SOMATULINE DEPOT

Warnings & Precautions, Steatorrhea and Malabsorption of Dietary Fats ( 5.6 ) 07/2024

1 INDICATIONS AND USAGE SOMATULINE DEPOT is a somatostatin analog indicated for: the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. ( 1.1 ) the treatment of adult patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. ( 1.2 ) the treatment of adults with carcinoid syndrome; when used, it reduces the frequency of short-acting somatostatin analog rescue therapy. ( 1.3 ) 1.1 Acromegaly SOMATULINE DEPOT is indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal. 1.2 Gastroenteropancreatic Neuroendocrine Tumors SOMATULINE DEPOT is indicated for the treatment of adult patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. 1.3 Carcinoid Syndrome SOMATULINE DEPOT is indicated for the treatment of adults with carcinoid syndrome; when used, it reduces the frequency of short-acting somatostatin analog rescue therapy.

2 DOSAGE AND ADMINISTRATION Administration ( 2.1 ): For deep subcutaneous injection only. Intended for administration by a healthcare provider. Administer in the superior external quadrant of the buttock. Alternate injection sites. Recommended Dosage ( 2.1 ) Acromegaly: 90 mg every 4 weeks for 3 months. Adjust thereafter based on GH and/or IGF-1 levels. See full prescribing information for titration regimen. GEP-NETs: 120 mg every 4 weeks. Carcinoid Syndrome: 120 mg every 4 weeks. If patients are already being treated with SOMATULINE DEPOT for GEP-NET, do not administer an additional dose for carcinoid syndrome. Dosage Adjustment: See full prescribing information for dosage adjustment in patients with acromegaly and renal or hepatic impairment. ( 2.3 , 2.4 ) 2.1 Important Administration Instructions For deep subcutaneous injection only. SOMATULINE DEPOT is intended for administration by a healthcare provider. Refer to the Instructions For Use (IFU) for complete administration instructions with illustrations. Preparation Remove SOMATULINE DEPOT from the refrigerator 30 minutes prior to administration and allow to come to room temperature. Keep pouch sealed until just prior to injection. Product left in its sealed pouch at room temperature (not to exceed 104°F or 40°C) for up to 72 hours may be returned to the refrigerator for continued storage and use at a later time. Prior to administration, inspect the SOMATULINE DEPOT syringe visually for particulate matter and discoloration. Do not administer if particulate matter or discoloration is observed. The content of the prefilled syringe is a semi-solid phase having a gel-like appearance, with viscous characteristics and a color varying from white to pale yellow. The supersaturated solution can also contain micro bubbles that can clear up during injection. These differences are normal and do not interfere with the quality of the product. Administration Slowly administer for 20 seconds as a deep subcutaneous injection in the superior external quadrant of the buttock. Alternate the injection site between the right and left sides from one injection to the next. 2.2 Recommended Dosage Acromegaly The recommended starting dosage of SOMATULINE DEPOT is 90 mg given via the deep subcutaneous route, at 4-week intervals for 3 months. After 3 months, the dosage may be adjusted as follows: GH greater than 1 ng/mL to less than or equal to 2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain SOMATULINE DEPOT dosage at 90 mg every 4 weeks. GH greater than 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled: increase SOMATULINE DEPOT dosage to 120 mg every 4 weeks. GH less than or equal to 1 ng/mL, IGF-1 normal, and clinical symptoms controlled: reduce SOMATULINE DEPOT dosage to 60 mg every 4 weeks. Thereafter, the dosage should be adjusted according to the response of the patient as judged by a reduction in serum GH and/or IGF-1 levels; and/or changes in symptoms of acromegaly. Patients who are controlled on SOMATULINE DEPOT 60 or 90 mg may be considered for an extended dosing interval of SOMATULINE DEPOT 120 mg every 6 or 8 weeks. GH and IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response. Continued monitoring of patient response with dosage adjustments for biochemical and clinical symptom control, as necessary, is recommended. Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) The recommended dosage of SOMATULINE DEPOT is 120 mg administered every 4 weeks by deep subcutaneous injection. Carcinoid Syndrome The recommended dosage of SOMATULINE DEPOT is 120 mg administered every 4 weeks by deep subcutaneous injection. If patients are already being treated with SOMATULINE DEPOT for GEP-NETs, do not administer an additional dose for the treatment of carcinoid syndrome. 2.3 Dosage Adjustment in Renal Impairment Acromegaly The recommended starting dosage of SOMATULINE DEPOT in acromegalic patients with …

3 DOSAGE FORMS AND STRENGTHS Injection: 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL sterile, single-dose, prefilled syringes fitted with an automatic safety system (attached retractable needle and needle guard). The prefilled syringes contain a white to pale yellow, semi-solid formulation. Injection: 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL single-dose prefilled syringes ( 3 )

4 CONTRAINDICATIONS SOMATULINE DEPOT is contraindicated in patients with history of a hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide [ see Adverse Reactions (6.3) ] . Hypersensitivity to lanreotide. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions to SOMATULINE DEPOT are discussed in greater detail in other sections of the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.1) ] Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.2) ] Cardiovascular Abnormalities [see Warnings and Precautions (5.3) ] Thyroid Function Abnormalities [see Warnings and Precautions (5.4) ] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.6) ] Most common adverse reactions are: Acromegaly (>5%): diarrhea, cholelithiasis, abdominal pain, nausea and injection site reactions. ( 6.1 ) GEP-NET (>10%): abdominal pain, musculoskeletal pain, vomiting, headache, injection site reaction, hyperglycemia, hypertension, and cholelithiasis. ( 6.1 ) Carcinoid Syndrome : (≥5% and at least 5% greater than placebo): headache, dizziness and muscle spasm. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 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 trials of another drug and may not reflect the rates observed in practice. Acromegaly The data described below reflect exposure to SOMATULINE DEPOT in 416 acromegalic patients in seven studies. One study was a fixed-dose pharmacokinetic study. The other six studies were open-label or extension studies, one had a placebo-controlled, run-in period, and another had an active control. The population was mainly Caucasian (329/353, 93%) with a median age of 53 years of age (range 19 to 84 years). Fifty-four subjects (13%) were age 66 to 74 and 18 subjects (4.3%) were 75 years of age and older. Patients were evenly matched for sex (205 males and 211 females). The median average monthly dose was 91.2 mg (e.g., 90 mg injected via the deep subcutaneous route every 4 weeks) over 385 days with a median cumulative dose of 1290 mg. Of the patients reporting acromegaly, severity at baseline (N=265), serum GH levels were less than 10 ng/mL for 69% (183/265) of the patients and 10 ng/mL or greater for 31% (82/265) of the patients. The most commonly reported adverse reactions reported by greater than 5% of patients who received SOMATULINE DEPOT (N=416) in the overall pooled safety studies in acromegaly patients were gastrointestinal disorders (diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose stools), cholelithiasis, and injection site reactions. Tables 1 and 2 present adverse reaction data from clinical studies with SOMATULINE DEPOT in acromegalic patients. The tables include data from a single clinical study and pooled data from seven clinical studies. Adverse Reactions in Parallel Fixed-Dose Phase of Study 1 The incidence of treatment-emergent adverse reactions for SOMATULINE DEPOT 60, 90, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 [see Clinical Studies (14.1) ] are provided in Table 1. Table 1: Adverse Reactions at an Incidence of Greater than 5% with SOMATULINE DEPOT Overall and Occurring at Higher Rate than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 By Dose Placebo-Controlled Double-Blind Phase Weeks 0 to 4 Fixed-Dose Phase Double-Blind + Single-Blind Weeks 0 to 20 Body System Preferred Term Placebo (N=25) SOMATULINE DEPOT Overall (N=83) SOMATULINE DEPOT 60 mg (N=34) SOMATULINE DEPOT 90 mg (N=36) SOMATULINE DEPOT 120 mg (N=37) SOMATULINE DEPOT Overall (N=107) N (%) N (%) N (%) N (%) N (%) N (%) A patient is counted only once for each body system and preferred term. Dictionary = WHOART. Gastrointestinal System Disorders 1 (4%) 30 (36%) 12 (35%) 21 (58%) 27 (73%) 60 (56%) Diarrhea 0 26 (31%) 9 (26%) 15 (42%) 24 (65%) 48 (45%) Abdominal pain 1 (4%) 6 (7%) 3 (9%) 6 (17%) 7 (19%) 16 (15%) Flatu …

7 DRUG INTERACTIONS Cyclosporine : SOMATULINE DEPOT may decrease the absorption of cyclosporine. Dosage adjustment of cyclosporine may be needed. ( 7.2 ) Bromocriptine : SOMATULINE DEPOT may increase the absorption of bromocriptine. ( 7.3 ) Bradycardia-Inducing Drugs (e.g., beta-blockers) : SOMATULINE DEPOT may decrease heart rate. Dosage adjustment of the coadministered drug may be necessary. ( 7.3 ) 7.1 Insulin and Oral Hypoglycemic Drugs Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when SOMATULINE DEPOT treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Warnings and Precautions (5.2) ] . 7.2 Cyclosporine Concomitant administration of cyclosporine with SOMATULINE DEPOT may decrease the absorption of cyclosporine, and therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic drug concentrations. [see Clinical Pharmacology (12.3) ] 7.3 Bromocriptine Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the absorption of bromocriptine [see Clinical Pharmacology (12.3) ] . 7.4 Bradycardia-Inducing Drugs Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dosage adjustments of concomitant drugs may be necessary. 7.5 Drug Metabolism Interactions The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that SOMATULINE DEPOT may have this effect, avoid other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine). Drugs metabolized by the liver may be metabolized more slowly during SOMATULINE DEPOT treatment and dose reductions of the concomitantly administered medications should be considered [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Lactation : Advise women not to breastfeed during treatment and for 6 months after the last dose. ( 8.2 ) 8.1 Pregnancy Risk Summary Limited available data based on postmarketing case reports with SOMATULINE DEPOT use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, decreased embryo/fetal survival was observed in pregnant rats and rabbits at subcutaneous doses 5- and 2-times the maximum recommended human dose (MRHD) of 120 mg, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Data Animal Data A reproductive study in pregnant rats given 30 mg/kg of lanreotide by subcutaneous injection every 2 weeks (5 times the human dose, based on body surface area comparisons) resulted in decreased embryo/fetal survival. A study in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day (2 times the human therapeutic exposures at the maximum recommended dose of 120 mg, based on comparisons of relative body surface area) shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities. 8.2 Lactation Risk Summary There is no information available on the presence of lanreotide in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that lanreotide acetate administered subcutaneously passes into the milk of lactating rats; however, due to specifies-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk . Because of the potential for serious adverse reactions in breastfed infants from SOMATULINE DEPOT, including effects on glucose metabolism and bradycardia, advise women not to breastfeed during treatment with SOMATULINE DEPOT and for 6 months (6 half-lives) following the last dose. 8.3 Females and Males of Reproductive Potential Infertility Females Based on results from animal studies conducted in female rats, SOMATULINE DEPOT may reduce fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use The safety and effectiveness of SOMATULINE DEPOT in pediatric patients have not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness were observed between elderly patients with acromegaly compared with younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Studies 3 and 4, conducted in patients with neuroendocrine tumors, did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment Acromegaly Lanreotide has been studied in patients with end-stage renal function on dialysis, but has not been studied in patients with mild, moderate, or severe renal impairment. It is recommended that patients with moderate or severe renal impairment receive a starting dose of lanreotide of 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of SOMATULINE DEPOT 120 mg every 6 or 8 weeks …

12.1 Mechanism of Action Lanreotide, the active component of SOMATULINE DEPOT is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin.

11 DESCRIPTION SOMATULINE DEPOT (lanreotide) Injection 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL is a prolonged-release formulation for deep subcutaneous injection. It contains the drug substance lanreotide acetate, a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, water for injection and acetic acid (for pH adjustment). SOMATULINE DEPOT is available as sterile, ready-to-use, single-dose prefilled syringes containing lanreotide acetate supersaturated bulk solution of 24.6% w/w lanreotide base. Each syringe contains: SOMATULINE DEPOT 60 mg/0.2 mL SOMATULINE DEPOT 90 mg/0.3 mL SOMATULINE DEPOT 120 mg/0.5 mL Lanreotide acetate 77.9 mg 113.6 mg 149.4 mg Acetic Acid q.s. q.s. q.s. Water for injection 186.6 mg 272.3 mg 357.8 mg Total Weight 266 mg 388 mg 510 mg Lanreotide acetate is a synthetic cyclical octapeptide analog of the natural hormone, somatostatin. Lanreotide acetate is chemically known as [cyclo S-S]-3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate salt. Its molecular weight is 1096.34 (base) and its amino acid sequence is: The SOMATULINE DEPOT in the prefilled syringe is a white to pale yellow, semi-solid formulation. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING SOMATULINE DEPOT is supplied in strengths of 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL as a white to pale yellow, semi-solid formulation in a single, sterile, prefilled, ready-to-use, polypropylene syringe fitted with an automatic safety system, a bromobutyl rubber plunger stopper and a 20 mm attached needle covered by a plastic cap. Each prefilled syringe is placed in a plastic tray, sealed in a laminated pouch and packed in a carton. NDC 15054-1060-4 60 mg/0.2 mL, sterile, prefilled syringe NDC 15054-1090-4 90 mg/0.3 mL, sterile, prefilled syringe NDC 15054-1120-4 120 mg/0.5 mL, sterile, prefilled syringe Storage and Handling Store SOMATULINE DEPOT in the refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in the original package.