Sandostatin® (octreotide acetate) alters the balance between the counter-regulatory
hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia
or hyperglycemia. Sandostatin (octreotide acetate) also suppresses secretion of thyroid stimulating
hormone, which may result in hypothyroidism. Cardiac conduction abnormalities
have also occurred during treatment with Sandostatin (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 (octreotide acetate) therapy is not clear, new
abnormalities of glycemic control, thyroid function and ECG developed during
Sandostatin (octreotide acetate) therapy as described below.
Risk of Pregnancy with Normalization of IGF-1 and GH
Although acromegaly may lead to infertility, there are reports of pregnancy
in acromegalic women. In women with active acromegaly who have been unable to
become pregnant, normalization of GH and IGF-1 may restore fertility. Female
patients of childbearing potential should be advised to use adequate contraception
during treatment with octreotide.
The hypoglycemia or hyperglycemia which occurs during Sandostatin (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 (octreotide acetate) in 3% and 16% of acromegalic patients, respectively.
Severe hyperglycemia, subsequent pneumonia, and death following initiation of
Sandostatin (octreotide acetate) therapy was reported in one patient with no history of hyperglycemia.
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 (octreotide acetate) Injection or Sandostatin (octreotide acetate) 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 (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 (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 (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 (octreotide acetate)
Sandostatin (octreotide acetate) may alter absorption of dietary fats in some patients.
In patients with severe renal failure requiring dialysis, the half-life of
Sandostatin (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 (octreotide acetate) therapy, and monitoring
of vitamin B12 levels is recommended during chronic Sandostatin (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
Acromegaly: Growth Hormone, IGF-I (somatomedin C) Responsiveness
to Sandostatin (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
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).
Carcinogenesis/Mutagenesis/Impairment of Fertility
Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin (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 (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 (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.
Pregnancy Category B
There are no adequate and well-controlled studies of octreotide use in pregnant
women. Reproduction studies have been performed in rats and rabbits at doses
up to 16 times the highest recommended human dose based on body surface area
and revealed no evidence of harm to the fetus due to octreotide. However, because
animal reproduction studies are not always predictive of human response, this
drug should be used during pregnancy only if clearly needed.
In postmarketing data, a limited number of exposed pregnancies have been reported
in patients with acromegaly. Most women were exposed to octreotide during the
first trimester of pregnancy at doses ranging from 100-300 mcg/day of Sandostatin (octreotide acetate)
s.c. or 20-30 mg/month of Sandostatin (octreotide acetate) LAR, however some women elected to continue
octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital
malformations were reported.
It is not known whether octreotide is excreted into human milk. Because many
drugs are excreted in human milk, caution should be exercised when octreotide
is administered to a nursing woman.
Safety and efficacy of Sandostatin (octreotide acetate) Injection in the pediatric population have
not been demonstrated.
No formal controlled clinical trials have been performed to evaluate the safety
and effectiveness of Sandostatin (octreotide acetate) in pediatric under age 6 years. In post-marketing
report, serious adverse events, including hypoxia, necrotizing enterocolitis,
and death, have been reported with Sandostatin (octreotide acetate) use in children, most notably
in children under 2 years of age. The relationship of these events to octreotide
has not been established as the majority of these pediatric patients had serious
underlying co-morbid conditions.
The efficacy and safety of Sandostatin (octreotide acetate) using the Sandostatin (octreotide acetate) LAR Depot formulation
was examined in a single randomized, double-blind, placebo-controlled, six–month
pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic
obesity resulting from cranial insult. The mean octreotide concentration after
6 doses of 40 mg Sandostatin (octreotide acetate) LAR Depot administered by IM injection every four
weeks was approximately 3 ng/ml. Steady-state concentrations was achieved after
3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m² in Sandostatin (octreotide acetate)
LAR Depot-treated subjects compared to 0.0 kg/m² in saline control-treated
subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%)
patients treated with Sandostatin (octreotide acetate) LAR Depot. No unexpected adverse events were
observed. However, with Sandostatin (octreotide acetate) LAR Depot 40 mg once a month, the incidence
of new cholelithiasis in this pediatric population (33%) was higher than that
seen in other adults indications such as acromegaly (22%) or malignant carcinoid
syndrome (24%), where Sandostatin (octreotide acetate) LAR Depot was 10 to 30 mg once a month.
Clinical studies of Sandostatin (octreotide acetate) 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.