In this section, you'll find the following information about the safety of Sandostatin® LAR Depot (octreotide acetate for injectable suspension):
Safety Profile of Sandostatin® LAR Depot
Safety data were obtained from all 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
- 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 reactions were generally mild to moderate and dose related1
- Short-lived injection-site pain after IM administration-discomfort lasting usually less than 1 hour-was reported in 2%, 9%, and 11% of patients, respectively, receiving 10 mg, 20 mg, and 30 mg of Sandostatin® LAR Depot1
Adverse Reactions1
Clinical Studies 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 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 14-81 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. 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 | |
|---|---|
| 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 post-marketing randomized phase 4 study. One hundred and four patients were randomized to either pituitary surgery or 20 mg of Sandostatin® LAR Depot. All the patients were treatment naïve ('de novo'). Cross over 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% African American. 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 | ||
|---|---|---|
| WHO Preferred Term |
Phase 4 Study SAS LAR® 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. Three 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) |
Only 2.6% of the patients on Sandostatin® Injection in U.S. clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving Sandostatin® LAR Depot discontinued therapy for a G.I. event.
In patients receiving Sandostatin® LAR Depot the incidence of diarrhea was dose related. 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% to 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. Diarrhea was reported as an adverse event in 14% of patients but since most of the patients had diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related 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% to 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 two 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.
Post-Marketing Experience
The following adverse reactions have been identified during the post-approval 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 post-marketing 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 post-marketing 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.
Important Safety Information
Carcinoid Syndrome:
Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and for the long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors in patients in whom initial treatment with immediate release Sandostatin® (octreotide acetate) Injection has been shown to be effective and tolerated.
Important Safety Information:
As with immediate release Sandostatin® Injection, the most frequently reported drug-related adverse events were biliary disorders (62%), gastrointestinal disorders (14% to 38%), and injection-site pain (20% to 50%). Hypoglycemia (4%), hyperglycemia (27%), sinus bradycardia (19%), conduction abnormalities (9%), and arrhythmias (3%) have been reported.
The controlled clinical trials that support the marketing clearance for Sandostatin® LAR Depot did not include determination of effect on tumor size or rate of growth. Sandostatin® LAR Depot is not indicated for tumor shrinkage.
Acromegaly
Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for 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.
Important Safety Information:
As with immediate release Sandostatin® Injection, the most frequently reported drug-related adverse events were biliary disorders (52%), gastrointestinal disorders (7% to 36%), and injection-site pain (2% to 11%). Hypoglycemia (2%), hyperglycemia (15%), and hypothyroidism (2%) have been reported. While not measured in acromegalic patients receiving Sandostatin® LAR Depot, ECG changes have been reported in patients receiving immediate release Sandostatin® Injection; the degree to which these abnormalities are related to octreotide acetate is not clear, as many acromegalics have cardiovascular disease. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
