Single doses of Sandostatin^Ò (octreotide acetate) have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials (primarily patients with acromegaly or psoriasis), 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^Ò (octreotide acetate) for 12 months or longer was 52%. Less than 2% of patients treated with Sandostatin^Ò (octreotide acetate) for 1 month or less developed gallstones. The incidence of gallstones did not appear related to age, sex or dose. Like patients without gallbladder abnormalities, the majority of patients developing gallbladder abnormalities on ultrasound had gastrointestinal symptoms. The symptoms were not specific for gallbladder disease. A few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during Sandostatin^Ò (octreotide acetate) therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin^Ò (octreotide acetate) therapy and died.

Sandostatin^Ò (octreotide acetate) alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia or hyperglycemia. Sandostatin^Ò (octreotide acetate) also suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with Sandostatin^Ò (octreotide acetate). However, the incidence of these adverse events during long-term therapy was determined vigorously only in acromegaly patients who, due to their underlying disease and/or the subsequent treatment they receive, are at an increased risk for the development of diabetes mellitus, hypothyroidism, and cardiovascular disease. Although the degree to which these abnormalities are related to Sandostatin^Ò (octreotide acetate) therapy is not clear, new abnormalities of glycemic control, thyroid function and ECG developed during Sandostatin^Ò (octreotide acetate) therapy as described below.

The hypoglycemia or hyperglycemia which occurs during Sandostatin^Ò (octreotide acetate) therapy is usually mild, but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. Hypoglycemia and hyperglycemia occurred on Sandostatin^Ò (octreotide acetate) in 3% and 16% of acromegalic patients, respectively. Severe hyperglycemia, subsequent pneumonia, and death following initiation of Sandostatin^Ò (octreotide acetate) therapy was reported in one patient with no history of hyperglycemia.

In patients with concomitant Type I diabetes mellitus, SandostatinÒ Injection and Sandostatin LARÒ 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.

In acromegalic patients, 12% developed biochemical hypothyroidism only, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin^Ò (octreotide acetate). Baseline and periodic assessment of thyroid function (TSH, total and/or free T₄) is recommended during chronic therapy.

In acromegalics, bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during Sandostatin^Ò (octreotide acetate) therapy. Other EKG changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R wave progression. These ECG changes are not uncommon in acromegalic patients. 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^Ò (octreotide acetate) therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge.

Several cases of pancreatitis have been reported in patients receiving Sandostatin^Ò (octreotide acetate) therapy.

Sandostatin^Ò (octreotide acetate) may alter absorption of dietary fats in some patients.

In patients with severe renal failure requiring dialysis, the half-life of Sandostatin^Ò (octreotide acetate) may be increased, necessitating adjustment of the maintenance dosage.

Depressed vitamin B₁₂ levels and abnormal Schilling's tests have been observed in some patients receiving Sandostatin^Ò (octreotide acetate) therapy, and monitoring of vitamin ^B12 levels is recommended during chronic Sandostatin^Ò (octreotide acetate) therapy.

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-I (somatomedin C) Responsiveness to Sandostatin^Ò (octreotide acetate) may be evaluated by determining growth hormone levels at 1-4 hour intervals for 8-12 hours post dose. Alternatively, a single measurement of IGF-I (somatomedin C) level may be made two weeks after drug initiation or dosage change.

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).

Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin^Ò (octreotide acetate).

No carcinogenic potential was demonstrated in mice treated subcutaneously for 85-99 weeks at doses up to 2000 mcg/kg/day (8x the human exposure based on body surface area). In a 116-week subcutaneous study in rats, 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 (10x 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^Ò (octreotide acetate) for up to 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.

Sandostatin^Ò (octreotide acetate) did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure based on body surface area.

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 Sandostatin^Ò (octreotide acetate). 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.

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^Ò (octreotide acetate) is administered to a nursing woman.

Experience with Sandostatin^Ò (octreotide acetate) in the pediatric population is limited. Although formal controlled clinical trials have not been performed to evaluate safety and effectiveness in this age group, there are reports of 49 cases in the literature of neonates and infants with congenital hyperinsulinism [also called familial hyperinsulinism (HI), persistent hyperinsulinemic hypoglycemia of infancy (PHHI), or nesidioblastosis] who have received Sandostatin^Ò as an inhibitor of insulin release. The following efficacy and safety information is derived from these 49 patients.

Sandostatin^Ò has been used to stabilize plasma glucose levels prior to pancreatectomy and to treat recurrent post-operative hypoglycemia. Although most use of octreotide in this setting is short-term, a few reports in the literature have documented longer-term therapy in pediatric patients (2.2-5.5 years). Octreotide is an alternative medical treatment to diazoxide for control of hypoglycemia in this disorder. Of 31 pediatric patients who received Sandostatin^Ò as prescribed for congenital hyperinsulinism and for which long-term follow-up was available, octreotide obviated the need for surgery in 3 patients (10%) and was replaced by diazoxide in 4 patients (13%) due to uncontrolled hypoglycemia. Although the remainder of these patients required surgery, there have been a few reports in the literature of patients who have responded to octreotide after failing treatment with surgery and/or diazoxide. Doses of 3-40 mcg/kg/day have been used. At these doses, the majority of side effects were gastrointestinal: diarrhea, steatorrhea, vomiting, and abdominal distention, each reported in 22%-35% (n = 11-17) of patients. However, they were generally short-lived — with resolution of vomiting and distention in 2-4 days, and diarrhea/steatorrhea, within 2-4 weeks. Steatorrhea was controlled in most patients with pancreatic enzyme supplements. Poor growth was reported in 37% of patients (n = 7) who received Sandostatin^Ò for 1-4.33 years. It was associated with low serum growth hormone and/or IGF-1 levels in 4/6 patients in whom these parameters were measured. Catch-up growth occurred in 3/3 patients who were followed after Sandostatin^Ò was discontinued. Poor weight gain was reported in 32% of patients (n = 6). Tachyphylaxis was reported in 35% (n = 17) of patients. Asymptomatic gallstones with sludge was reported in one infant after one year of therapy and was treated with ursodeoxycholic acid. There has been a single report of an infant with nesidioblastosis who experienced a seizure thought to be independent of Sandostatin^Ò therapy. A single death has been reported in a 16-month-old male with enterocutaneous fistula who developed sudden abdominal pain and increased nasogastric drainage and expired 8 hours after receiving a single 100 mcg subcutaneous dose of Sandostatin^Ò.

Clinical studies of Sandostatin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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