily resulted in statistically significant reductions in HbA1c from baseline at Week 24 (see Table 10).

Table 10: Placebo-Controlled Study in Patients with Type 2 Diabetes Mellitus in Combination with Insulin Glargine (24-week Results) – ITT Population

Background therapy	With Insulin glargine and metformin +/- Thiazolidinediones*
	Placebo (N= 223)	Adlyxin 20 mcg (N= 223)
ITT population = all randomized patients.
* 9% of patients in Adlyxin and 5% in the placebo had missing HbA1c data at Week 24 in the ITT population. † Using multiple imputation with respect to jump to placebo for missing data at Week 24 in the Adlyxin group. ‡ Patients with missing HbA1c value at Week 24 were considered non-responders.
HbA1c (%)
Baseline (mean)	7.60	7.56
LS mean change from baseline†	-0.42	-0.70
Difference from placebo (95% CI)		-0.28 (-0.434, -0.123) (p=0.0005)
Patients (%) achieving HbA1c <7.0%‡	39	50
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline (mean)	120.67	117.99
LS mean change from baseline†	6.05	5.74
Body weight (kg)
Baseline (mean)	86.75	87.31
LS mean change from baseline†	1.09	0.31
Difference from placebo (95% CI)		-0.78 (-1.388, -0.168) (p=0.0125)

In a 26-week open-label study, 894 patients with type 2 diabetes inadequately controlled on diet, exercise and basal insulin combined with 1 to 3 oral antidiabetic agents were randomized to Adlyxin 20 mcg once daily or insulin glulisine once daily (QD) or insulin glulisine three times a day (TID) combined with insulin glargine with or without metformin. The mean age of the study population was 59.8 years, and mean duration of type 2 diabetes mellitus was 12.2 years. 45.3% were male. 92.6% were White, 4.0% were Black or African American. 21.1% were Hispanic. 5.6% had an eGFR <60 mL/min/1.73 m2. The mean BMI was 32 kg/m2. At baseline, the mean insulin glargine dose was 65.9 units and 87.4% of individuals were receiving metformin.

Adlyxin 20 mcg once daily met the pre-specified non-inferiority margin of 0.4% versus insulin glulisine QD and TID for the difference in HbA1c reduction from baseline. However in this study, Adlyxin provided less HbA1c reduction than insulin glulisine TID and the difference was statistically significant (p=0.0002).

Table 11: Active-Controlled Study in Patients with Type 2 Diabetes Mellitus in Combination with a Basal Insulin with or without Metformin (26-week Treatment Period Results) - ITT population

	Adlyxin (N=298)	Insulin Glulisine QD (N=298)	Insulin Glulisine TID (N=298)
ITT population = all randomized patients. Non-inferiority margin = 0.4%.
12% of patients in Adlyxin, 8% in glulisine QD and 5.0% in glulisine TID had missing HbA1c data at Week 26 in the ITT population.
* Using multiple imputation with respect to use the baseline value for missing data at Week 26 in each group. † Patients with missing HbA1c value at Week 26 were considered non-responders.
HbA1c (%)
Baseline	7.77	7.73	7.79
LS Mean change from baseline*	-0.57	-0.53	-0.80
LS mean difference vs insulin glulisine*		-0.04	0.23
95% CI		(-0.161 to 0.080)	(0.112 to 0.352) (p=0.0002)
Patients (%) achieving HbA1c <7.0%†	38.6	36.6	47.7
Fasting Plasma Glucose (FPG) (mg/dL)
Baseline	118.55	123.21	119.80
LS Mean change from baseline*	-3.39	-3.68	-1.42
Body weight (kg)
Baseline	90.06	88.45	90.08
LS Mean change from baseline*	-0.64	0.98	1.26
LS mean difference vs insulin glulisine*			-1.91
95% CI			(-3.103 to -0.713) (p=0.0018)

ELIXA Cardiovascular Outcome Study

The ELIXA study was a randomized, double-blind, placebo-controlled, multinational study that evaluated cardiovascular (CV) outcomes during treatment with Adlyxin in patients with type 2 diabetes mellitus after a recent Acute Coronary Syndrome event. The primary composite endpoint was the time to the first occurrence of a major adverse cardiovascular event or MACE+, defined as any of the following positively adjudicated events:Cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, or hospitalization for unstable angina. The study was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio comparing Adlyxin to placebo.

Overall, 6068 patients were randomized 1:1 to either placebo or Adlyxin 20 mcg (following a starting dose of 10 mcg during the first 2 weeks) and were included in the primary analyses. The demographics and baseline characteristics were well-balanced between treatments. The median age at study entry was 60 years. Approximately 69% of the patients were males and 75% were Caucasian. The majority of patients were either obese or overweight with a median BMI of 29.4 kg/m2. The mean duration of diabetes was 9.3 years. More than 75% of patients had impaired renal function and more than 20% had an estimated GFR less than 60 mL/min/ 1.73 m2. Use of CV medications at baseline was similar between treatments; platelet aggregation inhibitors (aspirin and/or clopidogrel) were used by 97.5% of patients, statins by 92.7%, ACE inhibitors and/or angiotensin II antagonists by 86.8%, and beta-blockers by 84.4%. Prior to study entry, 93.9% of patients used at least 1 glucose-lowering medication, including metformin (69.9%), sulfonylureas (37.3%) and insulin (47.6%). During the study, antidiabetic medications were adjusted by the investigators per the local standard of care.

Ninety six percent of the patients in both treatment groups completed the study in accordance with the protocol, and the vital status was known at the end of the study for 99.0% and 98.6% of the patients in the Adlyxin and placebo group, respectively. Median treatment duration was 22.4 months in the Adlyxin group and 23.3 months in the placebo group, and the median duration of study follow-up was 25.8 and 25.7 months; respectively.

The results of the primary composite cardiovascular endpoint are shown in Table 12. The hazard ratio (HR) for Adlyxin versus placebo was 1.02, with an associated 2-sided 95% confidence interval (CI) of 0.89 to 1.17. The upper bound of this confidence interval, 1.17, excluded a risk margin larger than 1.3.

Table 12: Analysis of the primary cardiovascular endpoint (time to the first occurrence of the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina) -- ITT population

	Placebo (N=3,034)	Adlyxin (N=3,034)	Hazard ratio (95% CI)
CI: confidence interval, CV: cardiovascular. Only positively adjudicated events by the Cardiovascular Events Adjudication Committee are included.
Primary composite CV event			1.02 (0.89, 1.17)
No. of patients with event (%)	399 (13.2%)	406 (13.4%)
Total Person Year	6328.2	6356.8
Incidence Rate	6.31	6.39
Component CV event
Cardiovascular death	93 (3.1%)	88 (2.9%)
Non-fatal myocardial infarction	247 (8.1%)	255 (8.4%)
Non-fatal stroke	49 (1.6%)	54 (1.8%)
Hospitalization for unstable angina	10 (0.3%)	9 (0.3%)

The Kaplan-Meier based cumulative event probability is presented in Figure1 for the time to first occurrence of the primary CV composite endpoint by treatment arm.

Figure 1: Kaplan-Meier cumulative curves of the primary CV endpoint (time to the first occurrence of the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina) - ITT population

How Supplied

Adlyxin injection is supplied in a disposable single-patient use pen containing a sterile, clear solution for subcutaneous administration. Each prefilled pen contains 3 mL solution. The green starter pen contains 50 mcg/mL of Adlyxin and delivers 14 doses of 10 mcg, and the burgundy maintenance pen contains 100 mcg/mL of Adlyxin and delivers 14 doses of 20 mcg.

The following packages are available:

• Starter Pack: For treatment initiation, Starter Pack of 1 prefilled green pen of Adlyxin 10 mcg and 1 prefilled burgundy pen of Adlyxin 20 mcg. NDC 0024-5745-02.
• Maintenance Pack: 2 prefilled burgundy pens for Adlyxin 20 mcg. NDC 0024-5747-02.

Storage and Handling

Prior to first use, Adlyxin should be stored in a refrigerator, 36°–46°F (2°C–8°C). Do not freeze. Keep the prefilled pen in the original package to protect it from light.

After first use, store below 86°F (30°C). Replace the pen cap after each use to protect from light. Discard pen 14 days after first use.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, including anaphylaxis, have been reported in clinical trials of Adlyxin and during postmarketing use of GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, inform patients that they must stop taking Adlyxin 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 Adlyxin and contact their physician if persistent severe abdominal pain occurs. [see Warnings and Precautions (5.2)]

Never Share Adlyxin Pen Between Patients

Advise patients that they should never share Adlyxin 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)]

Risk of Hypoglycemia

Inform patients that the risk of hypoglycemia increased when Adlyxin is used in combination with a sulfonylurea or basal insulin. [see Warnings and Precautions (5.4)]

Dehydration and Renal Failure

Advise patients treated with Adlyxin of the potential risk of dehydration due to gastrointestinal adverse reactions and 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 (5.5)]

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)]

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

©2016 sanofi-aventis U.S. LLC

MEDICATION GUIDE Adlyxin (ad-LIX-in) (lixisenatide) injection, for subcutaneous use
What is the most important information I should know about Adlyxin?
Do not share your Adlyxin 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.
Adlyxin can cause serious side effects including inflammation of the pancreas (pancreatitis), which may be severe and lead to death. Before using Adlyxin, tell your healthcare provider if you have had:
pancreatitis stones in your gallbladder (cholelithiasis)		a history of alcoholism
These medical problems may make you more likely to get pancreatitis. Stop taking Adlyxin and call your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe, and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.
What is Adlyxin?
Adlyxin is an injectable prescription medicine that may improve blood sugar (glucose) control in adults with type 2 diabetes, when used with diet and exercise. Adlyxin is not insulin. Adlyxin is not a substitute for insulin and is not for use in people with type 1 diabetes or people with diabetic ketoacidosis. Adlyxin has not been studied in people with a history of pancreatitis. Adlyxin has not been studied in people who use short-acting insulin. Adlyxin has not been studied in people who have a stomach problem that causes slow emptying of the stomach (gastroparesis). Adlyxin is not for people with slow emptying of the stomach. It is not known if Adlyxin is safe and effective in children.
Who should not use Adlyxin? Do not use Adlyxin if you: are allergic to lixisenatide or any of the other ingredients in Adlyxin. See the end of this Medication Guide for a complete list of ingredients in Adlyxin.
Symptoms of a severe allergic reaction with Adlyxin may include:
	swelling of your face, lips, tongue, or throat problems breathing or swallowing severe rash or itching	fainting or feeling dizzy very rapid heartbeat
Before using Adlyxin, tell your healthcare provider if you: have or have had pancreatitis, stones in your gallbladder, or a history of alcoholism. have or have had kidney problems. have severe problems with your stomach, such as delayed emptying of your stomach (gastroparesis) or problems with digesting food. are pregnant or plan to become pregnant. It is not known if Adlyxin will harm your unborn baby. Tell your healthcare provider if you are pregnant or plan to become pregnant while using Adlyxin. are breastfeeding or plan to breastfeed. It is not known if Adlyxin passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you use Adlyxin.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.
Especially tell your healthcare provider if you take: antibiotics or the pain reliever acetaminophen. Take these medicines at least 1 hour before using Adlyxin. If you must take these medicines, take them with a meal or a snack. You should not take these medicines at the same time that you take Adlyxin. birth control pills that are taken by mouth (oral contraceptives). Adlyxin may lower the amount of the medicine in your blood from your birth control pills and they may not work as well to prevent pregnancy. Take your birth control pill at least 1 hour before your injection of Adlyxin or at least 11 hours after your Adlyxin injection. other anti-diabetes medicines, especially sulfonylurea medicines or insulin.
Ask your healthcare provider if you are not sure if your medicine is listed above.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.
How should I use Adlyxin? Read the detailed Instructions for Use that comes with your Adlyxin for instruction on using the Adlyxin pen and injecting Adlyxin. Adlyxin comes as a disposable prefilled pen. Use Adlyxin exactly as your healthcare provider tells you to. Do not change your dose unless your healthcare provider has told you to change your dose. Your healthcare provider should teach you how to inject Adlyxin before you use it for the first time. If you have questions or do not understand the instructions, talk to your healthcare provider. Use Adlyxin 1 time each day within 60 minutes (1 hour) before the first meal of the day and at the same time each day. If you miss a dose of Adlyxin, take it within 1 hour before your next meal. Check the label on the pen each time you give your Adlyxin injection to make sure you are using the correct medication. You must activate each Adlyxin pen before you use it for the first time. Do not re-use or share your needles with other people. You may give other people a serious infection, or get a serious infection from them. Inject your dose of Adlyxin under the skin (subcutaneously) of your abdomen, thigh or upper arm. Do not inject into a vein. Change (rotate) your injection sites within the area you chose with each dose. Do not use the same spot for each injection. Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.
Your dose of Adlyxin and other diabetes medicines may need to change because of: change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.
What are the possible side effects of Adlyxin?
Adlyxin may cause serious side effects including: See "What is the most important information I should know about Adlyxin?" Severe allergic reactions. Severe allergic reactions can happen with Adlyxin. Stop taking Adlyxin and get medical help right away if you have any symptoms of a severe allergic reaction. See "Who should not use Adlyxin?" Low blood sugar (hypoglycemia). Your risk for getting low blood sugar is higher if you use Adlyxin with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. The dose of your sulfonylurea or insulin medicine may need to be lowered while you use Adlyxin. Signs and symptoms of low blood sugar include:
	headache drowsiness weakness hunger fast heartbeat	dizziness confusion irritability sweating feeling jittery
Talk with your healthcare provider about how to treat low blood sugar.
Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse.
The most common side effects of Adlyxin include:
	nausea vomiting headache	diarrhea feeling dizzy
These are not all the possible side effects of Adlyxin. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Adlyxin? Store your new, unused Adlyxin pen in the refrigerator at 36°F to 46°F (2°C to 8°C). After activation, store your Adlyxin pen at room temperature no higher than 86°F (30°C). Do not freeze Adlyxin pens and do not use Adlyxin if it has been frozen. Protect the pen from light. Replace the pen cap after each use to protect the container window from light. After activation, use the Adlyxin pen for up to 14 days. Throw away the used Adlyxin pen after 14 days, even if there is some medicine left in the pen. Do not use Adlyxin past the expiration date printed on the label of the carton and pen. Do not store the Adlyxin pen with the needle attached. If the needle is left on, this might lead to contamination and cause air bubbles which might affect your dose of medicine. See the Instructions for Use about the right way to throw away the Adlyxin pen. Keep your Adlyxin pen, pen needles, and all medicines out of the reach of children.
General information about the safe and effective use of Adlyxin.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Adlyxin for a condition for which it was not prescribed. Do not give Adlyxin to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about Adlyxin that is written for health professionals.
What are the ingredients in Adlyxin?
Active ingredient: lixisenatide
Inactive ingredients: glycerol 85%, sodium acetate trihydrate, methionine, metacresol, hydrochloric acid, sodium hydroxide solution and water for injection.
Manufactured by: sanofi-aventis U.S. LLC, Bridgewater, NJ 08807. A SANOFI COMPANY.
For more information, go to www. Adlyxin.com or call sanofi-aventis at 1-800-633-1610.
This Medication Guide has been approved by the U.S. Food and Drug Administration			Approved: Jul 2016

INSTRUCTIONS FOR USE
Adlyxin (ad-LIX-in)
(lixisenatide)
Injection, for subcutaneous use

Starter pack - Contains two pre-filled pens each with 14 doses.

One 10 microgram (mcg) pen, each dose contains 10 micrograms in 0.2 ml.

One 20 microgram (mcg) pen, each dose contains 20 micrograms in 0.2 ml.

Section 1 - Important Information

Read these instructions carefully before using your Adlyxin pens.

Keep this leaflet for future reference.

Do not share your Adlyxin 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.

Adlyxin pen Information

• Adlyxin comes as a pre-filled pen for injection.
• Inject 1 dose per day.
• There is no need to measure each dose.
• Talk with your healthcare provider about how to use the Adlyxin pen and to inject correctly before using it.
• If you cannot follow all the instructions completely on your own, or are not able to handle the pen (for example, if you have vision problems), only use it if you have help.

About Your Starter Pack

The Adlyxin Starter pack includes two different colored pens that contain different strengths of Adlyxin. Both pens are used in the same way.

• The green pen contains 14 pre-set doses; each dose contains 10 micrograms of Adlyxin.
• The burgundy pen contains 14 pre-set doses; each dose contains 20 micrograms of Adlyxin.

You must start your treatment with the green 10 microgram Adlyxin pen. You must first use all 14 doses from this pen. Then use the burgundy 20 microgram Adlyxin pen.

About Your Adlyxin Pens

Green 10 microgram (mcg) Adlyxin pen

The plunger will advance along the dose scale after each injection. In the example above, the dose number shows there are 13 injections left in the Adlyxin pen.

Burgundy 20 microgram (mcg) Adlyxin pen

• Always check the label to make sure you have the correct Adlyxin pen. Also check that it has not passed the expiration date printed on the Adlyxin pen. Do not use Adlyxin past the expiration date. Using the wrong medicine could be harmful to your health.
• Inject Adlyxin only by using this pen injector. Never use a syringe to withdraw Adlyxin from the pen.

About pen needles (supplied separately)

• Pen needles are not included with your pen.
• Always use a new needle for each injection to prevent contamination of Adlyxin or possible needle blockage.
• Only use needles that have been approved for use with Adlyxin. The Adlyxin pen may be used with certain pen needles from Becton Dickinson, Ypsomed and Owen Mumford that are 8 mm long or shorter. Ask your healthcare provider which needle gauge and length is best for you.
• Do not reuse or share needles with another person. .

Section 2 – Getting Started

Begin with the green 10 mcg Adlyxin pen.

• Do not activate the burgundy 20 microgram Adlyxin pen until you have finished the green pen.

First activate your new pen

• Before injecting the first dose of Adlyxin you must activate the new pen. This is a one-time process called 'activation'. Steps 1 to 5 below show you how to do this.
• Activation is done to make sure that the pen is working correctly and that the dose for your first injection is correct.
• Do not repeat the activation process or you will not receive 14 doses from your Adlyxin pen.

The pictures below show how the activation window on the injection button of your pen changes after activation.

Before activation (orange window)	After activation (white window)
The pen is not activated when the activation window is orange. The pen must be activated before injecting your first dose of Adlyxin.	The pen is activated and ready for injections when the activation window is white.

How to activate your new Adlyxin pen

Step 1. Pull off cap and check pen

Step 2. Screw needle on and remove needle caps

• Always use a new needle for activation.
• Remove the protective seal from the outer needle cap.
• Line up the needle with the pen. Push the outer needle cap containing the needle straight onto the pen, then screw the needle on until secure.

Pull off (do not unscrew) the outer needle cap.

• Pull off the inner needle cap and throw it away.
• Keep the outer needle cap to remove the needle later.

Take care not to injure yourself when the needle is exposed.

Step 3. Pull the injection button out

Pull the injection button out firmly until it stops.

The arrow will now be pointing towards the needle.

Step 4. Firmly press and hold the injection button to remove the liquid

• Do not inject into the body.
• Point the needle into a container (like a paper cup or tissue).
• Firmly press the injection button all the way in to discard the liquid. You may feel or hear a "click".
• Keep the injection button pressed in and slowly count to 2, which is equal to 2 seconds.
• If no liquid comes out of your pen, see the Questions and Answers section at the end of this Instructions for Use.
• Check that the activation window is white.

Step 5. The pen is now ready for use.

• Do not activate this pen again.

For your first injection, go directly to Section 3 – Step 3.

You do not need to replace the needle between activation and first injection if you inject yourself immediately after activation.

Section 3 - Daily use of pen

Inject only 1 dose each day.

Check to make sure the activation window is white before continuing in this section.

Step 1. Pull off cap and check pen

Step 2. Attach a new needle and remove needle caps

• Always use a new needle for each injection.
• Remove the protective seal from the outer needle cap.
• Line up the needle with the pen. Put the outer needle cap containing the needle straight on the pen, then screw the needle on until secure.

• Pull off (do not unscrew) the outer needle cap.
  • Pull off the inner needle cap and throw it away.
  • Keep the outer needle cap to remove the needle later.
• Take care not to injure yourself when the needle is exposed.

Step 3. Pull the injection button out

The arrow in the window will be pointing towards the injection button.

Pull the injection button out firmly until it stops.

The arrow will now be pointing towards the needle.

Step 4. Choosing Injection Sites

Injection sites

Adlyxin must be injected under the skin and can be injected in any of the areas shown above in blue. These areas include the thigh, abdomen or upper arm. Ask your healthcare provider about how to inject correctly.

Step 5. Press and hold the injection button to inject the dose

• Grasp a fold of skin and insert the needle (see the Injection sites section about where to inject).
• Press the injection button all the way in. You may feel or hear a "click".
• Keep the injection button pressed in, hold the pen in place and slowly count to 2, which is equal to 2 seconds, before you pull the needle out of the skin.

If you do not hold the injection button in or remove the injector too early you may not get the full dose.

Your dose has now been given. Pull out the needle from your skin

Step 6. Remove and throw away needle after each injection

• Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap.
• Then push firmly on.
• The needle can puncture the cap if it is recapped at an angle.

• 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.

• Replace the pen cap.

• Put the needle in a puncture resistant container (or as instructed by your healthcare provider).

Step 7. Repeat all steps in Section 3 for each injection.

Throw away a pen 14 days after activation, even if there is some medicine left.

Once the green pen is discarded continue to Section 4 to begin using the burgundy pen.

Section 4 – Moving to the burgundy pen

Completed use of the green 10 mcg pen

The green 10 mcg Adlyxin pen is empty when the black plunger has reached '0' on the dose scale and the injection button cannot be pulled out fully.

Once the green 10 mcg Adlyxin pen is empty you must continue your treatment the next day using the burgundy 20 mcg Adlyxin pen. This is used in exactly the same way.

Use of burgundy 20 microgram pen

Burgundy 20 mcg pen activation

The burgundy 20 mcg Adlyxin pen must also be activated before use. Follow all steps in Section 2.

Burgundy 20 mcg pen use

To inject a dose with the burgundy 20 mcg Adlyxin pen, follow all steps in Section 3. Repeat Section 3 for your daily injections until your pen is empty.

Table of activation and disposal

In the table write the date when you activated your pen and the date to throw it away 14 days later.

Pen	Date of activation	Date to throw away
10 microgram	___ / ___ / ___	___ / ___ / ___
20 microgram	___ / ___ / ___	___ / ___ / ___

Storage

General information

• Keep your Adlyxin pens in a safe place out of the reach and sight of children.
• Protect your Adlyxin pens from dust and dirt.
• Replace the pen cap after each use in order to protect the container window from light.
• Protect the Adlyxin pen from light.
• Do not use Adlyxin after the expiration date, which is stated on the label and on the carton. The expiration date refers to the last day of that month.

Before activation of the pen:

• Store your unused Adlyxin pens in the refrigerator, 36°F to 46°F (2°C to 8°C).
• Do not freeze Adlyxin pens and do not use Adlyxin if it has been frozen.
• Allow your pen to warm at room temperature before using.

After activation of the pen:

• Once activated, store your Adlyxin pen at room temperature no higher than 86°F (30°C).
• Do not store your Adlyxin pen with the needle attached. An attached needle might lead to contamination and may cause air bubbles which might affect your dose of medicine.
• Once your Adlyxin pen is activated it can be used for up to 14 days. Discard a used Adlyxin pen after 14 days. Do this even if there is some medicine left in the pen.

Throwing your pen away

• Replace the pen cap before disposing of your Adlyxin pen.
• Put the used Adlyxin pen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the Adlyxin pen in your household trash.
• If you do not have an 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
• Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Maintenance

• Handle your Adlyxin pen with care.
• You can clean the outside of your Adlyxin pen by wiping it with a damp cloth.
• Do not soak, wash or put liquid on (lubricate) your Adlyxin pen - this may damage it.
• If you think your Adlyxin pen may be damaged, do not use it. Get a new one. Do not try to repair the pen.

Questions and Answers

What do I do if I forget to activate the Adlyxin Pen or inject myself before activation?

If you have injected yourself before activating the pen, do not correct this by giving yourself a second injection. Contact your healthcare provider for advice on checking your blood sugar.

What do I do if there are air bubbles in the container?

Small air bubbles in the container are normal and they will not harm you. Your dose will be correct and you can keep following the instructions. Contact your healthcare provider if you need help.

What do I do if no liquid comes out during activation?

The needle may be blocked or not properly attached. Remove the needle from the pen, attach a new one and repeat Steps 4 and 5 of Section 2 only. If still no liquid comes out, your Adlyxin pen may be damaged. Do not use this Adlyxin Starter pack. Contact your healthcare provider for help.

What do I do if it is hard to press the injection button all the way in?

The needle may be blocked or not properly attached. Pull the needle out of your skin and remove the needle from the pen. Attach a new needle and repeat Steps 5 and 6 of Section 3 only. If it is still hard to press in the injection button, your Adlyxin pen may be damaged. Do not use this Adlyxin starter pack. Contact your healthcare provider for help.

If you have any questions about Adlyxin or about diabetes, ask your healthcare provider or call sanofi-aventis U.S. LLC at 1-800-633-1610.

Date of Revision: Jul/2016a

INSTRUCTIONS FOR USE
Adlyxin (ad-LIX-in)
(lixisenatide)
Injection, for subcutaneous use

One pre-filled pen contains 14 doses, each dose contains 20 micrograms (mcg) in 0.2 ml.

Section 1 – Important Information

Read these instructions carefully before using your Adlyxin pen.

Keep this leaflet for future reference

Do not share your Adlyxin 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.

Adlyxin pen Information

• Adlyxin comes as a pre-filled pen for injection.
• Inject 1 dose per day.
• There is no need to measure each dose.
• Talk with your healthcare provider about how to use the Adlyxin pen and to inject correctly before using it.
• If you cannot follow all the instructions completely on your own, or are not able to handle the pen (for example, if you have vision problems), only use it if you have help.

About Your Adlyxin Pen

The plunger will move along the dose scale after each injection. In the example above the dose number shows there are 13 injections left in the Adlyxin pen.

• Always check the label to ensure you have the correct Adlyxin pen. Also, check that it has not passed the expiration date printed on the Adlyxin pen. Do not use Adlyxin past the expiration date. Using the wrong medicine could be harmful to your health.
• Inject Adlyxin only by using this pen injector. Never use a syringe to withdraw Adlyxin from the pen.

About your pen needles (supplied separately)

• Pen needles are not included with your pen.
• Always use a new needle for each injection. This helps prevent contamination of Adlyxin or possible needle blockage.
• Only use needles that have been approved for use with Adlyxin. The Adlyxin pen may be used with certain pen needles from Becton Dickinson, Ypsomed and Owen Mumford that are 8 mm long or shorter. Ask your healthcare provider which needle gauge and length is best for you.
• Do not reuse or share needles with another person.

Section 2 – Getting Started

• Activate the pen on the same day as your first injection with your new pen.

First activate your new pen

• Before injecting the first dose of Adlyxin, you must activate the new pen. This is a one-time process called 'activation'. Steps 1 to 5 below show you how to do this.
• Activation is done to make sure that the pen is working correctly and that the dose for your first injection is correct.
• Do not repeat the activation process or you will not receive 14 doses from your Adlyxin pen.

The pictures below show how the injection button of your pen changes after activation.

Before activation (orange window)	After activation (white window)
The pen is not activated when the activation window is orange. The pen must be activated before injecting your first dose of Adlyxin.	The pen is activated and ready for injections when the activation window is white.

How to activate your new Adlyxin pen

Step 1. Pull off the pen cap and check the pen

Step 2. Screw needle on and remove needle caps

• Always use a new needle for activation.
• Remove the protective seal from the outer needle cap.
• Line up the needle with the pen. Push the outer needle cap containing the needle straight onto the pen, then screw the needle on until secure.

• Pull off (do not unscrew) the outer needle cap.
  • Pull off the inner needle cap and throw it away.
  • Keep the outer needle cap to remove the needle later.
• Take care not to injure yourself when the needle is exposed.

Step 3. Pull injection button out

The arrow in the window will be pointing towards the injection button.

Pull the injection button out firmly until it stops.

The arrow will now be pointing towards the needle.

Step 4. Firmly press and hold injection button to remove the liquid

• Do not inject into the body
• Point the needle into a container (like a paper cup or tissue).
• Firmly press the injection button all the way in to discard the liquid. You may feel or hear a "click".
• Keep the injection button pressed in and slowly count to 2, which is equal to 2 seconds.
• If no liquid comes out of your pen, see the Questions and Answers section at the end of this Instructions for Use.
• Check that the activation window is now white.

Step 5. The pen is now ready for use.

• Do not activate this pen again.

For your first injection, go directly to Section 3 - Step 3.

• You do not need to replace the needle between activation and first injection if you inject yourself immediately after activation.

Section 3 - Daily use of pen

Inject only 1 dose each day.

Check to make sure the activation window is white before continuing in this section.

Step 1. Pull off pen cap and check pen

Step 2. Attach a new needle and remove the needle caps

• Always use a new needle for each injection.
• Remove the protective seal from the outer needle cap.
• Line up the needle with the pen. Put the outer needle cap containing the needle straight on the pen, then screw the needle on until secure.

• Pull off (do not unscrew) the outer needle cap.
  • Pull off the inner needle cap and throw it away.
  • Keep the outer needle cap to remove the needle later.
• Take care not to injure yourself when the needle is exposed.

Step 3. Pull the injection button out

The arrow in the window will be pointing towards the injection button.

Pull the injection button out firmly until it stops.

The arrow will now be pointing towards the needle.

Step 4. Choosing Injection Sites

Injection sites

Adlyxin must be injected under the skin and can be injected in any of the areas shown above in blue. These areas include the thigh, abdomen or upper arm. Ask your healthcare provider about how to inject correctly.

Step 5. Press and hold the injection button to inject the dose

• Grasp a fold of skin and insert the needle (see the Injection sites section about where to inject).
• Press the injection button all the way in. You may feel or hear a "click".
• Keep the injection button pressed in, hold the pen in place and slowly count to 2, which is equal to 2 seconds, before you pull the needle out of the skin.

If you do not hold the injection button in or remove the injector too early you may not get the full dose.

Your dose has now been given. Pull the needle out of your skin.

Step 6. Remove and throw away needle after each injection

• Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap.
• Then push firmly on.
• The needle can puncture the cap if it is recapped at an angle.

• 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.

• Replace the pen cap.

• Put the needle in a puncture resistant container (or as instructed by your healthcare provider).

Step 7. Repeat all steps in Section 3 for your each injection.

Throw away a pen 14 days after activation, even if there is some medicine left.

Table of activation and disposal

In the table, write the date when you activated your pen and the date to discard it 14 days later.

Pen	Date of activation	Date to discard
1
2
3
4
5
6

Storage

General information

• Keep your Adlyxin pen in a safe place out of the reach and sight of children.
• Protect your Adlyxin pen from dust and dirt.
• Replace the pen cap after each use in order to protect the container window from light.
• Protect the Adlyxin pen from light.
• Do not use Adlyxin after the expiration date, which is stated on the label and on the carton. The expiration date refers to the last day of that month.

Before activation of the pen:

• Store your unused Adlyxin pens in the refrigerator, 36°F to 46°F (2°C to 8°C).
• Do not freeze Adlyxin pens and do not use Adlyxin if it has been frozen.
• Allow your pen to warm at room temperature before using.

After activation of the pen:

• Once activated, store your Adlyxin pen at room temperature no higher than 86°F (30°C).
• Do not store your Adlyxin pen with the needle attached. An attached needle might lead to contamination and may cause air bubble which might affect your dose of medicine.
• Once your Adlyxin pen is activated it can be used for up to 14 days. Discard a used Adlyxin pen after 14 days. Do this even if there is some medicine left in the pen.

Throwing your pen away

• Replace the pen cap before disposing of your Adlyxin pen.
• Put the used Adlyxin pen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the Adlyxin pen and loose needles in your household trash.
• If you do not have an 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
• Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Maintenance

• Handle your Adlyxin pen with care.
• You can clean the outside of your Adlyxin pen by wiping it with a damp cloth.
• Do not soak, wash or put liquid on (lubricate) your Adlyxin pen. This may damage it.
• If you think your Adlyxin pen may be damaged, do not use it. Do not try to repair the pen.

Questions and Answers

What do I do if I forget to activate the Adlyxin pen or inject myself before activation?

If you have injected yourself before activating the pen, do not correct this by giving yourself a second injection. Contact your healthcare provider for advice on checking your blood sugar.

What do I do if there are air bubbles in the container?

Small air bubbles in the container are normal and they will not harm you. Your dose will be correct and you can keep following the instructions. Contact your healthcare provider if you need help.

What do I do if no liquid comes out during activation?

The needle may be blocked or not properly attached. Remove the needle from the pen, attach a new needle and repeat Steps 4 and 5 of Section 2 only. If still no liquid comes out, your Adlyxin pen may be damaged. Do not use this Adlyxin pen. Contact your healthcare provider for help.

What do I do if it is hard to press the injection button all the way in?

The needle may be blocked or not properly attached. Pull the needle out of your skin and remove the needle from the pen. Attach a new needle and repeat Steps 5 and 6 of Section 3 only. If it is still hard to press in the injection button, your Adlyxin pen may be damaged. Do not use this Adlyxin pen. Contact your healthcare professional for help.

If you have any questions about Adlyxin or about diabetes, ask your healthcare provider or call sanofi-aventis U.S. LLC at 1-800-633-1610.

Date of Revision: Jul/2016

Adlyxin is part of the drug class:

• Other blood glucose lowering drugs, excl. insulins

Mechanism of Action

Incretin mimetic; glucagonlike peptide-1 (GLP-1) receptor agonist; increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying

Absorption

Peak plasma concentration time: 1-3.5 hr

Peak plasma concentration increased with renal impairment

• Mild (CrCl 60-89 mL/min): Increased by 60%
• Moderate (CrCl 30-59 mL/min): Increased by 42%
• Severe (CrCl 15-29 mL/min): Increased by 83%

AUC increased with renal impairment

• Mild (CrCl 60-89 mL/min): Increased by 34%
• Moderate (CrCl 30-59 mL/min): Increased by 69%
• Severe (CrCl 15-29 mL/min): Increased by 124%

Distribution

Vd: 100 L

Metabolism

Not metabolized by the liver

Elimination

Half-life: 3 hr

Clearance: 25 L/hr

Presumed to be eliminated through glomerular filtration and proteolytic degradation

You should not use Adlyxin if you are allergic to lixisenatide.

To make sure this medicine is safe for you, tell your doctor if you have:

• a history of pancreatitis or gall stones;

• problems with digestion;

• kidney disease;

• a history of alcoholism; or

• diabetic ketoacidosis (call your doctor for treatment with insulin).

Follow your doctor's instructions about using Adlyxin if you are pregnant or breast-feeding a baby. Blood sugar control is very important during pregnancy, and your dose needs may be different during each trimester of pregnancy. Your dose needs may also be different while you are breast-feeding.

Adlyxin can make birth control pills less effective. Ask your doctor about using a nonhormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy.

Adlyxin is not approved for use by anyone younger than 18 years old.