Sandostatin LAR Depot

Warnings and Precautions, Steatorrhea and Malabsorption of Dietary Fats ( 5.5 ) 7/2024

1 INDICATIONS AND USAGE SANDOSTATIN LAR DEPOT 10 mg, 20 mg, and 30 mg is indicated in patients in whom initial treatment with Sandostatin Injection has been shown to be effective and tolerated. SANDOSTATIN LAR DEPOT is a somatostatin analogue indicated for: Treatment in patients who have responded to and tolerated Sandostatin Injection subcutaneous injection for: Acromegaly ( 1.1 ) Severe diarrhea/flushing episodes associated with metastatic carcinoid tumors ( 1.2 ) Profuse watery diarrhea associated with Vasoactive Intestinal Peptide (VIP) secreting tumors ( 1.3 ) 1.1 Acromegaly Long-term maintenance therapy in 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 GH and IGF-1 levels to normal [see Clinical Studies (14), Dosage and Administration (2)] . 1.2 Carcinoid Tumors Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors. 1.3 Vasoactive Intestinal Peptide Tumors (VIPomas) Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors. 1.4 Important Limitations of Use In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and SANDOSTATIN LAR DEPOT on tumor size, rate of growth and development of metastases, has not been determined.

2 DOSAGE AND ADMINISTRATION SANDOSTATIN LAR DEPOT should be administered by a trained healthcare provider. It is important to closely follow the mixing instructions included in the packaging. SANDOSTATIN LAR DEPOT must be administered immediately after mixing. Do not directly inject diluent without preparing suspension. The recommended needle size for administration of SANDOSTATIN LAR DEPOT is the 11⁄2” 19 gauge safety injection needle (supplied in the drug product kit). For patients with a greater skin to muscle depth, a size 2” 19 gauge needle (not supplied) may be used. SANDOSTATIN LAR DEPOT should be administered intramuscularly (IM) in the gluteal region at 4-week intervals. Administration of SANDOSTATIN LAR DEPOT at intervals greater than 4 weeks is not recommended. Injection sites should be rotated in a systematic manner to avoid irritation. Deltoid injections should be avoided due to significant discomfort at the injection site when given in that area. SANDOSTATIN LAR DEPOT should never be administered intravenously or subcutaneously. The following dosage regimens are recommended. Patients Not Currently Receiving Sandostatin Injection Subcutaneously: Acromegaly: 50 mcg three times daily Sandostatin Injection subcutaneously for 2 weeks followed by SANDOSTATIN LAR DEPOT 20 mg intragluteally every 4 weeks for 3 months ( 2.1 ) Carcinoid Tumors and VIPomas: Sandostatin Injection subcutaneously 100 to 600 mcg/day in 2-4 divided doses for 2 weeks followed by SANDOSTATIN LAR DEPOT 20 mg every 4 weeks for 2 months ( 2.2 ) Patients Currently Receiving Sandostatin Injection Subcutaneously: Acromegaly: 20 mg every 4 weeks for 3 months ( 2.1 ) Carcinoid Tumors and VIPomas: 20 mg every 4 weeks for 2 months ( 2.2 ) Renal Impairment, Patients on Dialysis: 10 mg every 4 weeks ( 2.3 ) Hepatic Impairment, Patients With Cirrhosis: 10 mg every 4 weeks ( 2.4 ) 2.1 Acromegaly Patients Not Currently Receiving Octreotide Acetate Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously in an initial dose of 50 mcg three times daily which may be titrated. Most patients require doses of 100 mcg to 200 mcg three times daily for maximum effect but some patients require up to 500 mcg three times daily. Patients should be maintained on Sandostatin Injection subcutaneous for at least 2 weeks to determine tolerance to octreotide acetate. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels and who tolerate the drug, can then be switched to SANDOSTATIN LAR DEPOT in the dosage scheme described below (Patients Currently Receiving Sandostatin Injection). Patients Currently Receiving Sandostatin Injection Patients currently receiving Sandostatin Injection can be switched directly to SANDOSTATIN LAR DEPOT in a dose of 20 mg given IM intragluteally at 4-week intervals for 3 months. After 3 months, dosage may be adjusted as follows: GH ≤ 2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain SANDOSTATIN LAR DEPOT dosage at 20 mg every 4 weeks GH > 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase SANDOSTATIN LAR DEPOT dosage to 30 mg every 4 weeks GH ≤ 1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce SANDOSTATIN LAR DEPOT dosage to 10 mg every 4 weeks If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended. In patients who have received pituitary irradiation, SANDOSTATIN LAR DEPOT should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, SANDOSTATIN LAR DEPOT therapy may be resumed. 2.2 Carcinoid Tumors and VIPomas Patients Not Currently Receiving Octreotide Acetate Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously. The suggested daily dosage for …

3 DOSAGE FORMS AND STRENGTHS SANDOSTATIN LAR DEPOT is available in single-dose kits for injectable suspension containing a 6-mL single-dose vial of 10 mg, 20 mg, or 30 mg strength, a prefilled syringe containing 2 mL of diluent, one vial adapter, and one sterile 11⁄2” 19 gauge safety injection needle. An instruction booklet for the preparation of drug suspension for injection is also included with each kit. For injectable suspension: strengths 10 mg per 6 mL, 20 mg per 6 mL, or 30 mg per 6 mL single-dose vials ( 3 )

4 CONTRAINDICATIONS None. None ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.1)] Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.2)] Thyroid Function Abnormalities [see Warnings and Precautions (5.3)] Cardiac Function Abnormalities [see Warnings and Precautions (5.4)] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.5)] Changes in Vitamin B12 Levels [see Warnings and Precautions (5.6)] Changes in Zinc Levels [see Warnings and Precautions (5.7)] Monitoring: Laboratory Tests [see Warnings and Precautions (5.8)] Drug Interactions [see Warnings and Precautions (5.9)] The most common adverse reactions, occurring in ≥ 20% of patients are: Acromegaly: diarrhea, cholelithiasis, abdominal pain, flatulence ( 6.1 ) Carcinoid Syndrome: back pain, fatigue, headache, abdominal pain, nausea, dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 trial of another drug and may not reflect the rates observed in practice. Acromegaly The safety of SANDOSTATIN LAR DEPOT in the treatment of acromegaly has been evaluated in three Phase 3 studies in 261 patients, including 209 exposed for 48 weeks and 96 exposed for greater than 108 weeks. SANDOSTATIN LAR DEPOT was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous Sandostatin Injection were switched to the LAR formulation followed by an open-label extension. The population age range was 14 to 81 years old and 53% were female. Approximately 35% of these acromegaly patients had not been treated with surgery and/or radiation. Most patients received a starting dose of 20 mg every 4 weeks intramuscularly. Dose was up or down titrated based on efficacy and tolerability to a final dose between 10 mg to 60 mg every 4 weeks. Table 1 below reflects adverse events from these studies regardless of presumed causality to study drug. Table 1. Adverse Events Occurring in ≥ 10% of Acromegalic Patients in the Phase 3 Studies Abbreviation: AEs, adverse events. WHO Preferred Term Phase 3 Studies (Pooled) Number (%) of Subjects with AEs 10 mg/20 mg/30 mg (n = 261) n (%) Diarrhea 93 (35.6) Abdominal Pain 75 (28.7) Flatulence 66 (25.3) Influenza-Like Symptoms 52 (19.9) Constipation 46 (17.6) Headache 40 (15.3) Anemia 40 (15.3) Injection-Site Pain 36 (13.8) Cholelithiasis 35 (13.4) Hypertension 33 (12.6) Dizziness 30 (11.5) Fatigue 29 (11.1) The safety of SANDOSTATIN LAR DEPOT in the treatment of acromegaly was also evaluated in a postmarketing randomized Phase 4 study. One-hundred four (104) patients were randomized to either pituitary surgery or 20 mg of SANDOSTATIN LAR DEPOT. All the patients were treatment naïve ( ‘de novo’ ). Crossover was allowed according to treatment response and a total of 76 patients were exposed to Sandostatin LAR. Approximately half of the patients initially randomized to SANDOSTATIN LAR DEPOT were exposed to SANDOSTATIN LAR DEPOT up to 1 year. The population age range was between 20 to 76 years old, 45% were female, 93% were Caucasian, and 1% Black. The majority of these patients were exposed to 30 mg every 4 weeks. Table 2 below reflects the adverse events occurring in this study regardless of presumed causality to study drug. Table 2. Adverse Events Occurring in ≥ 10% of Acromegalic Patients in Phase 4 Study WHO Preferred Term Phase 4 Study SANDOSTATIN LAR DEPOT N = 76 n (%) Phase 4 Study Surgery N = 64 n (%) Diarrhea 36 (47.4) 2 (3.1) Cholelithiasis 29 (38.2) 3 (4.7) Abdominal Pain 19 (25.0) 2 (3.1) Nausea 12 (15.8) 5 (7.8) Alopecia 10 (13.2) 5 (7.8) Injection-Site …

5.9 Drug Interactions Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine [see Drug Interactions (7.1)] .

7 DRUG INTERACTIONS The following drugs require monitoring and possible dose adjustment when used with SANDOSTATIN LAR DEPOT: Cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine ( 7 ) Lutetium Lu 177 Dotatate Injection: Discontinue SANDOSTATIN LAR DEPOT at least 4 weeks prior to each lutetium Lu 177 dotatate dose ( 7.6 ) 7.1 Cyclosporine Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. 7.2 Insulin and Oral Hypoglycemic Drugs Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when SANDOSTATIN LAR DEPOT treatment is initiated and when the dose is altered and anti-diabetic treatment should be adjusted accordingly. 7.3 Bromocriptine Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. 7.4 Other Concomitant Drug Therapy Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. 7.5 Drug Metabolism Interactions Limited published data 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 octreotide 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. 7.6 Lutetium Lu 177 Dotatate Injection Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue SANDOSTATIN LAR DEPOT at least 4 weeks prior to each lutetium Lu 177 dotatate dose.

8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy ( 8.3 ) 8.1 Pregnancy Risk Summary The limited data with SANDOSTATIN LAR DEPOT in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental effects were observed with intravenous administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7- and 13-times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA). Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre- and post-natal study of octreotide at intravenous doses below the MRHD based on BSA ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 In embryo-fetal development studies in rats and rabbits, pregnant animals received intravenous doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7- and 13-times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA. In a pre- and post-natal development rat study at intravenous doses of 0.02-1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of growth hormone inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA. 8.2 Lactation Risk Summary There is no information available on the presence of SANDOSTATIN LAR DEPOT in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that octreotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk ( see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SANDOSTATIN LAR DEPOT, and any potential adverse effects on the breastfed child from SANDOSTATIN LAR DEPOT or from the underlying maternal condition. Data Following a subcutaneous dose (1 mg/kg) of octreotide to lactating rats, transfer of octreotide into milk was observed at a low concentration compared to plasma (milk/plasma ratio of 0.009). 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with octreotide may lead to improved fertility. 8.4 Pediatric Use Safety and efficacy of SANDOSTATIN LAR DEPOT in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of SANDOSTATIN LAR DEPOT in pediatric patients under 6 years of age. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin use in children, most notably in children under 2 years of age. The relationship of these events to octreotide acetate has not been established as the majority of these pediatric patients had serious underlying comorbid conditions. The efficacy and safety of SANDOSTATIN LAR DEPOT was …

12.1 Mechanism of Action Octreotide exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea).

11 DESCRIPTION Octreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxy-methyl) propyl]-, cyclic (2→7)-disulfide; [R-(R*,R*)]. The molecular weight of octreotide is 1019.3 g/mol (free peptide, C 49 H 66 N 10 O 10 S 2 ) and its amino acid sequence is: SANDOSTATIN LAR DEPOT is available in a single-dose vial containing the sterile drug product, which when mixed with diluent, becomes a suspension that is given as a monthly intragluteal injection. The octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspendability. SANDOSTATIN LAR DEPOT is available as: sterile 6-mL single-dose vials in 3 strengths delivering 10 mg, 20 mg, or 30 mg octreotide-free peptide. Each single-dose vial of SANDOSTATIN LAR DEPOT delivers: *Equivalent to 10 mg, 20 mg, or 30 mg octreotide, respectively. Name of Ingredient 10 mg 20 mg 30 mg octreotide acetate 11.2 mg * 22.4 mg * 33.6 mg * D,L-lactic and glycolic acids copolymer 188.8 mg 377.6 mg 566.4 mg mannitol 41.0 mg 81.9 mg 122.9 mg Each prefilled syringe of diluent contains: carboxymethylcellulose sodium 14 mg mannitol 12 mg poloxamer 188 4 mg water for injection q.s. to 2 mL octreotide amino acid sequence

10 OVERDOSAGE Doses of 2.5 mg (2500 mcg) of Sandostatin Injection subcutaneously have caused hypoglycemia, flushing, dizziness, and nausea. Contact Poison Control (1-800-222-1222) for latest recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING SANDOSTATIN LAR DEPOT is available in single-dose kits containing a 6-mL single-dose vial of 10 mg, 20 mg or 30 mg strength, a prefilled syringe containing 2 mL of diluent, one vial adapter, and one sterile 11⁄2” 19 gauge safety injection needle. An instruction booklet for the preparation of drug suspension for injection is also included with each kit. Drug Product Kits 10 mg kit NDC 0078-0811-81 20 mg kit NDC 0078-0818-81 30 mg kit NDC 0078-0825-81 Demonstration kit 0078-9825-81 For prolonged storage, SANDOSTATIN LAR DEPOT should be stored at refrigerated temperatures between 2°C to 8°C (36°F to 46°F) and protected from light until the time of use. SANDOSTATIN LAR DEPOT drug product kit should remain at room temperature for 30 to 60 minutes prior to preparation of the drug suspension. However, after preparation the drug suspension must be administered immediately.