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Pregnancy

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.

Drug Interactions

7 DRUG INTERACTIONS Cyclosporine: SOMATULINE DEPOT may decrease the absorption of cyclosporine. Dosage adjustment of cyclosporine may 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)].

Indications And Usage

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.

Clinical Studies

14 CLINICAL STUDIES 14.1 Acromegaly The effect of SOMATULINE DEPOT on reducing GH and IGF-levels and control of symptoms in patients with acromegaly was studied in 2 long-term, multiple-dose, randomized, multicenter studies. Study 1 This 1-year study included a 4-week, double-blind, placebo-controlled phase; a 16-week single-blind, fixed-dose phase; and a 32-week, open-label, dose-titration phase. Patients with active acromegaly, based on biochemical tests and medical history, entered a 12-week washout period if there was previous treatment with a somatostatin analog or a dopaminergic agonist. Upon entry, patients were randomly allocated to receive a single, deep subcutaneous injection of SOMATULINE DEPOT 60, 90, or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of SOMATULINE DEPOT followed by a dose-titration phase of 8 injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at 4-week intervals. During the dose-titration phase of the study, the dose was titrated twice (every fourth injection), as needed, according to individual GH and IGF-1 levels. A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. Half (54/108) of the patients had never been treated with a somatostatin analog or dopamine agonist, or had stopped treatment for at least 3 months prior to their participation in the study and were required to have a mean GH level greater than 5 ng/mL at their first visit. The other half of the patients had received prior treatment with a somatostatin analog or a dopamine agonist before study entry and at study entry were required to have a mean GH concentration greater than 3 ng/mL and at least a 100% increase in mean GH concentration after washout of medication. One hundred and seven (107) patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase, and 99 patients completed the dose-titration phase. Patients not completing withdrew due to adverse events (5) or lack of efficacy (4). In the double-blind phase of Study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a greater than 50% decrease in mean GH from baseline to Week 4, including 52%, 44%, and 90% of patients in the 60, 90, and 120 mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of greater than 50%, including 68% (23/34), 64% (23/36), and 84% (31/37) of patients in the 60, 90, and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study (see Table 4). Table 4: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 1 Baseline Before Titration 1 Before Titration 2 Last Value AvailableLast Observation Carried Forward N=107 (16 weeks) N=107 (32 weeks) N=105 N=107 GH ≤5.0 ng/mL Number of Responders (%) 20 (19%) 72 (67%) 76 (72%) 74 (69%) ≤2.5 ng/mL Number of Responders (%) 0 (0%) 52 (49%) 59 (56%) 55 (51%) ≤1.0 ng/mL Number of Responders (%) 0 (0%) 15 (14%) 18 (17%) 17 (16%) Median GH ng/mL 10.27 2.53 2.20 2.43 GH Reduction Median % Reduction -- 75.5 78.2 75.5 IGF-1 NormalAge-adjusted Number of Responders (%) 9 (8%) 58 (54%) 57 (54%) 62 (58%) Median IGF-1 ng/mL 775.0 332.0n=105, 316.5n=102, 326.0 IGF-1 Reduction Median % Reduction -- 52.3 54.5 55.4 IGF-1 Normal + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 41 (38%) 46 (44%) 44 (41%) Study 2 This was a 48-week, open-label, uncontrolled, multicenter study that enrolled patients who had an IGF-1 concentration 1.3 times or greater than the upper limit of the normal age-adjusted range. Patients receiving treatment with a somatostatin analog (other than SOMATULINE DEPOT) or a dopaminergic agonist had to attain this IGF-1 concentration after a washout period of up to 3 months. Patients were initially enrolled in a 4-month, fixed-dose phase where they received 4 deep subcutaneous injections of SOMATULINE DEPOT 90 mg, at 4-week intervals. Patients then entered a dose-titration phase where the dose of SOMATULINE DEPOT was adjusted based on GH and IGF-1 levels at the beginning of the dose-titration phase and, if necessary, again after another 4 injections. Patients titrated up to the maximum dose (120 mg) were not allowed to titrate down again. A total of 63 patients (38 males, 25 females) entered the fixed-dose phase of the trial and 57 patients completed 48 weeks of treatment. Six patients withdrew due to adverse reactions (3), other reasons (2), or lack of efficacy (1). After 48 weeks of treatment with SOMATULINE DEPOT at 4-week intervals, 43% (27/63) of the acromegalic patients in this study achieved normal age-adjusted IGF-1 concentrations. Mean IGF-1 concentrations after treatment completion were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline. The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations. The proportion of patients with mean GH concentrations less than 2.5 ng/mL increased significantly from 35% to 77% after the fixed-dose phase and 85% at the end of the study. At the end of treatment, 24/63 (38%) of patients had both normal IGF-1 concentrations and a GH concentration of less than or equal to 2.5 ng/mL (see Table 5) and 17/63 patients (27%) had both normal IGF-1 concentrations and a GH concentration of less than 1 ng/mL. Table 5: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 2 Baseline Before Titration 1 (12 wks) Before Titration 2 (28 wks) Last Value Available Last Observation Carried Forward N=63 N=63 N=59 N=63 IGF-1 NormalAge-adjusted, Number of Responders (%) 0 (0%) 17 (27%) 22 (37%) 27 (43%) Median IGF-1 ng/mL 689.0 382.0 334.0 317.0 IGF-1 Reduction Median % Reduction -- 41.0 51.0 50.3 GH ≤5.0 ng/mL Number of Responders (%) 40 (64%) 59 (94%) 57 (97%) 62 (98%) ≤2.5 ng/mL Number of Responders (%) 21 (33%) 47 (75%) 47 (80%) 54 (86 %) ≤1.0 ng/mL Number of Responders (%) 8 (13%) 19 (30%) 18 (31%) 28 (44%) Median GH ng/Ml 3.71 1.65 1.48 1.13 GH Reduction Median % Reduction -- 63.2 66.7 78.6N= 62, IGF-1 normal + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 14 (22%) 20 (34%) 24 (38%) Examination of age and gender subgroups did not identify differences in response to SOMATULINE DEPOT among these subgroups. The limited number of patients in the different racial subgroups did not raise any concerns regarding efficacy of SOMATULINE DEPOT in these subgroups. 14.2 Gastroenteropancreatic Neuroendocrine Tumors The efficacy of SOMATULINE DEPOT was established in a multicenter, randomized, double-blind, placebo-controlled trial of 204 patients with unresectable, well or moderately differentiated, metastatic or locally advanced, gastroenteropancreatic neuroendocrine tumors. Patients were required to have non-functioning tumors without hormone-related symptoms. Patients were randomized 1:1 to receive SOMATULINE DEPOT 120 mg (n=101) or placebo (n=103) every 4 weeks until disease progression, unacceptable toxicity, or a maximum of 96 weeks of treatment. Randomization was stratified by the presence or absence of prior therapy and by the presence or absence of disease progression within 6 months of enrollment. The major efficacy outcome measure was progression-free survival (PFS), defined as time to disease progression as assessed by central independent radiological review using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) or death. The median patient age was 63 years (range 30 to 92 years) and 95% were Caucasian. Disease progression was present in nine of 204 patients (4.4%) in the 6 months prior to enrollment and 29 patients (14%) received prior chemotherapy. Ninety-one patients (45%) had primary sites of disease in the pancreas, with the remainder originating in the midgut (35%), hindgut (7%), or unknown primary location (13%). The majority (69%) of the study population had grade 1 tumors. Baseline prognostic characteristics were similar between arms with one exception; there were 39% of patients in the SOMATULINE DEPOT arm and 27% of patients in the placebo arm who had hepatic involvement by tumor of greater than 25%. Patients on the SOMATULINE DEPOT arm had a statistically significant improvement in PFS compared to patients receiving placebo (see Table 6 and Figure 1). Table 6: Efficacy Results in Study 3 SOMATULINE DEPOT Placebo n=101 n=103 Number of Events (%) 32 (31.7%) 60 (58.3%) Median PFS (months)(95% CI) NENE = not reached at 22 months (NE, NE) 16.6 (11.2, 22.1) HR (95% CI) 0.47 (0.30, 0.73)Hazard Ratio is derived from a Cox stratified proportional hazards model Log-rank p-value <0.001 Figure 1: Kaplan-Meier Curves of Progression-Free Survival Figure 1 14.3 Carcinoid Syndrome Study 4 was a multicenter, randomized, 16-week, double-blind, placebo-controlled trial in 115 patients with histopathologically-confirmed neuroendocrine tumors and a history of carcinoid syndrome (flushing and/or diarrhea) who were treatment naïve or stable on another somatostatin analog and who were randomized 1:1 to receive SOMATULINE DEPOT 120 mg (n=59) or placebo (n=56) by deep subcutaneous injection every 4 weeks. Patients were instructed to self-administer a short-acting somatostatin analog (octreotide) as rescue medication as needed for symptom control. The use of rescue therapy and the severity and frequency of diarrhea and flushing symptoms were reported daily in electronic patient diaries. During the 16 week double-blind phase, the primary efficacy outcome measure was the percentage of days in which patients administered at least one injection of rescue medication for symptom control. Average daily frequencies of diarrhea and flushing events were assessed secondarily. The patient population had a mean age of 59 years (range 27 to 85 years), 58% were female and 77% were Caucasian. Patients in the SOMATULINE DEPOT arm experienced 15% fewer days on rescue medication compared to patients in the placebo arm (34% vs. 49% of days, respectively; p=0.02). The average daily frequencies of diarrhea and flushing events in patients treated with SOMATULINE DEPOT (and rescue medication) were numerically lower relative to patients treated with placebo (and rescue medication), but were not statistically significantly different via hierarchical testing.

Warnings And Cautions

5 WARNINGS AND PRECAUTIONS Cholelithiasis and Gallbladder Sludge: Gallstones may occur; consider periodic monitoring. (5.1) Hyperglycemia and Hypoglycemia: Glucose monitoring is recommended and antidiabetic treatment adjusted accordingly. (5.2, 7.1) Cardiovascular Abnormalities: Decrease in heart rate may occur. Use with caution in at-risk patients. (5.3) Thyroid Function Abnormalities: Decreases in thyroid function may occur; perform tests where clinically indicated. (5.4) 5.1 Cholelithiasis and Gallbladder Sludge SOMATULINE DEPOT may reduce gallbladder motility and lead to gallstone formation; therefore, patients may need to be monitored periodically [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. 5.2 Hyperglycemia and Hypoglycemia Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with SOMATULINE DEPOT may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Adverse Reactions (6.1)]. 5.3 Cardiovascular Abnormalities The most common overall cardiac adverse reactions observed in three pooled SOMATULINE DEPOT cardiac studies in patients with acromegaly were sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%), and hypertension (12/217, 5.5%) [see Adverse Reactions (6.1)]. In 81 patients with baseline heart rates of 60 beats per minute (bpm) or greater treated with SOMATULINE DEPOT in Study 3, the incidence of heart rate less than 60 bpm was 23% (19/81) as compared to 16% (15/94) of placebo treated patients; 10 patients (12%) had documented heart rates less than 60 bpm on more than one visit. The incidence of documented episodes of heart rate less than 50 bpm as well as the incidence of bradycardia reported as an adverse event was 1% in each treatment group. Initiate appropriate medical management in patients who develop symptomatic bradycardia. In patients without underlying cardiac disease, SOMATULINE DEPOT may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to SOMATULINE DEPOT treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with SOMATULINE DEPOT in patients with bradycardia. 5.4 Thyroid Function Abnormalities Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (less than 1%). Thyroid function tests are recommended where clinically indicated. 5.5 Monitoring: Laboratory Tests Acromegaly: Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of treatment [see Dosage and Administration (2.2)].

Adverse Reactions

6 ADVERSE REACTIONS The following adverse reactions to SOMATULINE DEPOT are discussed in greater detail in other sections of the labeling: Cholelithiasis and Gallbladder Sludge [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)] 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%) Flatulence 0 5 (6%) 0 (0%) 3 (8%) 5 (14%) 8 (7%) Application Site Disorders 0 (0%) 5 (6%) 3 (9%) 4 (11%) 8 (22%) 15 (14%) (Injection site mass/ pain/ reaction/ inflammation) Liver and Biliary System Disorders 1 (4%) 3 (4%) 9 (26%) 7 (19%) 4 (11%) 20 (19%) Cholelithiasis 0 2 (2%) 5 (15%) 6 (17%) 3 (8%) 14 (13%) Heart Rate & Rhythm Disorders 0 8 (10%) 7 (21%) 2 (6%) 5 (14%) 14 (13%) Bradycardia 0 7 (8%) 6 (18%) 2 (6%) 2 (5%) 10 (9%) Red Blood Cell Disorders 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%) Anemia 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%) Metabolic & Nutritional Disorders 3 (12%) 13 (16%) 8 (24%) 9 (25%) 4 (11%) 21 (20%) Weight decrease 0 7 (8%) 3 (9%) 4 (11%) 2 (5%) 9 (8%) In Study 1, the adverse reactions of diarrhea, abdominal pain, and flatulence increased in incidence with increasing dose of SOMATULINE DEPOT. Adverse Reactions in Long-Term Clinical Trials Table 2 provides the most common adverse reactions (greater than 5%) that occurred in 416 acromegalic patients treated with SOMATULINE DEPOT pooled from 7 studies compared to those patients from the 2 efficacy studies (Studies 1 and 2). Patients with elevated GH and IGF-1 levels were either naive to somatostatin analog therapy or had undergone a 3-month washout [see Clinical Studies (14.1)]. Table 2: Adverse Reactions in SOMATULINE DEPOT-Treated Patients at an Incidence Greater than 5% in Overall Group Versus Adverse Reactions Reported in Studies 1 and 2 System Organ Class Number and Percentage of Patients Studies 1 & 2 Overall Pooled Data (N=170) (N=416) N % N % Dictionary = MedDRA 7.1 Patients with any Adverse Reactions 157 92 356 86 Gastrointestinal disorders 121 71 235 57 Diarrhea 81 48 155 37 Abdominal pain 34 20 79 19 Nausea 15 9 46 11 Constipation 9 5 33 8 Flatulence 12 7 30 7 Vomiting 8 5 28 7 Loose stools 16 9 23 6 Hepatobiliary disorders 53 31 99 24 Cholelithiasis 45 27 85 20 General disorders and administration site conditions 51 30 91 22 (Injection site pain /mass /induration/ nodule/pruritus) 28 17 37 9 Musculoskeletal and connective tissue disorders 44 26 70 17 Arthralgia 17 10 30 7 Nervous system disorders 34 20 80 19 Headache 9 5 30 7 In addition to the adverse reactions listed in Table 2, the following reactions were also seen: Sinus bradycardia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (13) of patients in the overall pooled studies. Hypertension occurred in 7% (11) of patients in the pooled Study 1 and 2 and in 5% (20) of patients in the overall pooled studies. Anemia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (14) of patients in the overall pooled studies. Gastrointestinal Adverse Reactions In the pooled clinical studies of SOMATULINE DEPOT therapy, a variety of gastrointestinal (GI) reactions occurred, the majority of which were mild to moderate in severity. One percent of acromegalic patients treated with SOMATULINE DEPOT in the pooled clinical studies discontinued treatment because of gastrointestinal reactions. Pancreatitis was reported in less than 1% of patients. Gallbladder Adverse Reactions In clinical studies involving 416 acromegalic patients treated with SOMATULINE DEPOT, cholelithiasis and gallbladder sludge were reported in 20% of the patients. Among 167 acromegalic patients treated with SOMATULINE DEPOT who underwent routine evaluation with gallbladder ultrasound, 17% had gallstones at baseline. New cholelithiasis was reported in 12% of patients. Cholelithiasis may be related to dose or duration of exposure [see Warnings and Precautions (5.1)]. Injection Site Reactions In the pooled clinical studies, injection site pain (4%) and injection site mass (2%) were the most frequently reported local adverse drug reactions that occurred with the administration of SOMATULINE DEPOT. In a specific analysis, 20 of 413 patients (5%) presented indurations at the injection site. Injection site adverse reactions were more commonly reported soon after the start of treatment and were less commonly reported as treatment continued. Such adverse reactions were usually mild or moderate but did lead to withdrawal from clinical studies in two subjects. Glucose Metabolism Adverse Reactions In the clinical studies in acromegalic patients treated with SOMATULINE DEPOT, adverse reactions of dysglycemia (hypoglycemia, hyperglycemia, diabetes) were reported by 14% (47/332) of patients and were considered related to study drug in 7% (24/332) of patients [see Warnings and Precautions (5.2)]. Cardiac Adverse Reactions In the pooled clinical studies, sinus bradycardia (3%) was the most frequently observed heart rate and rhythm disorder. All other cardiac adverse drug reactions were observed in less than 1% of patients. The relationship of these events to SOMATULINE DEPOT could not be established because many of these patients had underlying cardiac disease [see Warnings and Precautions (5.3)]. A comparative echocardiography study of lanreotide and another somatostatin analog demonstrated no difference in the development of new or worsening valvular regurgitation between the 2 treatments over 1 year. The occurrence of clinically significant mitral regurgitation (i.e., moderate or severe in intensity) or of clinically significant aortic regurgitation (i.e., at least mild in intensity) was low in both groups of patients throughout the study. Other Adverse Reactions For the most commonly occurring adverse reactions in the pooled analysis, diarrhea, abdominal pain, and cholelithiasis, there was no apparent trend for increasing incidence with age. GI disorders and renal and urinary disorders were more common in patients with documented hepatic impairment; however, the incidence of cholelithiasis was similar between groups. Gastroenteropancreatic Neuroendocrine Tumors The safety of SOMATULINE DEPOT 120 mg for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was evaluated in Study 3, a double-blind, placebo-controlled trial. Patients in Study 3 were randomized to receive SOMATULINE DEPOT (N=101) or placebo (N=103) administered by deep subcutaneous injection once every 4 weeks. The data below reflect exposure to SOMATULINE DEPOT in 101 patients with GEP-NETs, including 87 patients exposed for at least 6 months and 72 patients exposed for at least 1 year (median duration of exposure 22 months). Patients treated with SOMATULINE DEPOT had a median age of 64 years (range 30 to 83 years), 53% were men and 96% were Caucasian. Eighty-one percent of patients (83/101) in the SOMATULINE DEPOT arm and 82% of patients (82/103) in the placebo arm did not have disease progression within 6 months of enrollment and had not received prior therapy for GEP-NETs. The rates of discontinuation due to treatment-emergent adverse reactions were 5% (5/101 patients) in the SOMATULINE DEPOT arm and 3% (3/103 patients) in the placebo arm. Table 3 compares the adverse reactions reported with an incidence of 5% and greater in patients receiving SOMATULINE DEPOT 120 mg administered every 4 weeks and reported more commonly than placebo. Table 3: Adverse Reactions Occurring in 5% and Greater of SOMATULINE DEPOT-Treated Patients and at a Higher Rate Than in Placebo-Treated Patients in Study 3 Adverse Reaction SOMATULINE DEPOT 120 mg N=101 Placebo N=103 Any (%) SevereDefined as hazardous to well-being, significant impairment of function or incapacitation (%) Any (%) Severe (%) Any Adverse Reactions 88 26 90 31 Abdominal painIncludes preferred terms of abdominal pain, abdominal pain upper/lower, abdominal discomfort 34Includes one or more serious adverse events (SAEs) defined as any event that results in death, is life threatening, results in hospitalization or prolongation of hospitalization, results in persistent or significant disability, results in congenital anomaly/birth defect, or may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed. 6 24 4 Musculoskeletal painIncludes preferred terms of myalgia, musculoskeletal discomfort, musculoskeletal pain, back pain 19 2 13 2 Vomiting 19 2 9 2 Headache 16 0 11 1 Injection site reactionIncludes preferred terms of infusion site extravasation, injection site discomfort, injection site granuloma, injections site hematoma, injection site hemorrhage, injection site induration, injection site mass, injections site nodule, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling 15 0 7 0 HyperglycemiaIncludes preferred terms of diabetes mellitus, glucose tolerance impaired, hyperglycemia, type 2 diabetes mellitus 14 0 5 0 HypertensionIncludes preferred terms of hypertension, hypertensive crisis 14 1 5 0 Cholelithiasis 14 1 7 0 Dizziness 9 0 2 0 DepressionIncludes preferred terms of depression, depressed mood 7 0 1 0 Dyspnea 6 0 1 0 Carcinoid Syndrome The safety of SOMATULINE DEPOT 120 mg in patients with histopathologically confirmed neuroendocrine tumors and a history of carcinoid syndrome (flushing and/or diarrhea) was evaluated in Study 4, a double-blind, placebo-controlled trial. Patients were randomized to receive SOMATULINE DEPOT (N=59) or placebo (N=56) administered by deep subcutaneous injection once every 4 weeks. Patients in both arms of Study 4 had access to subcutaneous octreotide as rescue medication for symptom control. Adverse reactions reported in Study 4 were generally similar to those reported in Study 3 for the GEP-NETs population shown in Table 3 above. Adverse reactions occurring in Study 4 in 5% and greater of SOMATULINE DEPOT-treated patients and occurring at least 5% more than in placebo-treated patients were headache (12% vs 5%, respectively), dizziness (7% vs 0%, respectively), and muscle spasm (5% vs 0%, respectively) by week 16. 6.2 Immunogenicity As with all peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to lanreotide in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Laboratory investigations of acromegalic patients treated with SOMATULINE DEPOT in clinical studies show that the percentage of patients with putative antibodies at any time point after treatment is low (less than 1% to 4% of patients in specific studies whose antibodies were tested). The antibodies did not appear to affect the efficacy or safety of SOMATULINE DEPOT. In Study 3, development of anti-lanreotide antibodies was assessed using a radioimmunoprecipitation assay. In patients with GEP NETs receiving SOMATULINE DEPOT, the incidence of anti-lanreotide antibodies was 4% (3 of 82) at 24 weeks, 10% (7 of 67) at 48 weeks, 11% (6 of 57) at 72 weeks, and 10% (8 of 84) at 96 weeks. Assessment for neutralizing antibodies was not conducted. In Study 4, less than 2% (2 of 108) of the patients treated with SOMATULINE DEPOT developed anti-lanreotide antibodies. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SOMATULINE DEPOT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary: Steatorrhea, cholecystitis, pancreatitis Body as a Whole: angioedema and anaphylaxis

Recent major changes

Indications and Usage, Carcinoid Syndrome (1.3) 09/2017 Dosage and Administration, Carcinoid Syndrome (2.2) 09/2017

Mechanism

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.

Contraindications

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)