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
Recommended Dosage Acromegaly
The recommended starting dosage of Lanreotide Injection is 90 mg given via the deep subcutaneous route, at 4-week intervals for 3 months. GH greater than 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled: increase dosage to 120 mg every 4 weeks. GH less than or equal to 1 ng/mL, IGF-1 normal, and clinical symptoms controlled: reduce dosage to 60 mg every 4 weeks.
Thereafter, the dosage should be adjusted according to the response of the patient as judged by a reduction in serum GH and/or IGF-1 levels; and/or changes in symptoms of acromegaly. GH and IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response. Continued monitoring of patient response with dosage adjustments for biochemical and clinical symptom control, as necessary, is recommended.
Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) The recommended dosage of Lanreotide Injection is 120 mg administered every 4 weeks by deep subcutaneous injection. Carcinoid Syndrome The recommended dosage of Lanreotide Injection is 120 mg administered every 4 weeks by deep subcutaneous injection. If patients are already being treated with Lanreotide Injection for GEP-NETs, do not administer an additional dose for the treatment of carcinoid syndrome.
Important Preparation and Administration Instructions
- The following instructions explain how to inject Lanreotide Injection: Read all instructions carefully before starting the injection. Follow this procedure exactly, as it may differ from your past experience. This is a single-dose pre-filled syringe with a single-use safety needle with a green needle shield (that cannot be removed) in a clear needle cap. ALL the medication must be injected SLOWLY over 20 seconds during the use. If you drop or damage the device in any way, please call 1-866-604-3268.
- Figure 1 The box includes the following items: Sterile needle pack containing Sterile needle Sterile Laminated pouch with sterile syringe pre-filled with LANREOTIDE INJECTION Instructions for Use Leaflet Prescribing Information Leaflet CAUTION fig
| NEVER TOUCH OR TRY TO OPEN THE GREEN NEEDLE SHIELD throughout the course of operation of the device. Green needle shield is NOT a removable cap or cover for the needle. Green needle shield will automatically activate once the injection is complete. Green needle shield is a self-operating safety lock mechanism. Needle is fully covered by green needle shield. Needle is visible only through a small window in the green needle shield. | |
| Inject medication slowly over 20 seconds. DO NOT rush the injection. | |
| Remove box from refrigerator 30 minutes prior to injecting. Product left in its sealed pouch at room temperature (not to exceed 104°F or 40°C) for up to 72 hours may be returned to the refrigerator for continued storage and usage at a later time. | |
| Stretch out the skin around injection site to make it flat and tight using your thumb and index finger. DO NOT pinch the skin around injection site. |
| A. BEFORE YOU START | |
| Figure 2 | A1. Remove LANREOTIDE INJECTION from the refrigerator 30 minutes prior to injecting (Figure 2). Do not open the sterile pouch yet. Note: Product left in its sealed pouch at room temperature (not to exceed 104° F or 40 °C) for up to 72 hours may be returned to the refrigerator for continued storage and use at a later time. |
| Figure 3 | A2. Wash your hands with soap and dry your hands thoroughly before starting (Figure 3). |
| Follow the doctor or institution’s policy on the use of surgical gloves during the procedure | |
| Figure 4 | A3. Before opening the sterile pouch, confirm that it is intact, and that the medication has not expired. The Syringe is sterile only if the pouch is sealed and undamaged. Do not use if the pouch is opened, tampered with or damaged. The expiry date is printed on the outer carton and the pouch - Do not use if the medication has expired. (Figure 4). |
| Or Figure 5 | A4. Make sure there is a clean surface for preparation. Find a clean, comfortable area for the patient to relax during procedure (Figure 5). It's important that the patient remains as still as possible during the injection. |
| Figure 6 | A5. Choose injection site - the sites are upper outer areas of the buttock as shown below It is very important that you only inject in one of the areas marked OK in the picture (Figure 6). |
| Alternate the injection site between the right and left side each time an injection of LANREOTIDE INJECTION is administered. | |
| Figure 7 | A6. Prepare the injection site by cleaning it with alcohol wipes (Figure 7). |
| Figure 8 | A7. Tear open the sterile pouch and take out the sterile pre-filled syringe (Figure 8). |
| B. PREPARE THE SYRINGE | |
| Figure 9 | B1: Open the sterile needle cap (Figure 9) The needle is sterile only if the needle cap is sealed and undamaged. Do not use if the needle cap is opened, tampered with or damaged. Hold the clear needle cap and pull the lid off. DO NOT TOUCH THE OPEN END OF THE NEEDLE CAP TO MAINTAIN STERILITY. |
| Figure 10 | B2: Remove the cap from the sterile syringe (Figure 10) With one hand, hold the syringe barrel steady (not the plunger ). With the other hand, remove the cap by twisting it. |
| B3: Prepare the assembly (Figure 11) Figure 11 | Hold the needle cap with one hand and the syringe barrel ( not the plunger ) with the other Carefully insert the open end of the syringe into the open end of the needle cap Twist the syringe barrel clockwise until it is tight to make sure that the syringe is well connected to the safety needle. ENSURE THAT BOTH PARTS OF THE DEVICE (SYRINGE AND NEEDLE) ARE COMPLETELY CONNECTED. The assembly is fully locked when you cannot turn it any further. |
| B4: Remove the needle from the needle cap Figure 12 | Hold the syringe barrel ( not the plunger ). Pull the needle straight out from the needle cap without twisting or turning (Figure 12). |
| Figure 13 | CAUTION: NEVER TOUCH THE GREEN NEEDLE SHIELD. THERE IS A RISK OF NEEDLE STICK INJURY. (Figure 13) Green needle shield is a self-operating safety lock mechanism and is not a removable cover or cap for the needle. It will activate once the injection is complete. The needle is fully covered by the green shield and is visible only through the small round window at the end of the shield. |
| C.PERFORM INJECTION | |
| C1: Position the syringe assembly Figure 14 | Stretch out the skin around the injection site to make it flat and tight using your thumb and index finger. (Figure 14) |
| Figure 15 | DO NOT pinch the skin (Figure 15) |
| Figure 16 | Hold the assembly by the lower part of the syringe barrel ( not the plunger ) with your other hand. Position the syringe assembly at a 90-degree angle to the skin. The green collar at the bottom of the green shield should be perpendicular to the injection site (Figures 16 and 17) Figure 17 |
| C2: Insert the needle (Figure 18) Figure 18 | Holding the skin flat and tight, push the syringe assembly firmly into the skin. Do NOT pinch the skin. Keep pushing until you reach a “hard stop” and only the green collar at the end of the green needle shield remains visible. Do NOT push the plunger yet. DO NOT aspirate. Keep pressing against the skin. During this step you should not see the needle. |
| C3: Push the top of the plunger (Figure 19) Figure 19 | Keep holding your hand on the syringe barrel to maintain a 90-degree angle throughout the injection. While keeping the syringe pressed against the skin, slowly press down the plunger. You may want to use both hands while applying pressure during the injection of drug. Continue slowly pushing the plunger over 20 seconds until the Plunger top touches the syringe end. DO NOT rush the injection. The medication is thicker and harder to push than you might expect. Pushing the plunger too fast may cause discomfort to the patient. While depressing the plunger, slowly count to 20 and CONTINUE STEADY PRESSURE on the plunger. You may find it helpful to say: a “1 one-thousand” b “2 one-thousand” c “3 one-thousand” up to “20 one-thousand” During this step, as the needle is lowering, the green needle shield will retract. You should only see the green collar of the green needle shield. During this step you should not see the needle. |
| D. REMOVE AND THROW AWAY THE SYRINGE ASSEMBLY | |
| Figure 20 | D1: Remove from the skin (Figure 20) Lift the syringe straight up and away from the body. The green needle shield will return to its original position and will fully cover the needle. |
| Figure 21 | D2: Apply gentle pressure (Figure 21) Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding. Do NOT rub or massage the injection site after administration. |
| Figure 22 | D3: Check needle (Figure 22) Check through the green needle shield’s round windows that the needle was not damaged during administration. If any damage or malfunction to the needle is suspected please contact 1-866-604-3268 |
| Figure 23 | D4: Throw away / Disposal (Figure 23) DO NOT remove needle from syringe Dispose of complete product in sharps disposal container Do not dispose of the syringe or needle in the regular trash. The syringe and needle are not reusable. |
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.
Patients were evenly matched for sex (205 males and 211 females). Of the patients reporting acromegaly, severity at baseline (N= 5) 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. 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 In Study 1, the adverse reactions of diarrhea, abdominal pain, and flatulence increased in incidence with increasing dose of lanreotide injection.
Patients with elevated GH and IGF-1 levels were either naive to somatostatin analog therapy or had undergone a 3-month washout. 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. 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. 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 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 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. 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
| 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%) |
| Dictionary = MedDRA 7.1 | ||||
| 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 |
| 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 |
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%). 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 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.
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 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.
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. The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations.
Table 5: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Patients with Acromegaly in Study 2 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. 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 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 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. 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.
| 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 | 75.5 |
| 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 | 326.0 |
| 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%) |
| 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 | 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 | 78.6 2 |
| IGF-1 normal 1 + GH ≤2.5 ng/mL | Number of Responders (%) | 0 (0%) | 14 (22%) | 20 (34%) | 24 (38%) |
| 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) | 16.6 (11.2, 22.1) |
| HR (95% CI) | 0.47 (0.30, 0.73) 2 | |
| Log-rank p-value | <0.001 | |
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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