Octreotide: Package Insert and Label Information

OCTREOTIDE — octreotide acetate injection, solution
Fresenius Kabi USA, LLC

Rx only

Prescribing Information

DESCRIPTION

Octreotide Acetate Injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered acetate solution for administration by deep subcutaneous (intrafat) or intravenous (IV) injection. Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic (2 7)-disulfide; [R-(R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin.

Octreotide Acetate Injection is available as: sterile 1 mL single dose vials in 2 strengths, containing 100 mcg and 500 mcg octreotide (as acetate).

Each mL of the single dose vial also contains:

sodium chloride . . . . . . . . . . . . . . . . . 7 mg

glacial acetic acid, USP . . . . . . . . . . . 2 mg

sodium acetate trihydrate, USP . . . . . 2 mg

water for injection, USP . . . . . . .qs to 1 mL

The molecular weight of octreotide acetate is 1019.3 g/mol (free peptide, C49 H66 N10 O10 S2 ) and its amino acid sequence is:

Octreotide Acetate Amino Acid Sequence

CLINICAL PHARMACOLOGY:

Octreotide Acetate Injection exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone (GH), glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide (VIP), secretin, motilin, and pancreatic polypeptide.

By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea).

Octreotide substantially reduces GH and/or insulin growth factor-1 (IGF-1; somatomedin C) levels in patients with acromegaly.

Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased (see WARNINGS).

Octreotide suppresses secretion of thyroid stimulating hormone (TSH).

Pharmacokinetics

After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenous (IV) and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve (AUC) values were dose proportional after IV single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day).

In healthy volunteers, the distribution of octreotide from plasma was rapid (tα 1/2 = 0.2 h), the volume of distribution (Vdss ) was estimated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin.

The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1 to 3 minutes with the natural hormone. The duration of action of Octreotide Acetate Injection is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug.

In patients with acromegaly, the pharmacokinetics differs somewhat from those in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volume of distribution (Vdss ) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals.

In patients with renal impairment, the elimination of octreotide from plasma was prolonged and total body clearance reduced. In mild renal impairment (CLCR 40 to 60 mL/min), octreotide t1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (CLCR 10 to 39 mL/min) t1/2 was 3 hours and total body clearance 7.3 L/hr, and in severely renally impaired patients not requiring dialysis (CLCR <10 mL/min) t1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr).

Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr.

INDICATIONS AND USAGE

Acromegaly

Octreotide Acetate Injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. The goal is to achieve normalization of GH and IGF-1 (somatomedin C) levels (see DOSAGE AND ADMINISTRATION). In patients with acromegaly, Octreotide Acetate Injection reduces GH to within normal ranges in 50% of patients and reduces IGF-1 (somatomedin C) to within normal ranges in 50% to 60% of patients. Since the effects of pituitary irradiation may not become maximal for several years, adjunctive therapy with Octreotide Acetate Injection to reduce blood levels of GH and IGF-1 (somatomedin C) offers potential benefit before the effects of irradiation are manifested.

Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects.

Carcinoid Tumors

Octreotide acetate is indicated for the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease.

Octreotide acetate studies were not designed to show an effect on the size, rate of growth, or development of metastases.

Vasoactive Intestinal Peptide Tumors (VIPomas)

Octreotide acetate is indicated for the treatment of the profuse watery diarrhea associated with VIP-secreting tumors. Octreotide acetate studies were not designed to show an effect on the size, rate of growth, or development of metastases.

CONTRAINDICATIONS

Sensitivity to this drug or any of its components.

WARNINGS

Cholelithiasis and Complications of Cholelithiasis

Single doses of Octreotide Acetate Injection 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 octreotide acetate for 12 months or longer was 52%. Less than 2% of patients treated with 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 octreotide acetate therapy or following its withdrawal. One patient developed ascending cholangitis during octreotide acetate therapy and died. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications requiring cholecystectomy.

If complications of cholelithiasis are suspected, discontinue octreotide acetate and treat appropriately.

Complete Atrioventricular Block

Patients who receive Octreotide Acetate Injection intravenously may be at increased risk for higher degree atrioventricular blocks. In postmarketing reports, complete atrioventricular block was reported in patients receiving intravenous octreotide acetate during surgical procedures. In majority of patients, octreotide acetate was given at higher than recommended doses and/or as a continuous intravenous infusion. The safety of continuous intravenous infusion has not been established in patients receiving octreotide acetate for the approved indications. Consider cardiac monitoring in patients receiving octreotide acetate intravenously.

PRECAUTIONS

General

Octreotide Acetate Injection alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone (GH), 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 electrocardiogram (ECG) developed during octreotide acetate therapy, as described below.

Risk of Pregnancy with Normalization of Insulin Growth Factor-1 (IGF-1; somatomedin C) and Growth Hormone (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 (somatomedin C) may restore fertility. Female patients of childbearing potential should be advised to use adequate contraception during treatment with octreotide.

Hyperglycemia and Hypoglycemia

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 may affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in these patients. In nondiabetics and Type II diabetics with partially intact insulin reserves, Octreotide Acetate Injection administration may result in decreases in plasma insulin levels and hyperglycemia. It is therefore recommended that glucose tolerance and anti-diabetic treatment be periodically monitored during therapy with these drugs.

Thyroid Function Abnormalities

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.

Cardiac Function Abnormalities [see WARNINGS; Complete Atrioventricular Block]

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 electrocardiogram (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 congestive heart failure with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge.

Pancreatitis

Several cases of pancreatitis have been reported in patients receiving octreotide acetate therapy.

Dietary fats malabsorption

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

Decreased vitamin B12 levels and Abnormal Schilling’s Tests

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.

Increased half-life of octreotide acetate in patients with renal failure on dialysis

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

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. Inform patients that cholelithiasis has been reported with the use of octreotide acetate. Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of gallstones (e.g., cholecystitis, cholangitis, and pancreatitis).

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

Carcinoid: urinary 5-hydroxyindole acetic acid (5-HIAA), plasma serotonin, plasma Substance P

VIPoma: plasma vasoactive intestinal peptide (VIP)

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 Acetate 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 hormone (GH). 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 to 99 weeks at doses up to 2,000 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 1,250 mcg/kg/day (10x the human exposure based on body surface area) compared to an incidence of 8% to 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 1,250 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 1,000 mcg/kg/day, which represents 7x the human exposure based on body surface area.

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 to 300 mcg/day of Octreotide Acetate Injection or 20 to 30 mg once a 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.

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