Octreotide acetate for injectable suspension 10 mg, 20 mg, and 30 mg is indicated in patients in whom initial treatment with octreotide acetate injection has been shown to be effective and tolerated. Octreotide acetate for injectable suspension is a somatostatin analogue indicated for: Treatment in patients who have responded to and tolerated octreotide acetate injection subcutaneous injection for:
Acromegaly ( 1.1 )
Severe diarrhea/flushing episodes associated with metastatic carcinoid tumors ( 1.2 )
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) ] .
1.2Carcinoid Tumors
Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.
1.3Vasoactive Intestinal Peptide Tumors (VIPomas)
Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.
1.4Important Limitations of Use
In patients with carcinoid syndrome and VIPomas, the effect of octreotide acetate injection and octreotide acetate for injectable suspension on tumor size, rate of growth and development of metastases, has not been determined.
Contraindications
None. None ( 4 )
Warnings and precautions
Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected ( 5.1 )
Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment ( 5.2 )
Cardiac Function: Bradycardia, arrhythmia, or conduction abnormalities may occur. Use with caution in at-risk patients ( 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 )
5.1Cholelithiasis and Complications of Cholelithiasis
Octreotide acetate for injectable suspension may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis, cholangitis, pancreatitis and requiring cholecystectomy in patients taking octreotide acetate for injectable suspension [see Adverse Reactions (6) ] .
Patients should be monitored periodically. If complications of cholelithiasis are suspected, discontinue octreotide acetate for injectable suspension and treat appropriately.
5.2Hyperglycemia and Hypoglycemia
Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone (GH), which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when octreotide acetate for injectable suspension treatment is initiated, or when the dose is altered. Anti-diabetic treatment should be adjusted accordingly [see Adverse Reactions (6) ] .
5.3Thyroid Function Abnormalities
Octreotide suppresses the 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 octreotide therapy [see Adverse Reactions (6) ] .
5.4Cardiac Function Abnormalities
In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other electrocardiogram (ECG) changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease.
Dose adjustments in drugs such as beta-blockers that have bradycardic effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of octreotide acetate injection-therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge [see Adverse Reactions (6) ] .
5.5Steatorrhea and Malabsorption of Dietary Fats
New onset steatorrhea, stool discoloration and loose stool have been reported in patients receiving somatostatin analogs, including octreotide acetate for injectable suspension. 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 octreotide acetate for injectable suspension, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly .
5.6Changes in Vitamin B12 Levels
Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with octreotide acetate for injectable suspension.
5.7Changes in Zinc Levels
Octreotide has been investigated for the reduction of excessive fluid loss from the GI tract in patients with conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is reversed. Patients on TPN and octreotide should have periodic monitoring of zinc levels.
5.8Monitoring: Laboratory Tests
Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy [see Dosage and Administration (2.1 , 2.2) ] . Acromegaly: Growth Hormone, IGF-1 (somatomedin C) Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P VIPoma: VIP (plasma vasoactive intestinal peptide) baseline and periodic total and/or free T 4 measurements should be performed during chronic therapy
5.9Drug 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) ] .
Interactions
The following drugs require monitoring and possible dose adjustment when used with octreotide acetate for injectable suspension: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine ( 7 )
Lutetium Lu 177 Dotatate Injection: Discontinue octreotide acetate for injectable suspension at least 4 weeks prior to each lutetium Lu 177 dotatate dose ( 7.6 )
7.1Cyclosporine
Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.
7.2Insulin and Oral Hypoglycemic Drugs
Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when octreotide acetate for injectable suspension treatment is initiated and when the dose is altered and anti-diabetic treatment should be adjusted accordingly.
7.3Bromocriptine
Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.
7.4Other 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.
7.5Drug 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.
7.6Lutetium Lu 177 Dotatate Injection
Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue octreotide acetate for injectable suspension at least 4 weeks prior to each lutetium Lu 177 dotatate dose.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
The limited data with octreotide acetate for injectable suspension 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 to 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.
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:
Carcinoid Syndrome: back pain, fatigue, headache, abdominal pain, nausea, dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 trial of another drug and may not reflect the rates observed in practice. Acromegaly The safety of octreotide acetate for injectable suspension 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.
Octreotide acetate for injectable suspension was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous octreotide acetate 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 octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension. All the patients were treatment naïve ( ‘de novo’ ). Crossover was allowed according to treatment response and a total of 76 patients were exposed to octreotide acetate for injectable suspension. Approximately half of the patients initially randomized to octreotide acetate for injectable suspension were exposed to octreotide acetate for injectable suspension 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 Octreotide Acetate for Injectable Suspension 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 Pain 9 (11.8) 0 Abdominal Pain Upper 8 (10.5) 0 Headache 8 (10.5) 6 (9.4) Epistaxis 0 7 (10.9) Gallbladder Abnormalities Single doses of octreotide acetate injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers.
In clinical trials with octreotide acetate injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide acetate, 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 octreotide acetate injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related to age, sex, or dose but was related to duration of exposure.
In clinical trials, 52% of acromegalic patients, most of whom received octreotide acetate for injectable suspension for 12 months or longer, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge, and dilatation. The incidence of new cholelithiasis was 22%, of which 7% were microstones. Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide therapy or following its withdrawal.
One patient developed ascending cholangitis during octreotide acetate injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide acetate, 1% of patients developed acute symptoms requiring cholecystectomy. Glucose Metabolism - Hypoglycemia/Hyperglycemia In acromegaly patients treated with either octreotide acetate injection or octreotide acetate for injectable suspension, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients [see Warnings and Precautions (5.2) ] .
Hypothyroidism In acromegaly patients receiving octreotide acetate injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving octreotide acetate injection. In acromegalic patients treated with octreotide acetate for injectable suspension, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving octreotide acetate for injectable suspension required initiation of thyroid hormone replacement therapy [see Warnings and Precautions (5.3) ] .
Cardiac In acromegalic patients, sinus bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during octreotide acetate injection-therapy. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5.4) ] . Gastrointestinal The most common symptoms are gastrointestinal.
The overall incidence of the most frequent of these symptoms in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 3. Table 3. Number (%) of Acromegalic Patients With Common GI Adverse Events Adverse Event Octreotide Acetate Injection S.C. Three Times Daily n = 114 Octreotide Acetate for Injectable Suspension Every 28 Days n = 261 n % n % Diarrhea 66 (57.9) 95 (36.4) Abdominal Pain or Discomfort 50 (43.9) 76 (29.1) Nausea 34 (29.8) 27 (10.3) Flatulence 15 (13.2) 67 (25.7) Constipation 10 (8.8) 49 (18.8) Vomiting 5 (4.4) 17 (6.5) Only 2.6% of the patients on octreotide acetate injection in US clinical trials discontinued therapy due to these symptoms.
No acromegalic patient receiving octreotide acetate for injectable suspension discontinued therapy for a GI event. In patients receiving octreotide acetate for inje
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Composition
Active ingredients
OCTREOTIDE ACETATE EQ 30MG BASE/VIAL
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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