WARNINGS
Adverse events that have been reported in patients receiving Sandostatin® (octreotide acetate) Injection can also be expected in patients receiving Sandostatin LAR® Depot (octreotide acetate for injectable suspension). Incidence figures in the WARNINGS and ADVERSE REACTIONS sections, below, are those obtained in clinical trials of Sandostatin® Injection and Sandostatin LAR® Depot.
GALLBLADDER AND RELATED EVENTS
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.
In clinical trials 62% of malignant carcinoid patients who received Sandostatin LAR® Depot for up to 18 months developed new biliary abnormalities including gallstones, sludge and dilatation. New gallstones occurred in a total of 24% of patients.
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.
PRECAUTIONS (See ADVERSE REACTIONS .)
GENERAL
Growth hormone secreting tumors may sometimes expand and cause serious complications (e.g., visual field defects). Therefore, all patients with these tumors should be carefully monitored.
Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia or hyperglycemia. Octreotide also suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with octreotide.
GLUCOSE METABOLISM
The hypoglycemia or hyperglycemia which occurs during octreotide therapy is usually mild, but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. Severe hyperglycemia, subsequent pneumonia, and death following initiation of Sandostatin® (octreotide acetate) Injection therapy was reported in one patient with no history of hyperglycemia (see ADVERSE REACTIONS).
In patients with concomitant Type I diabetes mellitus, Sandostatin Injection and Sandostatin LAR® Depot (octreotide acetate for injectable suspension) are likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in these patients. In non-diabetics and Type II diabetics with partially intact insulin reserves, Sandostatin Injection or Sandostatin LAR Depot administration may result in decreases in plasma insulin levels and hyperglycemia. It is therefore recommended that glucose tolerance and antidiabetic treatment be periodically monitored during therapy with these drugs.
THYROID FUNCTION
Hypothyroidism has been reported in acromegaly and carcinoid patients receiving octreotide therapy. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic octreotide therapy (see ADVERSE REACTIONS).
CARDIAC FUNCTION
In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other EKG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease (see PRECAUTIONS). Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, 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 (see ADVERSE REACTIONS).
NUTRITION
Octreotide may alter absorption of dietary fats in some patients.
Depressed vitamin B12 levels and abnormal Schilling's tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR® Depot.
Octreotide has been investigated for the reduction of excessive fluid loss from the G.I. 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.
INFORMATION FOR PATIENTS
Patients with carcinoid tumors and VIPomas should be advised to adhere closely to their scheduled return visits for reinjection in order to minimize exacerbation of symptoms.
Patients with acromegaly should also be urged to adhere to their return visit schedule to help assure steady control of GH and IGF-1 levels.
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:
Acromegaly: Growth Hormone, IGF-1 (somatomedin C)
Responsiveness to octreotide may be evaluated by determining growth hormone levels at 1-4 hour intervals for 8-12 hours after subcutaneous injection of Sandostatin® Injection (not Sandostatin LAR® Depot). Alternatively, a single measurement of IGF-1 (somatomedin C) level may be made two weeks after initiation of Sandostatin® Injection or dosage change. After patients are switched from Sandostatin® Injection to Sandostatin LAR® Depot, GH and IGF-1 determinations may be made after 3 monthly injections of Sandostatin LAR® Depot. (Steady-state serum levels of octreotide are reached only after a period of 3 months of monthly injections.) Growth hormone can be determined using the mean of 4 assays taken at 1-hour intervals. Somatomedin C can be determined with a single assay. All GH and IGF-1 determinations should be made 4 weeks after the previous Sandostatin LAR® Depot.
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 T4 measurements should be performed during chronic therapy (see PRECAUTIONS -- General).
DRUG 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 and result in transplant rejection.
Patients receiving insulin, oral hypoglycemic agents, beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may require dose adjustments of these therapeutic agents.
Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. 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 growth hormones. 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.
DRUG LABORATORY TEST INTERACTIONS
No known interference exists with clinical laboratory tests, including amine or peptide determinations.
CARCINOGENESIS/MUTAGENESIS/IMPAIRMENT OF FERTILITY
Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin®. No mutagenic potential of the polymeric carrier in Sandostatin LAR® Depot, D,L-lactic and glycolic acids copolymer, was observed in the Ames mutagenicity test.
No carcinogenic potential was demonstrated in mice treated subcutaneously with octreotide for 85-99 weeks at doses up to 2000 mcg/kg/day (8 × the human exposure based on body surface area). In a 116-week subcutaneous study in rats administered octreotide, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10 × the human exposure based on body surface area) compared to an incidence of 8%-10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with Sandostatin® Injection for at least 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females
compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans.
Octreotide did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7 × the human exposure based on body surface area.
PREGNANCY CATEGORY B
Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest human dose based on body surface area and have revealed no evidence of impaired fertility or harm to the fetus due to octreotide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
NURSING MOTHERS
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when Sandostatin LAR® Depot is administered to a nursing woman.
PEDIATRIC USE
Sandostatin LAR® Depot has not been studied in pediatric patients.
Experience with Sandostatin® Injection in the pediatric population is limited. Its use has been primarily in patients with congenital hyperinsulinism (also called nesidioblastosis). The youngest patient to receive the drug was 1 month old. At doses of 1-40 mcg/kg body weight/day, the majority of side effects observed were gastrointestinal-steatorrhea, diarrhea, vomiting and abdominal distention. Poor growth has been reported in several patients treated with Sandostatin® Injection for more than 1 year; catch-up growth occurred after Sandostatin® Injection was discontinued. A 16-month-old male with enterocutaneous fistula developed sudden abdominal pain and increased nasogastric drainage and died 8 hours after receiving a single 100 mcg subcutaneous dose of Sandostatin® Injection.
ADVERSE REACTIONS (See WARNINGS and PRECAUTIONS.)
Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic octreotide therapy (see WARNINGS). Few patients, however, develop acute symptoms requiring cholecystectomy.
CARDIAC
In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin® (octreotide acetate) Injection therapy. Electrocardiograms were performed only in carcinoid patients receiving Sandostatin LAR® Depot (octreotide acetate for injectable suspension). 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 PRECAUTIONS).
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 4.
Table 4 Number (%) of Acromegalic Patients with Common G.I. Adverse Events
|
|
Sandostatin®
Injection S.C. t.i.d. n=114 |
Sandostatin® LAR Depot
q. 28 days n=261 |
| Adverse Event |
N |
% |
N |
% |
|
Diarrhea
|
66
|
(57.9) |
95
|
(36.4) |
|
Abdominal Pain or Discomfort
|
50
|
(43.9) |
76
|
(29.1) |
|
Flatulence
|
15
|
(13.2) |
67
|
(25.7) |
|
Constipation
|
10
|
(8.8) |
49
|
(18.8) |
|
Nausea
|
34
|
(29.8) |
27
|
(10.3) |
|
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%-6% of patients.
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.
HYPO/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. In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with Sandostatin LAR® Depot (see PRECAUTIONS).
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 acro-megalics 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. In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported (see PRECAUTIONS).
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.
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