Octreotide Acetate

Sandostatin Injection is a somatostatin analogue indicated: Acromegaly : To reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. ( 1.1 ) Carcinoid Tumors : For the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. ( 1.2 ) Vasoactive Intestinal Peptide Tumors (VIPomas) : For the treatment of profuse watery diarrhea associated with VIP-secreting tumors. ( 1.3 ) Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Sandostatin Injection; these trials were not optimally designed to detect such effects. ( 1.4 )

1.1 Acromegaly Sandostatin Injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses.

1.2 Carcinoid Tumors Sandostatin Injection is indicated for treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.

1.3 Vasoactive Intestinal Peptide Tumors Sandostatin Injection is indicated for the treatment of the profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas)-secreting tumors.

1.4 Important Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Sandostatin Injection; these trials were not optimally designed to detect such effects.

Injection: 50 mcg/mL, 100 mcg/mL, or 500 mcg/mL of octreotide (as acetate) as a clear solution in a single-dose ampul. Injection: 50 mcg/mL, 100 mcg/mL, or 500 mcg/mL of octreotide (as acetate) in a single-dose ampul. ( 3 )

Sensitivity to this drug or any of its components. Sensitivity to this drug or any of its components. ( 4 )

Cardiac Function Abnormalities : Increased risk for higher degree of atrioventricular blocks. Consider cardiac monitoring in patients receiving Sandostatin Injection intravenously. Bradycardia, arrhythmias, or conduction abnormalities may occur. Use with caution in at-risk patients. Dosage adjustment of cardiac medications may be necessary. ( 5.1 ) Cholelithiasis and Complications of Cholelithiasis : Monitor periodically. Discontinue if complications of cholelithiasis are suspected. ( 5.2 ) Glucose Metabolism : Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment. ( 5.3 ) Thyroid Function : Hypothyroidism may occur. Monitor thyroid levels periodically. ( 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. ( 5.5 )

5.1 Cardiac Function Abnormalities Complete Atrioventricular Block Patients who receive Sandostatin Injection intravenously may be at increased risk for higher degree atrioventricular blocks. In postmarketing reports, complete atrioventricular block was reported in patients receiving IV Sandostatin Injection during surgical procedures. In the majority of patients, Sandostatin Injection was given at higher than recommended doses and/or as a continuous IV infusion. The safety of continuous IV infusion has not been established in patients receiving Sandostatin Injection for the approved indications. Consider cardiac monitoring in patients receiving Sandostatin Injection intravenously. Other Cardiac Conduction Abnormalities Other cardiac conduction abnormalities have occurred during treatment with Sandostatin Injection. In acromegalic patients, bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during Sandostatin Injection therapy [see Adverse Reactions (6)] . Other electrocardiogram (ECG) changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R-wave progression. These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs, such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of Sandostatin Injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge.

5.2 Cholelithiasis and Complications of Cholelithiasis Sandostatin Injection may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis have been reported with Sandostatin Injection therapy. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin Injection for 12 months or longer was 52%. Less than 2% of patients treated with Sandostatin Injection for 1 month or less developed gallstones. One patient developed ascending cholangitis during Sandostatin Injection therapy and died. If complications of cholelithiasis are suspected, discontinue Sandostatin Injection and treat appropriately.

5.3 Hyperglycemia and Hypoglycemia Sandostatin Injection alters the balance between the counter-regulatory hormones, insulin, glucagon and GH, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during Sandostatin Injection therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other anti-diabetic agents. Hypoglycemia and hyperglycemia occurred on Sandostatin Injection in 3% and 16% of acromegalic patients, respectively [see Adverse Reactions (6)] . Severe hyperglycemia, subsequent pneumonia, and death following initiation of Sandostatin Injection therapy was reported in one patient with no history of hyperglycemia. Monitor glucose levels during Sandostatin Injection therapy. Adjust dosing of insulin or other anti-diabetic therapy accordingly.

5.4 Thyroid Function Abnormalities Octreotide suppresses secretion of thyroid stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T 4 ) is recommended during chronic therapy [see Adverse Reactions (6)] .

5.5 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including Sandostatin. 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 Sandostatin, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly.

5.6 Changes in Vitamin B12 Levels Depressed vitamin B 12 levels and abnormal Schilling’s tests have been observed in some patients receiving Sandostatin Injection therapy, and monitoring of vitamin B 12 levels is recommended during Sandostatin Injection therapy.

The following clinically significant adverse reactions are described elsewhere in the labeling: Complete Atrioventricular Block [see Warnings and Precautions (5.1)] Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.2)] Hyperglycemia and Hypoglycemia [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 (5.5)] Changes in Vitamin B12 Levels [see Warnings and Precautions (5.6)] Most common adverse reactions (incidence > 10%) in patients with acromegaly are gallbladder abnormalities, sinus bradycardia, diarrhea, loose stools, nausea, abdominal discomfort, hyperglycemia, and hypothyroidism. In other patients, most common adverse reactions (incidence > 10%) are gallbladder abnormalities. ( 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 trials of another drug and may not reflect the rates observed in practice. Gallbladder Abnormalities Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic Sandostatin Injection therapy [see Warnings and Precautions (5.1)] . In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin Injection for 12 months or longer was 52%. Less than 2% of patients treated with Sandostatin Injection for 1 month or less developed gallstones. Cardiac In acromegalics, sinus bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin Injection therapy [see Warnings and Precautions (5.1)] . Gastrointestinal Diarrhea, loose stools, nausea, and abdominal discomfort were each seen in 34% to 61% of acromegalic patients in U.S. studies. 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5% to 10% of patients with carcinoid tumors and VIPomas. The frequency of these symptoms was not dose related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and constipation were each seen in less than 10% of patients. In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness, and guarding. Hypo/Hyperglycemia Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients. Hypothyroidism In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in 8% and 4% required initiation of thyroid replacement therapy during Sandostatin Injection therapy [see Warnings and Precautions (5.4)] . In patients without acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has not been reported. Other Adverse Events Pain on injection was reported in 7.7%, headache in 6%, and dizziness in 5%. Pancreatitis was also observed [see Warnings and Precautions (5.2)] . Other Adverse Events 1% to 4% Other events, each observed in 1% to 4% of patients, included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat malabsorption, hair loss, visual disturbance, and depression. Anaphylactoid reactions, including anaphylactic shock, have been reported in several patients receiving Sandostatin Injection.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Sandostatin Injection. 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. Hepatobiliary : cholelithiasis, cholecystitis, cholangitis and pancreatitis, which have sometimes required cholecystectomy Gastrointestinal : intestinal obstruction, pancreatic exocrine insufficiency Hematologic : thrombocytopenia

The following drugs require monitoring and possible dose adjustment when used with Sandostatin Injection : Cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine. ( 7 ) Lutetium Lu 177 Dotatate Injection : Discontinue Sandostatin Injection at least 24 hours prior to each lutetium Lu 177 dotatate dose. ( 7.6 )

7.1 Cyclosporine Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of Sandostatin 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 Injection treatment is initiated or 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 might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of GH. 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 Injection at least 24 hours prior to each lutetium Lu 177 dotatate dose.

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 Injection 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 IV 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 IV 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 Human Data In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of Sandostatin Injection or 20 mg to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received IV 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 IV 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 GH 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 Injection 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 Injection, and any potential adverse effects on the breastfed child from Sandostatin Injection 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 Injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin Injection in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin Injection use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of Sandostatin Injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean body mass index (BMI) increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications, such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month.

8.5 Geriatric Use Clinical studies of Sandostatin Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment In patients with severe renal failure requiring dialysis, the half-life of Sandostatin may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment-Cirrhotic Patients In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)] .

Sandostatin Injection exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, 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).