Lanreotide Injection 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 )
1.1Acromegaly 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.
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.
1.3Carcinoid 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.
Contraindications
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 [ see Adverse Reactions ( 6.3 )] . Hypersensitivity to lanreotide. ( 4 )
Warnings and precautions
Cholelithiasis and Complications of Cholelithiasis : Monitor periodically. Discontinue if complications of cholthiasis are suspected. 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 ) Steatorrhea and Malabsorption of Dietary Fats : New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency. ( 5.6 )
5.1Cholelithiasis and Complications of Cholelithiasis Lanreotide
Injection 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 )] . 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.
5.2Hyperglycemia 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 [see Adverse Reactions ( 6.1 )] .
5.3Cardiovascular 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%) [see Adverse Reactions ( 6.1 )]. 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.
5.4Thyroid 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.
5.5Monitoring: Laboratory Tests
Acromegaly : Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of treatment [see Dosage and Administration ( 2.1 )] .
5.6Steatorrhea 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.
Interactions
Cyclosporine : Lanreotide Injection may decrease the absorption of cyclosporine. Dosage adjustment of cyclosporine may be needed. ( 7.2 ) Bromocriptine : Lanreotide Injection may increase the absorption of bromocriptine. ( 7.3 ) Bradycardia-Inducing Drugs (e.g., beta-blockers) : Lanreotide Injection may decrease heart rate. Dosage adjustment of the coadministered drug may be necessary. ( 7.3 )
7.1Insulin 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 [see Warnings and Precautions ( 5.2 )] .
7.2Cyclosporine
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. [see Clinical Pharmacology ( 12.3 )]
7.3Bromocriptine
Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the absorption of bromocriptine [see Clinical Pharmacology ( 12.3 )] .
7.4Bradycardia-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.
7.5Drug 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 [see Clinical Pharmacology ( 12.3 )] .
Pregnancy and breastfeeding
8.1Pregnancy 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.
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions ( 5.1 )] Hyperglycemia and Hypoglycemia [see Warnings and Precautions ( 5.2 )] Cardiovascular Abnormalities [see Warnings and Precautions ( 5.3 )] Thyroid Function Abnormalities [see Warnings and Precautions ( 5.4 )] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions ( 5.6 )] Most common adverse reactions are: Acromegaly : (>5%): diarrhea, cholelithiasis, abdominal pain, nausea and injection site reactions.
( 6.1 ) GEP-NET : (>10%): abdominal pain, musculoskeletal pain, vomiting, headache, injection site reaction, hyperglycemia, hypertension, and cholelithiasis. ( 6.1 ) Carcinoid Syndrome : (≥5% and at least 5% greater than placebo): headache, dizziness and muscle spasm. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. Inc. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical 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 [see Clinical Studies ( 14 )] .
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 [see Clinical Studies ( 14.1 )] 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.
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 [see Clinical Studies ( 14.1 )] .
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
7.1System 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% (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 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 [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 lanreotide. In a spe
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