b'SOMATULINE DEPOT (lanreotide) injection, for subcutaneous use In patients without underlying cardiac disease, SOMATULINE DEPOTand underlying disease. For these reasons, comparison of the incidence ofLactationBrief Summary of full Prescribing InformationGEP-NETs andmay lead to a decrease in heart rate without necessarily reaching theantibodies to lanreotide in the studies described below with the incidenceRisk SummaryCarcinoid Syndrome. See full Prescribing Information. Rx Only. threshold of bradycardia. In patients suffering from cardiac disorders priorof antibodies in other studies or to other products may be misleading. There is no information available on the presence of lanreotide in human INDICATIONS AND USAGE: to SOMATULINE DEPOT treatment, sinus bradycardia may occur. CareLaboratory investigations of acromegalic patients treated withmilk, the effects of the drug on the breastfed infant, or the effects of the Gastroenteropancreatic Neuroendocrine Tumors: SOMATULINEshould be taken when initiating treatment with SOMATULINE DEPOT inSOMATULINE DEPOT in clinical studies show that the percentage ofdrug on milk production. Studies show that lanreotide acetate administered DEPOT is indicated for the treatment of adult patients with unresectable,patients with bradycardia. patients with putative antibodies at any time point after treatment is lowsubcutaneously passes into the milk of lactating rats; however, due to well or moderately differentiated, locally advanced or metastatic gas- ADVERSE REACTIONS (less than 1% to 4% of patients in specific studies whose antibodies werespecifies-specific differences in lactation physiology, animal data may not troenteropancreatic neuroendocrine tumors (GEP-NETs) to improveThe following adverse reactions to SOMATULINE DEPOT are discussed intested). The antibodies did not appear to affect the efficacy or safety ofreliably predict drug levels in human milk. Because of the potential for progression-free survival. greater detail in other sections of the labeling:SOMATULINE DEPOT. serious adverse reactions in breastfed infants from SOMATULINE DEPOT, Carcinoid Syndrome: SOMATULINE DEPOT is indicated for the treatment Cholelithiasis and Complications of Cholelithiasis [see Warnings andIn Study 3, development of anti-lanreotide antibodies was assessed usingincluding effects on glucose metabolism and bradycardia, advise women of adults with carcinoid syndrome; when used, it reduces the frequency ofPrecautions (5.1)] a radioimmunoprecipitation assay. In patients with GEP-NETs receivingnot to breastfeed during treatment with SOMATULINE DEPOT and for 6 short-acting somatostatin analog rescue therapy.Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.2)] SOMATULINE DEPOT, the incidence of anti-lanreotide antibodies wasmonths (6 half-lives) following the last dose. Cardiovascular Abnormalities [see Warnings and Precautions (5.3)] 4% (3 of 82) at 24 weeks, 10% (7 of 67) at 48 weeks, 11% (6 of 57) atFemales and Males of Reproductive PotentialDOSAGE AND ADMINISTRATION Clinical Trials Experience 72 weeks, and 10% (8 of 84) at 96 weeks. Assessment for neutralizingInfertilityImportant Administration Instructions Because clinical trials are conducted under widely varying conditions,antibodies was not conducted. In Study 4, less than 2% (2 of 108) of theFemales For deep subcutaneous injection only. adverse reaction rates observed in the clinical trials of a drug cannot bepatients treated with SOMATULINE DEPOT developed anti-lanreotideBased on results from animal studies conducted in female rats,SOMATULINE DEPOT is intended for administration by a healthcaredirectly compared to rates in the clinical trials of another drug and mayantibodies. SOMATULINE DEPOT may reduce fertility in females of reproductive provider. not reflect the rates observed in practice.Postmarketing Experience: The following adverse reactions have beenpotential [see Nonclinical Toxicology (13.1)].Preparation Gastroenteropancreatic Neuroendocrine Tumors: The safety ofidentified during postapproval use of SOMATULINE DEPOT. Because 1. Remove SOMATULINE DEPOT from the refrigerator 30 minutes prior toSOMATULINE DEPOT 120 mg for the treatment of patients with gastro- these reactions are reported voluntarily from a population of uncertainPediatric Useadministration and allow to come to room temperature. enteropancreatic neuroendocrine tumors (GEP-NETs) was evaluated insize, it is not always possible to reliably estimate their frequency orThe safety and effectiveness of SOMATULINE DEPOT in pediatric patients 2.Keep pouch sealed until just prior to injection. Study 3, a double-blind, placebo-controlled trial. Patients in Study 3 wereestablish a causal relationship to drug exposure.have not been established.3. Product left in its sealed pouch at room temperature (not to exceedrandomized to receive SOMATULINE DEPOT (N=101) or placebo (N=103)Hepatobiliary: steatorrhea; cholecystitis, cholangitis, pancreatitis, whichGeriatric Use104F or 40C) for up to 24 hours may be returned to the refrigeratoradministered by deep subcutaneous injection once every 4 weeks. Thehave sometimes required cholecystectomy Studies 3 and 4, conducted in patients with neuroendocrine tumors, did for continued storage and use at a later time. data below reflect exposure to SOMATULINE DEPOT in 101 patientsHypersensitivity: angioedema and anaphylaxisnot include sufficient numbers of patients aged 65 and over to determine 4.Prior to administration, inspect the SOMATULINE DEPOT syringewith GEP-NETs, including 87 patients exposed for at least 6 months andInjection site reactions: injection site abscess whether they respond differently from younger patients.visually for particulate matter and discoloration. Do not administer72 patients exposed for at least 1 year (median duration of exposureDRUG INTERACTIONS Other reported clinical experience has not identified differences in if particulate matter or discoloration is observed. The content of the22 months). Patients treated with SOMATULINE DEPOT had a medianInsulin and Oral Hypoglycemic Drugs: Lanreotide, like somatostatin andresponses between the elderly and younger patients. In general, dose prefilled syringe is a semi-solid phase having a gel-like appearance, withage of 64 years (range 30 to 83 years), 53% were men and 96% wereother somatostatin analogs, inhibits the secretion of insulin and glucagon.selection for an elderly patient should be cautious, usually starting at viscous characteristics and a color varying from white to pale yellow.Caucasian. Eighty-one percent of patients (83/101) in the SOMATULINETherefore, blood glucose levels should be monitored when SOMATULINEthe low end of the dosing range, reflecting the greater frequency of The supersaturated solution can also contain micro bubbles that canDEPOT arm and 82% of patients (82/103) in the placebo arm did notDEPOT treatment is initiated or when the dose is altered, and antidiabeticdecreased hepatic, renal, or cardiac function, and of concomitant disease clear up during injection. These differences are normal and do nothave disease progression within 6 months of enrollment and had nottreatment should be adjusted accordingly [see Warnings and Precautions (5.2)]. or other drug therapy.interfere with the quality of the product. received prior therapy for GEP-NETs. The rates of discontinuation due toCyclosporine: Concomitant administration of cyclosporine with Administration treatment-emergent adverse reactions were 5% (5/101 patients) in theSOMATULINE DEPOT may decrease the absorption of cyclosporine, andRenal Impairment1.Administer as a deep subcutaneous injection in the superior externalSOMATULINE DEPOT arm and 3% (3/103 patients) in the placebo arm. therefore, may necessitate adjustment of cyclosporine dose to maintainNeuroendocrine Tumors (NET)Gastroenteropancreatic Neuroendocrine quadrant of the buttock. Adverse reactions occurring in 5% and greater of patients receivingtherapeutic drug concentrations. [see Clinical Pharmacology (12.3)]. Tumors2.Alternate the injection site between the right and left sides from oneSOMATULINE DEPOT 120 mg (N=101) rated as either Any or SevereBromocriptine: Limited published data indicate that concomitantNo effect was observed in total clearance of lanreotide in patients with injection to the next. (defined as hazardous to well-being, significant impairment of function oradministration of a somatostatin analog and bromocriptine may increasemild to moderate renal impairment receiving SOMATULINE DEPOT 120 Recommended Dosage incapacitation) and at a higher rate than Placebo (N=103), also rated asthe absorption of bromocriptine [see Clinical Pharmacology (12.3)]. mg. Patients with severe renal impairment were not studied [see Clinical Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) either Any or Severe, respectively, were: Any Adverse Reactions (88%,Bradycardia-Inducing Drugs: Concomitant administration of bradycar- Pharmacology (12.3)].The recommended dosage of SOMATULINE DEPOT is 120 mg26%, 90%, 31%); Abdominal pain: includes upper/lower, abdominaldia-inducing drugs (e.g., beta-blockers) may have an additive effect on theHepatic Impairmentadministered every 4 weeks by deep subcutaneous injection. discomfort (34%*, 6%*, 24%*, 4%); Musculoskeletal pain: includesreduction of heart rate associated with lanreotide. Dosage adjustments ofNeuroendocrine Tumors (NET)Gastroenteropancreatic Neuroendocrine Carcinoid Syndrome myalgia, musculoskeletal discomfort, musculoskeletal pain, back painconcomitant drugs may be necessary.TumorsThe recommended dosage of SOMATULINE DEPOT is 120 mg(19%*, 2%*, 13%*, 2%*); Vomiting (19%*, 2%*, 9%*, 2%*); HeadacheDrug Metabolism Interactions: The limited published data availableSOMATULINE DEPOT has not been studied in patients with hepatic administered every 4 weeks by deep subcutaneous injection. If patients(16%, 0%, 11%, 1%); Injection site reaction: includes infusion siteindicate that somatostatin analogs may decrease the metabolic clearanceimpairment.are already being treated with SOMATULINE DEPOT for GEP-NETs, doextravasation, injection site discomfort, injection site granuloma, injectionsof compounds known to be metabolized by cytochrome P450 enzymes,PATIENT COUNSELING INFORMATIONnot administer an additional dose for the treatment of carcinoid syndrome. site hematoma, injection site hemorrhage, injection site induration,which may be due to the suppression of growth hormone. Since it cannotAdvise the patient to read the FDA-approved patient labeling (Patient CONTRAINDICATIONS injection site mass, injections site nodule, injection site pain, injection sitebe excluded that SOMATULINE DEPOT may have this effect, avoid otherInformation).SOMATULINE DEPOT is contraindicated in patients with history of apruritus, injection site rash, injection site reaction, injection site swellingdrugs mainly metabolized by CYP3A4 and which have a low therapeuticHypersensitivity Reactionshypersensitivity to lanreotide. Allergic reactions (including angioedema(15%, 0%, 7%, 0%); Hyperglycemia: includes diabetes mellitus, glucoseindex (e.g., quinidine, terfenadine). Drugs metabolized by the liver mayAdvise patients to immediately contact their healthcare provider if they and anaphylaxis) have been reported following administration oftolerance impaired, hyperglycemia, type 2 diabetes mellitus (14%*,be metabolized more slowly during SOMATULINE DEPOT treatment andexperience serious hypersensitivity reactions, such as angioedema or lanreotide [see Adverse Reactions (6.3)]. 0%, 5%, 0%); Hypertension: includes hypertensive crisis (14%*, 1%*,dose reductions of the concomitantly administered medications should beanaphylaxis [see Contraindications (4)]. 5%, 0%); Cholelithiasis (14%*, 1%*, 7%, 0%); Dizziness (9%, 0%, 2%*,considered [see Clinical Pharmacology (12.3)]. Cholelithiasis and Complications of CholelithiasisWARNINGS AND PRECAUTIONS 0%); Depression: includes depressed mood (7%, 0%, 1%, 0%); DyspneaUSE IN SPECIFIC POPULATIONS Advise patients to contact their healthcare provider if they experience Cholelithiasis and Complications of Cholelithiasis: SOMATULINE(6%, 0%, 1%, 0%). * Includes one or more serious adverse events (SAEs)Pregnancy signs or symptoms of gallstones (cholelithiasis) or complications of DEPOT may reduce gallbladder motility and lead to gallstonedefined as any event that results in death, is life threatening, results inRisk Summary gallstones (e.g., cholecystitis, cholangitis, or pancreatitis) [see Warnings formation; therefore, patients may need to be monitored periodicallyhospitalization or prolongation of hospitalization, results in persistent orLimited available data based on postmarketing case reports withand Precautions (5.1)].[see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. There havesignificant disability, results in congenital anomaly/birth defect, or maySOMATULINE DEPOT use in pregnant women are not sufficient toHyperglycemia and Hypoglycemia been postmarketing reports of cholelithiasis (gallstones) resulting injeopardize the patient and may require medical or surgical intervention todetermine a drug-associated risk of adverse developmental outcomes.Advise patients to immediately contact their healthcare provider if they complications, including cholecystitis, cholangitis, and pancreatitis, andprevent one of the outcomes listed. In animal reproduction studies, decreased embryo/fetal survival wasexperience signs or symptoms of hyper- or hypoglycemia [see Warnings requiring cholecystectomy in patients taking SOMATULINE DEPOT. IfCarcinoid Syndrome: The safety of SOMATULINE DEPOT 120 mg inobserved in pregnant rats and rabbits at subcutaneous doses 5- andand Precautions (5.2)].complications of cholelithiasis are suspected, discontinue SOMATULINEpatients with histopathologically confirmed neuroendocrine tumors2-times the maximum recommended human dose (MRHD) of 120 mg,Cardiovascular AbnormalitiesDEPOT and treat appropriately.and a history of carcinoid syndrome (flushing and/or diarrhea) wasrespectively (see Data). Advise patients to immediately contact their healthcare provider if they Hyperglycemia and Hypoglycemia: Pharmacological studies inevaluated in Study 4, a double-blind, placebo-controlled trial. PatientsThe estimated background risk of major birth defects and miscarriage forexperience bradycardia [see Warnings and Precautions (5.3)].animals and humans show that lanreotide, like somatostatin and otherwere randomized to receive SOMATULINE DEPOT (N=59) or placebothe indicated populations is unknown. All pregnancies have a backgroundLactation somatostatin analogs, inhibits the secretion of insulin and glucagon.(N=56) administered by deep subcutaneous injection once every 4 weeks.risk of birth defect, loss, or other adverse outcomes. In the U.S. generalAdvise women not to breastfeed during treatment with SOMATULINE Hence, patients treated with SOMATULINE DEPOT may experiencePatients in both arms of Study 4 had access to subcutaneous octreotide aspopulation, the estimated background risk of major birth defects andDEPOT and for 6 months after the last dose [see Use in Specific hypoglycemia or hyperglycemia. Blood glucose levels should berescue medication for symptom control. miscarriage in clinically recognized pregnancies is 2% to 4% and 15% toPopulations (8.2)].monitored when lanreotide treatment is initiated, or when the dose isAdverse reactions reported in Study 4 were generally similar to those20%, respectively. Infertilityaltered, and antidiabetic treatment should be adjusted accordingly [seereported in Study 3 for the GEP-NETs population. Adverse reactionsDataAdvise females of reproductive potential of the potential for reduced Adverse Reactions (6.1)]. occurring in Study 4 in 5% and greater of SOMATULINE DEPOT-treatedAnimal Data fertility from SOMATULINE DEPOT [see Use in Specific Populations (8.3)].Cardiovascular Abnormalities: In 81 patients with baseline heart rates ofpatients and occurring at least 5% more than in placebo-treatedA reproductive study in pregnant rats given 30 mg/kg of lanreotide by 60 beats per minute (bpm) or greater treated with SOMATULINE DEPOTpatients were headache (12% vs 5%, respectively), dizziness (7% vs 0%,subcutaneous injection every 2 weeks (5 times the human dose, basedManufactured by:in Study 3, the incidence of heart rate less than 60 bpm was 23% (19/81)respectively), and muscle spasm (5% vs 0%, respectively) by week 16. on body surface area comparisons) resulted in decreased embryo/fetalIpsen Pharma Biotechas compared to 16% (15/94) of placebo treated patients; 10 patients (12%)Immunogenicity: As with all peptides, there is potential forsurvival. A study in pregnant rabbits given subcutaneous injections of 0.4583870 Signes, Francehad documented heart rates less than 60 bpm on more than one visit.immunogenicity. The detection of antibody formation is highly dependentmg/kg/day (2 times the human therapeutic exposures at the maximumDistributed by:The incidence of documented episodes of heart rate less than 50 bpmon the sensitivity and specificity of the assay. Additionally, the observedrecommended dose of 120 mg, based on comparisons of relative bodyIpsen Biopharmaceuticals, Inc.as well as the incidence of bradycardia reported as an adverse event wasincidence of antibody (including neutralizing antibody) positivity in ansurface area) shows decreased fetal survival and increased fetal skeletal/ Cambridge, MA, 02142 USA 1% in each treatment group. Initiate appropriate medical management inassay may be influenced by several factors including assay methodology,soft tissue abnormalities.patients who develop symptomatic bradycardia. sample handling, timing of sample collection, concomitant medications,'