"An investigational long-acting form of recombinant human growth hormone (rhGH) given twice a month has achieved efficacy and safety at 2 years, new data show.
The novel long-acting recombinant human growth hormone fusion protein somav"...
The following adverse reactions to SOMATULINE DEPOT (lanreotide) Injection are discussed in greater detail in other sections of the labeling:
- Cholelithiasis and Gallbladder Sludge [see WARNINGS AND PRECAUTIONS]
- Hyperglycemia and Hypoglycemia [see WARNINGS AND PRECAUTIONS]
- Thyroid Function Abnormalities [see WARNINGS AND PRECAUTIONS]
- Cardiovascular Abnormalities [see WARNINGS AND PRECAUTIONS]
Clinical Studies 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 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 53.0 years of age (range 19-84 years). Fifty-four subjects (13%) were age 66-74 and eighteen subjects (4.3%) were ≥ 75 years of age. Patients were evenly matched for gender (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 < 10 ng/mL for 69% (183/265) of the patients and ≥ 10 ng/mL for 31% (82/265) of the patients.
The most commonly reported adverse reactions reported by > 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 mg, 90 mg, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 [see Clinical Studies] are provided in Table 1.
Table 1: Adverse Reactions at an Incidence > 5%
with Lanreotide Overall and Occurring at Higher Rate in Drug 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|
(N=25) N (%)
(N=83) N (%)
|Lanreotide 60 mg
(N=34) N (%)
|Lanreotide 90 mg
(N=36) N (%)
|Lanreotide 120 mg
(N=37) N (%)
(N=107) N (%)
|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 (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%)|
|A patient is counted only once for each body system and preferred term. Dictionary = WHOART.|
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 that occurred in 416 acromegalic patients treated with SOMATULINE DEPOT in seven studies. The analysis of safety compares adverse reaction rates of patients at baseline from the two efficacy studies, to the overall pooled data from seven studies. 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].
Table 2: Adverse Reactions at an Incidence > 5.0%
in Overall Group Reported in Studies 1 and 2
|System Organ Class||Number and Percentage of Patients|
|Studies 1 & 2
(N = 170)
|Overall Pooled Data
(N = 416)
|Patients with any Adverse Reactions||157||92||356||86|
|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|
|Nervous system disorders||34||20||80||19|
|Dictionary -MedDRA 7.1|
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 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 < 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, 17.4% had gallstones at baseline. New cholelithiasis was reported in 12.0% of patients. Cholelithiasis may be related to dose or duration of exposure [see WARNINGS AND PRECAUTIONS].
Injection Site Reactions
In the pooled clinical studies, injection site pain (4.1%) and injection site mass (1.7%) 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 (4.8%) 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].
Cardiac Adverse Reactions
In the pooled clinical studies, sinus bradycardia (3.1%) was the most frequently observed heart rate and rhythm disorder. All other cardiac adverse drug reactions were observed in < 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].
A comparative echocardiography study of lanreotide and another somatostatin analog demonstrated no difference in the development of new or worsening valvular regurgitation between the two treatments over one 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 ≥ 6 months and 72 patients exposed for ≥ 1 year (median duration of exposure 22.1 months). Patients treated with SOMATULINE DEPOT had a median age of 64 years (range 30-83 years), 53% were men and 96% were Caucasian. Eighty-one percent of patients (83/101) in the SOMATULINE DEPOT arm and eighty-two percent 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% in patients receiving SOMATULINE DEPOT 120 mg administered every 4 weeks and reported more commonly than placebo.
Table 3: Adverse Reactions Occurring in > 5% of
Somatuline Depot-Treated Patients and Occurring More Commonly Than in
Placebo-Treated Patients ( > 5% higher incidence) in Study 3
|Adverse Reaction||Somatuline Depot 120 mg
|Any (%)||Severe** (%)||Any (%)||Severe** (%)|
|Any Adverse Reactions||88||26||90||31|
|Injection site reaction3||15||0||7||0|
|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
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 ( < 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 3.7% (3 of 82) at 24 weeks, 10.4% (7 of 67) at 48 weeks, 10.5% (6 of 57) at 72 weeks, and 9.5% (8 of 84) at 96 weeks. Assessment for neutralizing antibodies was not conducted.
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 SOMATULINE DEPOT with the incidence of antibodies to other products may be misleading.
As adverse reactions experienced post-approval use 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.
The profile of reported adverse reactions for SOMATULINE DEPOT was consistent with that observed for treatment-related adverse reactions in the clinical studies. Those reported most frequently being gastrointestinal disorders (abdominal pain, diarrhea, and steatorrhea), hepatobiliary disorders (cholecystitis), and general disorders and administration site conditions (injection site reactions). Occasional cases of pancreatitis have also been observed.
Read the Somatuline Depot (lanreotide) Side Effects Center for a complete guide to possible side effects
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 treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly.
Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic levels.
Other Concomitant Drug Therapy
The pharmacological gastrointestinal effects of SOMATULINE DEPOT may reduce the intestinal absorption of concomitant drugs. Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the availability of bromocriptine.
Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dose adjustments of concomitant medication may be necessary.
Vitamin K absorption was not affected when concomitantly administered with lanreotide.
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 may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Drugs metabolized by the liver may be metabolized more slowly during lanreotide treatment and dose reductions of the concomitantly administered medications should be considered.
Read the Somatuline Depot Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/5/2015
Additional Somatuline Depot Information
Report Problems to the Food and Drug Administration
Find out what women really need.