Lanreotide Acetate Drug Information
Generic name: LANREOTIDE ACETATE
Uses of Lanreotide Acetate
Acromegaly Lanreotide Injection 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.
Gastroenteropancreatic Neuroendocrine Tumors Lanreotide Injection 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.
Carcinoid Syndrome Lanreotide Injection is indicated for the treatment of adults with
carcinoid syndrome; when used, it reduces the frequency of short-acting somatostatin analog rescue therapy.
Dosage & Administration of Lanreotide Acetate
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Side Effects of Lanreotide Acetate
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. The safety of Lanreotide Injection was established from adequate and well-controlled studies of another lanreotide injection product . Adverse reactions observed in these adequate and well-controlled studies are described below. Acromegaly The data described below reflect exposure to lanreotide injection 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 White (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 lanreotide (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 lanreotide 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 lanreotide injection 60, 90, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 are provided in Table 1. Table 1: Adverse Reactions in Patients with Acromegaly at an Incidence of Greater than 5% with Lanreotide Overall and Occurring at Higher Rate than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 By Dose A patient is counted only once for each body system and preferred term.
Dictionary = WHOART. 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) Lanreotide Overall (N=83) Lanreotide 60 mg (N=34) Lanreotide 90 mg (N=36) Lanreotide 120 mg (N=37) Lanreotide Overall (N=107) N (%) N (%) N (%) N (%) N (%) N (%) Gastrointestinal System Disorders 1 (4%) 30 (36%) 12 (35%) 21 (58%) 27 (73%) 60 (56%) Diarrhea Abdominal pain Flatulence 0 1 (4%) 0 26 (31%) 6 (7%) 5 (6%) 9 (26%) 3 (9%) 0 (0%) 15 (42%) 6 (17%) 3 (8%) 24 (65%) 7 (19%) 5 (14%) 48 (45%) 16 (15%) 8 (7%) Application Site Disorders (Injection site mass/ pain/ reaction/ inflammation) 0 (0%) 5 (6%) 3 (9%) 4 (11%) 8 (22%) 15 (14%) 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 lanreotide injection. 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 lanreotide injection 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 . Table 2: Adverse Reactions in Lanreotide -Treated Patients with Acromegaly at an Incidence Greater than 5% in Overall Group Versus Adverse Reactions Reported in Studies 1 and 2 Dictionary = MedDRA
System Organ Class Number and Percentage of Patients Studies 1 & 2
(N=170) Overall Pooled Data (N=416) N % N % 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% of patients in the pooled Study 1 and 2 and in 3% of patients in the overall pooled studies. Hypertension occurred in 7% of patients in the pooled Study 1 and 2 and in 5% of patients in the overall pooled studies. Anemia occurred in 7% of patients in the pooled Study 1 and 2 and in 3% of patients in the overall pooled studies.
Gastrointestinal Adverse Reactions In the pooled clinical studies of lanreotide 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 lanreotide 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 lanreotide, cholelithiasis and gallbladder sludge were reported in 20% of the patients. Among 167 acromegalic patients treated with lanreotide 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 . 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 lanreotide. 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 lanreotide, 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 . 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 lanreotide could not be established because many of these patients had underlying cardiac disease . 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 lanreotide injection 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 lanreotide (N=101) or placebo (N=103) administered by deep subcutaneous injection once every 4 weeks.
The data below reflect exposure to lanreotide 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 lanreotide had a median age of 64 years (range 30 to 83 years), 53% were men and 96% were White. Eighty-one percent of patients (83/101) in the lanreotide 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 lanreotide 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 lanreotide injection 120 mg administered every 4 weeks and reported more commonly than placebo. Table 3: Adverse Reactions Occurring in 5% and Greater of Lanreotide -Treated Patients with GEP-NETs and at a Higher Rate Than in Placebo -Treated Patients in Study 3 1 Includes preferred terms of abdominal pain, abdominal pain upper/lower, abdominal discomfort 2 Includes preferred terms of myalgia, musculoskeletal discomfort, musculoskeletal pain, back pain 3 Includes 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 4 Includes preferred terms of diabetes mellitus, glucose tolerance impaired, hyperglycemia, type 2 diabetes mellitus 5 Includes preferred terms of hypertension, hypertensive crisis 6 Includes preferred terms of depression, depressed mood * Includes 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. ** Defined as hazardous to well-being, significant impairment of function or incapacitation Adverse Reaction Lanreotide 120 mg N=101 Placebo N=103 Any (%) Severe** (%) Any (%) Severe** (%) Any Adverse Reactions 88 26 90 31 Abdominal pain 1 34* 6* 24* 4 Musculoskeletal pain 2 19* 2* 13* 2 Vomiting 19* 2* 9* 2* Headache 16 0 11 1 Injection site reaction 3 15 0 7 0 Hyperglycemia 4 14* 0 5 0 Hypertension 5 14* 1* 5 0 Cholelithiasis 14* 1* 7 0 Dizziness 9 0 2* 0 Depression 6 7 0 1 0 Dyspnea 6 0 1 0 Carcinoid Syndrome The safety of lanreotide injection 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 lanreotide injection (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 lanreotide-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.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of lanreotide. 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. Gastrointestinal disorders: pancreatic exocrine insufficiency Hepatobiliary: steatorrhea; cholecystitis, cholangitis, pancreatitis, which have sometimes required cholecystectomy Hypersensitivity: angioedema and anaphylaxis Injection site reactions : injection site abscess
Warnings & Cautions for Lanreotide Acetate
Cholelithiasis and Complications of Cholelithiasis Lanreotide Injection may reduce gallbladder motility and
lead to gallstone formation; therefore, patients may need to be monitored periodically . There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis, cholangitis, and pancreatitis, and requiring cholecystectomy in patients taking lanreotide. If complications of cholelithiasis are suspected, discontinue Lanreotide Injection and treat appropriately.
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 Lanreotide Injection may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Lanreotide Injection treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly .
Cardiovascular Abnormalities
The most common overall cardiac adverse reactions observed in three pooled lanreotide injection cardiac studies in patients with acromegaly were sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%), and hypertension (12/217, 5.5%). In 81 patients with baseline heart rates of 60 beats per minute (bpm) or greater treated with lanreotide 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, Lanreotide Injection may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to Lanreotide Injection treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with Lanreotide Injection in patients with bradycardia.
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.
Monitoring: Laboratory Tests Acromegaly : Serum GH and
IGF-1 levels are useful markers of the disease and the effectiveness of treatment .
Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and
loose stools have been reported in patients receiving somatostatin analogs, including lanreotide products. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving Lanreotide Injection, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly.
Drug Interactions with Lanreotide Acetate
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 Lanreotide Injection treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly .
Cyclosporine
Concomitant administration of cyclosporine with Lanreotide Injection may decrease the absorption of cyclosporine, and therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic drug concentrations.
Bromocriptine Limited published data indicate that concomitant administration of a somatostatin analog
and bromocriptine may increase the absorption of bromocriptine .
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.
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 Lanreotide Injection 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 Lanreotide Injection treatment and dose reductions of the concomitantly administered medications should be considered .
Pregnancy Safety for Lanreotide Acetate
Pregnancy Risk Summary Limited available data based on post-marketing case reports with lanreotide 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 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.
Pediatric Use of Lanreotide Acetate
Pediatric Use The safety and effectiveness of Lanreotide Injection in pediatric patients have not been established.
Contraindications for Lanreotide Acetate
Lanreotide Injection is contraindicated in patients with history of a hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide . Hypersensitivity to lanreotide.
Clinical Studies of Lanreotide Acetate
Acromegaly
The effect of lanreotide 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 lanreotide 60, 90, or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of lanreotide 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 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 or lack of efficacy. 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 Patients with Acromegaly in Study 1 1 n=105, 2 n=102, 3 Age-adjusted *Last Observation Carried Forward Baseline N=107 Before Titration 1 (16 weeks) N=107 Before Titration 2 (32 weeks) N=105 Last Value Available* N=107 IGH ≤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
IGF-1 Normal 3 Number of Responders (%) 9 (8%) 58 (54%) 57
(54%) 62 (58%) Median IGF-1 ng/mL 775.0 332.0 1 316.5 2
IGF-1 Reduction Median % Reduction -- 52.3 1 54.5 2 55.4
IGF-1 Normal 3 + GH ≤2.5 ng/m L 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 lanreotide) 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 lanreotide 90 mg, at 4-week intervals.
Patients then entered a dose-titration phase where the dose of lanreotide 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, other reasons, or lack of efficacy. After 48 weeks of treatment with lanreotide 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 Patients with Acromegaly in Study 2 1 Age-adjusted, 2 N= 62, * Last Observation Carried Forward Baseline N=63 Before Titration 1 (12 wks) N=63 Before Titration 2 (28 wks) N=59 Last Value Available* N=63 IGF-1 Normal1 Number of Responders (%) 0 (0%) 17 (27%) 22 (37%) 27 (43%) Median IGF-1 ng/mL 689.0 382.0 334.0
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 78.6 2 IGF-1 normal 1 + 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 lanreotide among these subgroups. The limited number of patients in the different racial subgroups did not raise any concerns regarding efficacy of lanreotide in these subgroups.
Gastroenteropancreatic Neuroendocrine Tumors
The efficacy of lanreotide was established in a multicenter, randomized, double-blind, placebo-controlled trial of 204 patients with unresectable, well or moderately differentiated, metastatic or locally advanced, GEP-NETs. Patients were required to have non-functioning tumors without hormone-related symptoms. Patients were randomized 1:1 to receive lanreotide injection 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 White.
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 lanreotide arm and 27% of patients in the placebo arm who had hepatic involvement by tumor of greater than 25%. Patients in the lanreotide arm had a statistically significant improvement in PFS compared to patients receiving placebo (see Table 6 and Figure 1). Table 6: Efficacy Results in Patients with GEP-NETs in Study 3 1 NE = not reached at 22 months 2 Hazard Ratio is derived from a Cox stratified proportional hazards model Lanreotide Placebo n=101 n=103 Number of Events (%) 32 (31.7%) 60 (58.3%) Median PFS (months)(95% CI) NE 1 (NE, NE)
HR (95% CI) 0.47 2 Log-rank p-value <0.001 Figure 1: Kaplan-Meier Curves
of Progression-Free Survival in Patients with GEP-NETs in Study 3 Figure 30.jpg
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 lanreotide injection 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 White.
Patients in the lanreotide 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 lanreotide (and rescue medication) were numerically lower relative to patients treated with placebo (and rescue medication), but were not statistically significantly different via hierarchical testing.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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