Octreotide Acetate (Page 2 of 4)

PRECAUTIONS

General

Octreotide acetate alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia or hyperglycemia. Octreotide acetate also suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with 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 octreotide acetate therapy is not clear, new abnormalities of glycemic control, thyroid function and ECG developed during 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 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 octreotide acetate in 3% and 16% of acromegalic patients, respectively. Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide acetate therapy was reported in one patient with no history of hyperglycemia.

In patients with concomitant Type I diabetes mellitus, octreotide acetate injection and 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, octreotide acetate injection or octreotide acetate for injectable suspension 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 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 octreotide acetate therapy. Other ECG 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 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 octreotide acetate therapy.

Octreotide acetate may alter absorption of dietary fats in some patients.

In patients with severe renal failure requiring dialysis, the half-life of 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 octreotide acetate therapy, and monitoring of vitamin B12 levels is recommended during chronic octreotide acetate therapy.

Information for Patients

Careful instruction in sterile subcutaneous injection technique should be given to the patients and to other persons who may administer octreotide acetate injection.

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-I (somatomedin C) Responsiveness to 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).

Drug Interactions

Octreotide acetate has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide acetate 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 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 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.

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 octreotide acetate s.c. or 20-30 mg/month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported.

Nursing Mothers

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.

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