Liraglutide

Indications and Usage ( 1 ).......................................................................5/2025 Dosage and Administration, Patient Selection ( 2.1 ).............................(Removed) 5/2025 Contraindications, Pregnancy ( 4 )....................................................................(Removed) 5/2025 Warnings and Precautions, Severe Gastrointestinal Adverse Reactions ( 5.7 ).........................................10/2025 Suicidal Behavior and Ideation ( 5.9 )..........................................(Removed) 2/2026

1 INDICATIONS AND USAGE Liraglutide injection is indicated in combination with a reduced calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: Adults and pediatric patients aged 12 years and older with body weight greater than 60 kg and obesity. Adults with overweight in the presence of at least one weight-related comorbid condition. Limitations of Use Liraglutide injection contains liraglutide. Coadministration with other liraglutide-containing products or with any other glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended. The safety and effectiveness of liraglutide injection in pediatric patients with type 2 diabetes have not been established. Liraglutide injection is a glucagon like peptide 1 (GLP-1) receptor agonist indicated in combination with a reduced calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: • Adults and pediatric patients aged 12 years and older with body weight greater than 60 kg and obesity. ( 1 ) • Adults with overweight in the presence of at least one weight-related comorbid condition. ( 1 ) Limitations of Use: Coadministration with other liraglutide-containing products or with any other GLP-1 receptor agonist is not recommended. ( 1 ) The safety and effectiveness of liraglutide injection in pediatric patients with type 2 diabetes have not been established. ( 1 )

2 DOSAGE AND ADMINISTRATION Inject liraglutide injection subcutaneously in the abdomen, thigh, or upper arm once daily at any time of day, without regard to the timing of meals. ( 2.1 ) The recommended dose of liraglutide injection is 3 mg daily ( 2.2 ). Initiate at 0.6 mg per day for one week. In weekly intervals, increase the dose until a dose of 3 mg is reached. ( 2.2 ) If pediatric patients do not tolerate an increased dose during dose escalation, the dose may also be lowered to the previous level. Dose escalation for pediatric patients may take up to 8 weeks. ( 2.2 ) Pediatric patients who do not tolerate 3 mg daily may have their dose reduced to 2.4 mg daily. ( 2.2 ) Adult patients with type 2 diabetes should monitor blood glucose prior to starting liraglutide injection and during liraglutide injection treatment. ( 2.2 ) 2.1 Important Administration Instructions Prior to initiation of liraglutide injection, train patients on proper injection technique. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. Inspect liraglutide injection visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. Administer liraglutide injection in combination with a reduced-calorie diet and increased physical activity. Inject liraglutide injection subcutaneously once daily at any time of day, without regard to the timing of meals. Inject liraglutide injection subcutaneously in the abdomen, thigh, or upper arm. No dosage adjustment is needed if changing the injection site and/or timing. Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis [see Adverse Reactions ( 6.2 )]. If a dose is missed, 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. If more than 3 days have elapsed since the last liraglutide injection dosage, reinitiate liraglutide injection at 0.6 mg daily and follow the dosage escalation schedule in Table 1 , to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment. 2.2 Dosage in Adults and Pediatric Patients Aged 12 Years and Older Initiate liraglutide injection with a dose of 0.6 mg daily for one week. Then follow the dosage escalation schedule in Table 1 to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.1 )] . Table 1: Dosage Escalation Schedule Week Daily Dose 1 0.6 mg 2 1.2 mg 3 1.8 mg 4 2.4 mg 5 and onward 3 mg Adult Patients For adults, the recommended dosage of liraglutide injection is 3 mg daily, lower dosages are for titration only. Discontinue liraglutide injection if the patient cannot tolerate the 3 mg dosage. If patients do not tolerate an increased dose during dosage escalation, consider delaying dosage escalation for approximately one additional week. Evaluate the change in body weight 16 weeks after initiating liraglutide injection and discontinue liraglutide injection if the patient has not lost at least 4% of baseline body weight, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. In adult patients with type 2 diabetes, monitor blood glucose prior to starting liraglutide injection and during liraglutide injection treatment. Pediatric Patients For pediatric patients, the recommended maintenance dosage of liraglutide injection is 3 mg daily. Pediatric patients who do not tolerate 3 mg daily may have their maintenance dose reduced to 2.4 mg daily. Discontinue liraglutide injection if the patient cannot tolerate the 2.4 mg dose. If pediatric patients do not tolerate an increased dose during dosage escalation, the dose may also be lowered to the previous level. Dosage escalation for pediatric patients may take up to 8 weeks. Evaluate the change in BMI after 12 weeks on the maintenance dos …

3 DOSAGE FORMS AND STRENGTHS Injection: 6 mg/mL clear, colorless solution in a 3 mL prefilled, single-patient-use pen that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3 mg. Injection: 6 mg/mL solution in a 3 mL pre-filled, single-patient-use pen that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg. ( 3 )

4 CONTRAINDICATIONS Liraglutide injection is contraindicated in patients with a: personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide injection. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide injection [see Warnings and Precautions ( 5.7 )] . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. ( 4 ) Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-Cell Tumors [see Warnings and Precautions (5.1) ] Acute Pancreatitis [see Warnings and Precautions (5.2) ] Acute Gallbladder Disease [see Warnings and Precautions (5.3) ] Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions (5.4) ] Heart Rate Increase [see Warnings and Precautions (5.5) ] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.6) ] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.9) ] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10) ] Most common adverse reactions, reported in greater than or equal to 5% are: nausea, diarrhea, constipation, vomiting, injection site reactions, headache, hypoglycemia, dyspepsia, fatigue, dizziness, abdominal pain, increased lipase, upper abdominal pain, pyrexia, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc. at 1-866-924-626 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Liraglutide was evaluated for safety in 5 double-blind, placebo controlled trials that included 3384 overweight or obese adult patients treated with liraglutide for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), and 32 weeks (1 trial) and one trial of 56 weeks in 125 pediatric patients with obesity aged 12 years and older [see Clinical Studies ( 14.1 , 14.2 )]. All patients received study drug in addition to a reduced-calorie diet and increased physical activity counseling. In the adult trials, patients received liraglutide for a mean treatment duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean age of 47 years, 71% female, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m 2 , and 9% with cardiovascular disease. In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at randomization) [see Clinical Studies ( 14.1 )] were enrolled for a placebo-controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received liraglutide for a mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose. In adult clinical trials, 9.8% of patients treated with liraglutide and 4.3% of patients treated with placebo prematurely discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (2.9% versus 0.2% for liraglutide and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea (1.4% versus 0%). Adverse reactions reported in greater than or equal to 2% of liraglutide-treated adult patients and more frequently than in placebo-treated patients are shown in Table 2 . Adverse reactions reported in greater than or equal to 3% of liraglutide-treated pediatric patients and more frequently than in placebo-treated patients are shown in Table 3 . Table 2. Adverse Reactions Occurring in > 2% of Liraglutide-treated Adult Patients and More Frequently than Placebo Placebo N=1941 % Liraglutide N=3384 % Nausea 13.8 39.3 Diarrhea 9.9 20.9 Constipation 8.5 19.4 Vomiting 3.9 15.7 Injection Site Reaction 1 10.5 13.9 Headache 12.6 13.6 Hypoglycemia in T2DM 2 6.6 12.6 Dyspepsia 2.7 9.6 Fatigue 4.6 7.5 Dizzin …

7 DRUG INTERACTIONS Effects of delayed gastric emptying on oral medications : Liraglutide injection delays gastric emptying and may impact absorption of concomitantly administered oral medications ( 7 ). 7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide injection causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide injection did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide injection. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide injection stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide injection, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Liraglutide injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ( 8.1 ) 8.1 Pregnancy Risk Summary Based on animal reproduction studies, there may be risks to the fetus from exposure to liraglutide injection during pregnancy. Liraglutide injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD (see Animal Data) . The estimated background risk of major birth defects for women with uncontrolled pre-gestational diabetes (Hemoglobin A 1C >7) is 6 to 10%. The major birth defect rate has been reported to be as high as 20 to 25% in women with a Hemoglobin A 1C >10. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Animal Data Female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group. In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures …

12.1 Mechanism of Action Liraglutide is an acylated human GLP-1 receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1 (7-37). Like endogenous GLP-1, liraglutide binds to and activates the GLP-1 receptor, a cell-surface receptor coupled to adenylyl cyclase activation through the stimulatory G-protein, Gs. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase 4 (DPP-4) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once-daily administration, is a result of self-association that delays absorption, plasma protein binding, and stability against metabolic degradation by DPP-4 and NEP. GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. In animal studies, peripheral administration of liraglutide resulted in the presence of liraglutide in specific brain regions regulating appetite, including the hypothalamus. Although liraglutide activated neurons in brain regions known to regulate appetite, specific brain regions mediating the effects of liraglutide on appetite were not identified in rats.

11 DESCRIPTION Liraglutide injection contains liraglutide, an analog of the fragment 7-37 of the naturally occurring human glucagon-like peptide 1 (GLP-1[7 - 37]), containing one amino acid substitution (Arg for Lys at position 34 of the GLP-1 sequence) and an additional fatty acid chain. Liraglutide is a linear peptide with 31 amino acids and a γ-glutamyl-palmitoyl residue linked to the ɛ-amino group of Lys 20 . All amino acid residues with exception of the archiral glycines are in the L-configuration. The structural formula ( Figure 1 ) is: Figure 1. Structural Formula of liraglutide C 172 H 265 N 43 O 51 M.W. 3751.26 Daltons Liraglutide is manufactured by chemical synthesis. Liraglutide injection is a sterile, aqueous, clear, colorless solution for subcutaneous use. Each 1 mL of liraglutide injection solution contains 6 mg of liraglutide and the following inactive ingredients: phenol, 5.5 mg; propylene glycol, 14 mg; sodium phosphate dibasic dihydrate, 1.42 mg; and water for injection. Liraglutide injection has a pH of approximately 8.15, hydrochloric acid or sodium hydroxide may be added to adjust pH. Each prefilled pen contains a 3 mL solution of liraglutide injection equivalent to 18 mg liraglutide (free-base, anhydrous). structural formula

10 OVERDOSAGE Overdoses have been reported in clinical trials and post-marketing use of liraglutide injection. Observed effects have included severe nausea, severe vomiting, and severe hypoglycemia. In the event of overdosage, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Initiate appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Liraglutide Injection: 6 mg/mL clear, colorless solution in a 3 mL single-patient-use prefilled pen that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg is available in the following package sizes: Carton NDC Pack Description Pen NDC 70377-095-52 3 X Liraglutide injection pens in a carton 70377-095-51 70377-095-53 5 X Liraglutide injection pens in a carton Recommended Storage Prior to first use, liraglutide injection should be stored in a refrigerator between 36oF to 46oF (2oC to 8oC). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze liraglutide injection and do not use liraglutide injection if it has been frozen. After initial use of the liraglutide injection pen, the pen can be stored for 30 days at controlled room temperature 59°F to 86°F (15°C to 30°C) or in a refrigerator 36°F to 46°F (2°C to 8°C). Keep the pen cap on when not in use. Protect liraglutide injection from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the liraglutide injection pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy.