KIT FOR THE PREPARATION OF INDIUM IN 111 PENTETREOTIDE- indium in-111 pentetreotide

CLINICAL PHARMACOLOGY
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. 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. For several hours after administration, plasma radioactivity is predominantly in parent form. Ten percent of the radioactivity excreted is nonpeptide-bound. Indium In 111 pentetreotide binds to cell surface receptors for somatostatin. In nonclinical pharmacologic studies, the hormonal effect of indium In 111 pentetreotide injection 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. Indium In 111 pentetreotide injection 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. Indium In 111 pentetreotide injection results were consistent with the final diagnosis (success) in 267 of 309 evaluable patients (86. Compared with carcinoids and gastrinomas, lower success rates were noted for localization of insulinomas, neuroblastomas, pituitary adenomas and medullary thyroid carcinomas. Indium In-111 pentetreotide injection success was observed in 27 of 32 patients (84. 4%) with clinically nonfunctioning neuroendocrine tumors (i. , no symptom of a clinical syndrome mediated by abnormally elevated hormones). Indium In 111 pentetreotide injection 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 Indium In 111 pentetreotide injection scintigraphy was 85. 7%; for CT/MRI the rate was 68%. The specificity rate for Indium In 111 pentetreotide injection 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 Indium In 111 pentetreotide administration. These patients had an overall 95% success rate. The effect of different dose levels of octreotide on success rates has not been evaluated.
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 indium In 111 pentetreotide injection 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.

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 Table 1 Table 1: Principal Radiation Emission Data* Radiation Mean Percent Per Disintegration Energy (keV) Gamma-2 90.2 171.3 Gamma-3 94.0 245.4 * Kocher, David C., “Radioactive Decay Data Tables,” DOE/TIC- 11026, 115 (1981). The specific gamma ray constant for In-111 is 3.21 R/hr-mCi at 1 cm1. 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 1 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) 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 * Calibration Time

Indium In 111 pentetreotide injection, after radiolabeling is an agent for the scintigraphic localization of primary and metastatic neuroendocrine tumors bearing somatostatin receptors.

Before administration, a patient should be well hydrated. After administration, the patient must be encouraged to drink fluids liberally. Elimination of extra fluid intake will help reduce the radiation dose by flushing out unbound, labelled pentetreotide by glomerular filtration. It is also recommended that a mild laxative (e. , bisacodyl or lactulose) be given to the patient starting the evening before the radioactive drug is administered, and continuing for 48 hours. Ample fluid uptake is necessary during this period as a support both to renal elimination and the bowel-cleansing process. In a patient with an insulinoma, bowel-cleansing should be undertaken only after consultation with an endocrinologist. The recommended intravenous dose for planar SPECT The dose should be confirmed by a suitably calibrated radioactivity ionization chamber immediately before administration. As with all intravenously administered products, indium In 111 pentetreotide injection should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Preparations containing particulate matter or discoloration should not be administered. They should be disposed of in a safe manner, in compliance with applicable regulations. Aseptic techniques and effective shielding should be employed in withdrawing doses for administration to patients. Waterproof gloves should be worn during the administration procedure. Do not administer indium In 111 pentetreotide injection in TPN solutions or through the same intravenous line. The estimated radiation doses 2 Table 4 3 Table 4: Estimated Absorbed Radiation Doses after Intravenous Administration of Indium In 111 Pentetreotide* to a 70 kg Patient PLANAR SPECT Organ mGy/111 MBq rads/3 mCi mGy/222 MBq rads/6 mCi Kidneys 54. 83 Liver 12. 43 Spleen 73. 77 Uterus 6. 27 Ovaries 4. 98 Testes 2. 58 Red Marrow 3. 69 Urinary Bladder Wall 30. 05 GI Tract Stomach Wall 5. 13 Small Intestine 4. 96 Upper Large Intestine 5. 16 Lower Large Intestine 7. 55 Adrenals 7. 51 Thyroid 7. 49 mSv/111 MBq * Assumes 4. 8 hour voiding interval and International Commission on Radiological Protection (ICRP) 30 model for the gastrointestinal tract calculations. rem/3 mCi mSv/222 MBq rem/6 mCi Effective Dose dagger 13.

The following adverse effects were observed in clinical trials at a frequency of less than 1% of 538 patients: dizziness, fever, flush, headache, hypotension, changes in liver enzymes, joint pain, nausea, sweating, and weakness. These adverse effects were transient. Also in clinical trials, there was one reported case of bradycardia and one case of decreased hematocrit and hemoglobin. Pentetreotide is derived from octreotide which is used as a therapeutic agent to control symptoms from certain tumors. The usual dose for indium In 111 pentetreotide injection is approximately 5 to 20 times less than for octreotide and is subtherapeutic. The following adverse reactions have been associated with octreotide in 3% to 10% of patients: nausea, injection site pain, diarrhea, abdominal pain/discomfort, loose stools, and vomiting. Hypertension and hyper- and hypoglycemia have also been reported with the use of octreotide. The following adverse reactions have been identified during postapproval use of indium In 111 pentetreotide injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders

None known.

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.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when indium In 111 pentetreotide injection is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

The Kit for the Preparation of Indium In 111 Pentetreotide Injection should be stored refrigerated at 2° to 8°C (36° to 46°F). After reconstitution, store at controlled room temperature 20° to 25°C (68° to 77°F). Indium In 111 pentetreotide injection must be used within 6 hours of preparation.

Clinical Trials
Indium In 111 pentetreotide injection 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). Indium In 111 pentetreotide injection 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. Indium In-111 pentetreotide injection 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). Indium In 111 pentetreotide injection 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 Indium In 111 pentetreotide injection scintigraphy was 85.7%; for CT/MRI the rate was 68%. The specificity rate for Indium In 111 pentetreotide injection 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 Indium In 111 pentetreotide administration. These patients had an overall 95% success rate. The effect of different dose levels of octreotide on success rates has not been evaluated.
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.
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.
Radiation Dosimetry
The estimated radiation doses 2 Table 4 3 Table 4: Estimated Absorbed Radiation Doses after Intravenous Administration of Indium In 111 Pentetreotide* to a 70 kg Patient PLANAR SPECT Organ mGy/111 MBq rads/3 mCi mGy/222 MBq rads/6 mCi Kidneys 54.16 5.42 108.32 10.83 Liver 12.15 1.22 24.31 2.43 Spleen 73.86 7.39 147.73 14.77 Uterus 6.34 0.63 12.67 1.27 Ovaries 4.89 0.49 9.79 0.98 Testes 2.90 0.29 5.80 0.58 Red Marrow 3.46 0.35 6.91 0.69 Urinary Bladder Wall 30.24 3.02 60.48 6.05 GI Tract Stomach Wall 5.67 0.57 11.34 1.13 Small Intestine 4.78 0.48 9.56 0.96 Upper Large Intestine 5.80 0.58 11.59 1.16 Lower Large Intestine 7.73 0.77 15.46 1.55 Adrenals 7.55 0.76 15.11 1.51 Thyroid 7.43 0.74 14.86 1.49 mSv/111 MBq * Assumes 4 .8 hour voiding interval and International Commission on Radiological Protection (ICRP) 30 model for the gastrointestinal tract calculations. rem/3 mCi mSv/222 MBq rem/6 mCi Effective Dose dagger 13.03 1.30 26.06 2.61

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KIT FOR THE PREPARATION OF INDIUM IN 111 PENTETREOTIDE- indium in-111 pentetreotide Product manual source documgent