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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.
The safety of Sandostatin LAR 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 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 10-60 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
|WHO Preferred Term||Phase 3 Studies (Pooled)
Number (%) of Subjects with AE's 10 mg/20 mg/30 mg
(n=261) n (%)
|Abdominal Pain||75 (28.7)|
|Influenza-Like Symptoms||52 (19.9)|
|Injection Site Pain||36 (13.8)|
The safety of Sandostatin LAR 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. All the patients were treatment na´ve ('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 were exposed to Sandostatin LAR 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 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 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)|
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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 G.I.
|Adverse Event||Sandostatin Injection S.C.Three Times Daily
|Sandostatin LAR Depot Every 28 Days
|Abdominal Pain or Discomfort||50||(43.9)||76||(29.1)|
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 a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27%-38% and constipation or vomiting in 15%-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%-25% at a 10-mg dose and about 30%-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.
Carcinoid and VIPomas
The safety of Sandostatin LAR in the treatment of carcinoid tumors and VIPomas has been evaluated in one phase 3 study. Study 1 randomized 93 patients with carcinoid syndrome to Sandostatin LAR 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label Sandostatin Injection subcutaneously. The population age range was between 25-78 years old and 44% were female, 95% were Caucasian and 3% Black. All the patients had symptom control on their previous Sandostatin subcutaneous treatment. 80 patients finished the initial 24 weeks of Sandostatin exposure in Study 1. In Study 1, comparable numbers of patients were randomized to each dose. Table 4 below reflects the adverse events occurring in > 15% of patients regardless of presumed causality to study drug.
Table 4: Adverse Events Occurring in ≥ 15% of Carcinoid Tumor and VIPoma Patients in Study 1
|WHO Preferred Term||Number (%) of Subjects with (n=93)|
|Abdominal Pain||8 (30.8)||8 (35.4)||2 (10.0)||5 (20.0)|
|Arthropathy||5 (19.2)||2 (9.1)||3 (15.0)||2 (8.0)|
|Back Pain||7 (26.9)||6 (27.3)||2 (10.0)||2 (8.0)|
|Dizziness||4 (15.4)||4 (18.2)||4 (20.0)||5 (20.0)|
|Fatigue||3 (11.5)||7 (31.8)||2 (10.0)||2 (8.0)|
|Flatulence||3 (11.5)||2 (9.1)||2 (10.0)||4 (16.0)|
|Generalized Pain||4 (15.4)||2 (9.1)||3 (15.0)||1 (4.0)|
|Headache||5 (19.2)||4 (18.2)||6 (30.0)||4(16.0)|
|Musculoskeletal Pain||4 (15.4)||0||1 (5.0)||0|
|Myalgia||0||4 (18.2)||1 (5.0)||1 (4.0)|
|Nausea||8 (30.8)||9 (40.9)||6 (30.0)||6 (24.0)|
|Rash||1 (3.8)||0||3 (15.0)||0|
|Sinusitis||4 (15.4)||0||1 (5.0)||3 (12.0)|
|URTI||6 (23.1)||4 (18.2)||2 (10.0)||3 (12.0)|
|Vomiting||3 (11.5)||0||0||4 (16.0)|
In clinical trials, 62% of malignant carcinoid patients who received Sandostatin LAR Depot for up to 18 months developed new biliary abnormalities including jaundice, gallstones, sludge, and dilatation. New gallstones occurred in a total of 24% of patients.
Glucose Metabolism - Hypoglycemia/Hyperglycemia
In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with Sandostatin LAR Depot [see WARNINGS AND PRECAUTIONS].
In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported [see WARNINGS AND PRECAUTIONS].
Electrocardiograms were performed only in carcinoid patients receiving Sandostatin LAR Depot. In carcinoid syndrome patients, sinus bradycardia developed in 19%, conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see WARNINGS AND PRECAUTIONS].
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.
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.
Read the Sandostatin LAR (octreotide acetate injection) Side Effects Center for a complete guide to possible side effects
Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.
Insulin and Oral Hypoglycemic Drugs
Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Sandostatin LAR treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.
Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.
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.
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.
Read the Sandostatin LAR Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 10/10/2011
This monograph has been modified to include the generic and brand name in many instances.
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