In this section, you'll find the following information about the safety of Sandostatin® LAR Depot:
Safety Profile of Sandostatin® LAR Depot
Safety data were obtained from 3 trials with the following results:
- Clinical symptoms of acromegaly were reduced during treatment1
- The body system most commonly affected in acromegalic patients treated for 12 to 30 months was the GI system1
- Severe diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with Sandostatin® LAR Depot, with new cases occurring infrequently later in treatment1
- Many other adverse events also diminished in frequency with continued therapy, with no statistically significant differences noted between the 20-mg and 30-mg groups2
- Local tolerability at the injection site was demonstrated; injection-site pain—lasting usually less than 1 hour—was reported in 2%, 9%, and 11% of patients receiving, respectively, 10 mg, 20 mg, and 30 mg of Sandostatin® LAR Depot1
Adverse Reactions1
Acromegaly
The safety of Sandostatin® LAR Depot in the treatment of acromegaly has been evaluated in 3 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-60 mg every 4 weeks. The table below reflects adverse events from these studies regardless of presumed causality to study drug.
| Adverse Events Occurring in ≥10% of Acromegalic Patients in the Phase 3 Studies | |
|---|---|
| Adverse Event |
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. 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 Depot. 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 20-76 years old and 45% were female, 93% were Caucasian, and 1% black. The majority of these patients were exposed to 30 mg every 4 weeks. Table below reflects the adverse events occurring in this study regardless of presumed causality to study drug.
| Adverse Events Occurring in ≥10% of Acromegalic Patients in Phase 4 Study | ||
|---|---|---|
| Adverse Event |
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 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 Sandostatin® Injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with Sandostatin® Injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide, 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%. 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 Sandostatin® LAR Depot 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 Sandostatin® Injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide, 1% of patients developed acute symptoms requiring cholecystectomy.
Glucose Metabolism—Hypoglycemia/Hyperglycemia
In acromegaly patients treated with either Sandostatin® Injection or Sandostatin® LAR Depot, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients.
Hypothyroidism
In acromegaly patients receiving Sandostatin® Injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin® Injection. In acromegalics treated with Sandostatin® LAR Depot, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving Sandostatin® LAR Depot required initiation of thyroid hormone replacement therapy.
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. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease.
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 the table below.
| Number (%) of Acromegalic Patients with Common G.I. Adverse Events | ||
|---|---|---|
| Adverse Event |
Sandostatin® Injection S.C. 3 Times Daily (n=114) n (%) |
Sandostatin® LAR Depot Every 28 Days (n=261) 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) |
2.6% of the patients on Sandostatin® Injection in US clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving Sandostatin® LAR Depot discontinued therapy for a GI event.
In patients receiving Sandostatin® LAR Depot the incidence of severe diarrhea was dose related. Severe diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with Sandostatin® LAR Depot. Thereafter, new cases of these events were uncommon. The vast majority of these events were mild-to-moderate in severity.
In rare instances gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding.
Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4%-6% of patients.
In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27% to 38% and constipation or vomiting in 15% to 21% of patients treated with Sandostatin® LAR Depot. Severe diarrhea was reported as an adverse event in 14% of patients but since most of the patients had severe diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related severe diarrhea.
Pain at the Injection Site
Pain on injection, which is generally mild-to-moderate, and short-lived (usually about 1 hour) is dose related, being reported by 2%, 9%, and 11% of acromegalics receiving doses of 10 mg, 20 mg and 30 mg, respectively, of Sandostatin® LAR Depot. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20%-25% at a 10-mg dose and about 30% to 50% at the 20-mg and 30-mg dose.
Antibodies to Octreotide
Studies to date have shown that antibodies to octreotide develop in up to 25% of patients treated with octreotide acetate. These antibodies do not influence the degree of efficacy response to octreotide; however, in 2 acromegalic patients who received Sandostatin® Injection, the duration of GH suppression following each injection was about twice as long as in patients without antibodies. It has not been determined whether octreotide antibodies will also prolong the duration of GH suppression in patients being treated with Sandostatin® LAR Depot.
Other Clinical Studies Adverse Events
Other clinically significant adverse events (relationship to drug not established) in acromegalic and/or carcinoid syndrome patients receiving Sandostatin® LAR Depot were malignant hyperpyrexia, cerebral vascular disorder, rectal bleeding, ascites, pulmonary embolism, pneumonia, and pleural effusion.
Postmarketing Experience
The following adverse reactions have been identified during the postapproval use of Sandostatin®. 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.
Myocardial infarction has been observed in the postmarketing setting, mainly in patients with cardiovascular risk factors. Hypoadrenalism has been reported in some reports in patients 18 months of age and under.
Additional events reported in the postmarketing setting include anaphylactoid reactions, including anaphylactic shock, cardiac arrest, renal failure, renal insufficiency, convulsions, atrial fibrillation, aneurysm, hepatitis, increased liver enzymes, gastrointestinal hemorrhage, pancreatitis, pancytopenia, thrombocytopenia, arterial thrombosis of the arm, retinal vein thrombosis, intracranial hemorrhage, hemiparesis, paresis, deafness, visual field defect, aphasia, scotoma, status asthmaticus, pulmonary hypertension, diabetes mellitus, intestinal obstruction, peptic/gastric ulcer, appendicitis, creatinine increased, CK increased, arthritis, joint effusion, pituitary apoplexy, breast carcinoma, suicide attempt, paranoia, migraines, urticaria, facial edema, generalized edema, hematuria, orthostatic hypotension, Raynaud's syndrome, glaucoma, pulmonary nodule, pneumothorax aggravated, cellulitis, Bell's palsy, diabetes insipidus, gynecomastia, galactorrhea, gallbladder polyp, fatty liver, abdomen enlarged, libido decrease, and petechiae.
INDICATIONS AND USAGE
Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for patients in whom initial treatment with immediate release Sandostatin® (octreotide acetate) Injection has been shown to be effective and tolerated for:
- Long-term maintenance therapy in acromegalic patients who have had 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).
- Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.
- Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.
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.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions:
- Gallbladder abnormalities may occur: Patients should be monitored periodically.
- Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Blood glucose levels should be monitored when Sandostatin LAR Depot treatment is initiated or when the dose is altered. Antidiabetic treatment should be adjusted accordingly.
- Thyroid Function: Hypothyroidism may occur. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended.
- Cardiac Function: Bradycardia, arrhythmia, conduction abnormalities, and other EKG changes may occur. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Use with caution in at-risk patients.
- Nutrition: Octreotide may alter absorption of dietary fats. Monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot. Patients on total parenteral nutrition (TPN) and octreotide should have periodic monitoring of zinc levels.
Drug Interactions: The following drugs require monitoring and possible dose adjustment when used with Sandostatin LAR Depot: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, bromocriptine. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Drugs mainly metabolized by CYP3A4 and which have a low therapeutic index should be used with caution.
Adverse Reactions: The most common adverse reactions occurring in patients receiving Sandostatin LAR Depot are:
- Acromegaly: biliary abnormalities (52%), diarrhea (36-48%), cholelithiasis (13-38%), abdominal pain or discomfort (11-29%), flatulence (26%), influenza-like symptoms (20%), constipation (19%), headache (15%), anemia (15%), hyperglycemia (15%), injection site pain (2-14%), hypertension (13%), dizziness (12%), fatigue (11%), nausea (10%), vomiting (7%), hypothyroidism (2%), hypoglycemia (2%), and goiter (2%).
- Carcinoid Tumors and VIPomas: biliary abnormalities (62%), injection site pain (20-50%), nausea (24-41%), abdominal pain (10-35%), fatigue (8-32%), headache (16-30%), hyperglycemia (27%), back pain (8-27%), constipation or vomiting (15-21%), dizziness (18-20%), sinus bradycardia (19%), pruritus (18%), URTI (10-18%), myalgia (4-18%), flatulence (9-16%), arthropathy (8-15%), rash (15%), generalized pain (4-15%), sinusitis (5-12%), conduction abnormalities (9%), hypoglycemia (4%), and arrhythmia (3%).
