OCTREOSCAN: Package Insert and Label Information

OCTREOSCAN- indium in -111 pentetreotide
Curium US LLC

DESCRIPTION

Octreoscan^™ is a kit for the preparation of Indium In 111 Pentetreotide Injection, a radioactive diagnostic agent. It is a kit consisting of two components:

1) A 10-mL Octreoscan Reaction Vial which contains a lyophilized mixture of:
(i) 10 mcg pentetreotide [N-(diethylenetriamine-N,N,N′,N″-tetraacetic acid-N″-acetyl)-D-phenylalanyl-L-hemicystyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-L-hemicystyl-L-threoninol cyclic (2→7) disulfide], (also known as octreotide DTPA),
(ii) 2 mg gentisic acid [2, 5-dihydroxybenzoic acid],
(iii) 4.9 mg trisodium citrate, anhydrous,
(iv) 0.37 mg citric acid, anhydrous, and (v) 10 mg inositol.

Pentetreotide has the following structural formula:

Prior to lyophilization, sodium hydroxide or hydrochloric acid may have been added for pH adjustment. The vial contents are sterile and nonpyrogenic. No bacteriostatic preservative is present.

2) A 10-mL vial of Indium In 111 Chloride Solution, which contains: 1.1 mL or 111 MBq/mL (3 mCi/mL) indium In 111 chloride in 0.02N HCl at time of calibration. The vial also contains ferric chloride at a concentration of 3.5 mcg/mL (ferric ion, 1.2 mcg/mL). The vial contents are sterile and nonpyrogenic. No bacteriostatic preservative is present.

Indium In 111 Pentetreotide Injection is prepared by combining the two kit components (see INSTRUCTIONS FOR THE PREPARATION OF INDIUM In 111 PENTETREOTIDE INJECTION ). Indium In-111 reacts with the diethylenetriaminetetraacetic acid portion of the pentetreotide molecule to form indium In 111 pentetreotide. The pH of the resultant Indium In 111 Pentetreotide Injection is between 3.8 and 4.3. No bacteriostatic preservative is present.

The Indium In 111 Pentetreotide Injection is suitable for intravenous administration as is, or it may be diluted to a maximum volume of 3 mL with 0.9% Sodium Chloride Injection, USP, immediately before intravenous administration. In either case, the radiolabeling yield of Indium In 111 Pentetreotide Injection should be determined before administration to the patient. A method recommended for determining the radiolabeling yield is presented at the end of this package insert (see RECOMMENDED METHOD FOR DETERMINATION OF RADIOLABELING YIELD OF INDIUM In 111 PENTETREOTIDE INJECTION).

Physical Characteristics

Indium In-111 decays by electron capture to cadmium-111 (stable) and has a physical half-life of 2.805 days (67.32 hours) (see Table 2).1 The principal photons that are useful for detection and imaging are listed in Table 1.

Table 1. Principal Radiation Emission Data *

* Kocher, David C., “Radioactive Decay Data Tables,” DOE/TIC-11026, 115 (1981).
Radiation	Mean Percent Per Disintegration	Energy (keV)
Gamma-2	90.2	171.3
Gamma-3	94.0	245.4

The specific gamma ray constant for In-111 is 3.21 R/hr-mCi at 1 cm 1. The first half-value thickness of lead (Pb) for In-111 is 0.023 cm. Selected coefficients of attenuation are listed in Table 2 as a function of lead shield thickness. For example, the use of 0.834 cm of lead will attenuate the external radiation by a factor of about 1000.

Table 2. Radiation Attenuation by Lead Shielding

Shield Thickness (Pb) cm	Coefficient of Attenuation
0.023	0.5
0.203	0.1
0.513	0.01
0.834	0.001
1.12	0.0001

Table 3 lists fractions remaining at selected time intervals before and after calibration. This information may be used to correct for physical decay of the radionuclide.

Table 3. Physical Decay Chart: Indium In-111, Half-life 2.805 Days (67.32 hours)

* Calibration time
Hours	Fraction Remaining	Hours	Fraction Remaining
-72	2.100	0*	1.000
-60	1.854	3	0.970
-48	1.639	6	0.940
-36	1.448	12	0.885
-24	1.280	24	0.781
-12	1.131	36	0.690
-6	1.064	48	0.610

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1

From Radiopharmaceutical Internal Dosimetry Information Center, Oak Ridge Associated Universities, Oak Ridge, TN 37831-0117, February 1985.

CLINICAL PHARMACOLOGY

General

Pentetreotide is a DTPA conjugate of octreotide, which is a long-acting analog of the human hormone, somatostatin. Indium In 111 pentetreotide binds to somatostatin receptors on cell surfaces throughout the body. Within an hour of injection, most of the dose of indium In 111 pentetreotide distributes from plasma to extravascular body tissues and concentrates in tumors containing a high density of somatostatin receptors. After background clearance, visualization of somatostatin receptor-rich tissue is achieved. In addition to somatostatin receptor-rich tumors, the normal pituitary gland, thyroid gland, liver, spleen and urinary bladder also are visualized in most patients, as is the bowel, to a lesser extent. Excretion is almost exclusively via the kidneys.

Pharmacokinetics

Radioactivity leaves the plasma rapidly; one third of the radioactive injected dose remains in the blood pool at 10 minutes after administration. Plasma levels continue to decline so that by 20 hours post-injection, about 1% of the radioactive dose is found in the blood pool. The biological half-life of indium In 111 pentetreotide is 6 hours.

Half of the injected dose is recoverable in urine within 6 hours after injection, 85% is recovered in the first 24 hours, and over 90% is recovered in urine by two days.

Hepatobiliary excretion represents a minor route of elimination, and less than 2% of the injected dose is recovered in feces within three days after injection.

Metabolism

For several hours after administration, plasma radioactivity is predominantly in parent form. Ten percent of the radioactivity excreted is nonpeptide-bound.

Pharmacodynamics

Indium In 111 pentetreotide binds to cell surface receptors for somatostatin. In nonclinical pharmacologic studies, the hormonal effect of Octreoscan in vitro is one-tenth that of octreotide. Since diagnostic imaging doses of indium In 111 pentetreotide are lower than the therapeutic doses of octreotide, indium In 111 pentetreotide is not expected to exert clinically significant somatostatin effects.

Indium In 111 pentetreotide is cleared from the body primarily by renal excretion. Indium In 111 pentetreotide elimination has not been studied in anephric patients or in those with poorly functioning kidneys. It is not known whether indium In 111 pentetreotide can be removed by dialysis. Dosage adjustments in patients with decreased renal function have not been studied.

Clinical Trials

Octreoscan was studied in nine unblinded clinical studies in a total of 365 patients. Of these patients, 174 were male and 191 were female. Their mean age was 54.0 years (range 1.8 to 86 years). One patient was under the age of 2 and 2 patients were between the ages of 2 and 12; 223 patients (61.1%) were between 18 and 60 years; and 136 patients (37.3%) were older than 60 years. A racial distribution is not available.

Eligible patients had a demonstrated or high clinical suspicion of a neuroendocrine tumor. The most common tumors were carcinoids (132 of 309 evaluable patients). Scintigraphic results were compared to results of conventional localization procedures (CT, ultrasound, MRI, angiography, surgery and/or biopsy). The mean dose of radioactivity administered was 173.4 MBq (4.7 mCi).

Octreoscan results were consistent with the final diagnosis (success) in 267 of 309 evaluable patients (86.4%). Compared with carcinoids and gastrinomas, lower success rates were noted for localization of insulinomas, neuroblastomas, pituitary adenomas and medullary thyroid carcinomas. Octreoscan success was observed in 27 of 32 patients (84.4%) with clinically nonfunctioning neuroendocrine tumors (i.e., no symptom of a clinical syndrome mediated by abnormally elevated hormones).

Octreoscan localized previously unidentified tumors in 57/204 patients. In 55/195 patients, indium In 111 pentetreotide uptake occurred in lesions not thought to have somatostatin receptors. In a small subgroup of 39 patients who had tissue confirmation, the sensitivity rate for Octreoscan scintigraphy was 85.7%; for CT/MRI the rate was 68%. The specificity rate for Octreoscan scintigraphy was 50%, the rate for CT/MRI was 12%. Larger studies are needed to confirm these comparisons. Overall, including all tumor types with or without the presence of somatostatin receptors, there were 3/508 false positives and 104/508 false negatives.

Of the 309 patients, 87 had received octreotide for therapeutic purposes within 72 hours of Octreoscan administration. These patients had an overall 95% success rate. The effect of different dose levels of octreotide on success rates has not been evaluated.

INDICATIONS AND USAGE

Octreoscan, after radiolabeling, is an agent for the scintigraphic localization of primary and metastatic neuroendocrine tumors bearing somatostatin receptors.

CONTRAINDICATIONS

None known.

WARNINGS

DO NOT ADMINISTER IN TOTAL PARENTERAL NUTRITION (TPN) ADMIXTURES OR INJECT INTO TPN INTRAVENOUS ADMINISTRATION LINES; IN THESE SOLUTIONS, A COMPLEX GLYCOSYL OCTREOTIDE CONJUGATE MAY FORM.

The sensitivity of scintigraphy with indium In 111 pentetreotide may be reduced in patients concurrently receiving therapeutic doses of octreotide acetate. Consideration should be given to temporarily suspending octreotide acetate therapy before the administration of Indium In 111 Pentetreotide Injection and to monitoring the patient for any signs of withdrawal.

Hypersensitivity reactions following administration of somatostatin receptor imaging agents predominantly consisted of cutaneous reactions such as rash and pruritus. Reactions reversed either spontaneously or with routine symptomatic management. Less frequently hypersensitivity reactions included angioedema or cases with features of anaphylaxis.

PRECAUTIONS

General

1. Therapy with octreotide acetate can produce severe hypoglycemia in patients with insulinomas. Since pentetreotide is an analog of octreotide, an intravenous line is recommended in any patient suspected of having an insulinoma. An intravenous solution containing glucose should be administered just before and during administration of Indium In 111 Pentetreotide Injection.
2. The contents of the two vials supplied with the kit are intended only for use in the preparation of Indium In 111 Pentetreotide Injection and are NOT to be administered separately to the patient.
3. Since indium In 111 pentetreotide is eliminated primarily by renal excretion, use in patients with impaired renal function should be carefully considered.
4. To help reduce the radiation dose to the thyroid, kidneys, bladder, and other target organs, patients should be well hydrated before the administration of Indium In 111 Pentetreotide Injection. They should increase fluid intake and void frequently for one day after administration of this drug. In addition, it is recommended that patients be given a mild laxative (e.g., bisacodyl or lactulose) before and after administration of Indium In 111 Pentetreotide Injection (see DOSAGE AND ADMINISTRATION).
5. Indium In 111 Pentetreotide Injection should be tested for radiolabeling yield of radioactivity prior to administration. The product must be used within 6 hours of preparation.
6. Components of the kit are sterile and nonpyrogenic. To maintain sterility, it is essential that directions are followed carefully. Aseptic technique must be used during the preparation and administration of Indium In 111 Pentetreotide Injection.
7. Octreotide acetate and the natural somatostatin hormone may be associated with cholelithiasis, presumably by altering fat absorption and possibly by decreasing motility of the gallbladder. A single dose of Indium In 111 Pentetreotide Injection is not expected to cause cholelithiasis.
8. As with any other radioactive material, appropriate shielding should be used to avoid unnecessary radiation exposure to the patient, occupational workers, and other persons.
9. Radiopharmaceuticals should be used only by physicians who are qualified by specific training in the safe use and handling of radionuclides.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been performed with indium In 111 pentetreotide to evaluate carcinogenic potential or effects on fertility. Pentetreotide was evaluated for mutagenic potential in an in vitro mouse lymphoma forward mutation assay and an in vivo mouse micronucleus assay; evidence of mutagenicity was not found.

Pregnancy

Animal reproduction studies have not been conducted with indium In 111 pentetreotide. It is not known whether indium In 111 pentetreotide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Therefore, Indium In 111 Pentetreotide Injection should not be administered to a pregnant woman unless the potential benefit justifies the potential risk to the fetus.