Indium

INDICATIONS AND USAGE Indium In 111 Oxyquinoline Solution is indicated for radiolabeling autologous leukocytes. Indium In 111 oxyquinoline labeled leukocytes may be used as an adjunct in the detection of inflammatory processes to which leukocytes migrate, such as those associated with abscesses or other infection, following reinjection and detection by appropriate imaging procedures. The degree of accuracy may vary with labeling techniques and with the size, location and nature of the inflammatory process. Indium In 111 oxyquinoline labeled leukocyte imaging is not the preferred technique for the initial evaluation of patients with a high clinical probability of an abscess in a known location. Ultrasound or computed tomography may provide a better anatomical delineation of the infectious process and information may be obtained more quickly than with labeled leukocytes. If localization by these techniques is successful, labeled leukocytes should not be used as a confirmatory procedure. If localization or diagnosis by these methods fails or is ambiguous, indium In 111 oxyquinoline labeled leukocyte imaging may be appropriate.

DOSAGE AND ADMINISTRATION 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.g., 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 imaging is 111 MBq (3 mCi) of Indium In 111 Pentetreotide Injection prepared from an Octreoscan kit. The recommended intravenous dose for SPECT imaging is 222 MBq (6 mCi) of Indium In 111 Pentetreotide Injection. The dose should be confirmed by a suitably calibrated radioactivity ionization chamber immediately before administration. As with all intravenously administered products, Octreoscan 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 Octreoscan in TPN solutions or through the same intravenous line. Radiation Dosimetry The estimated radiation doses Values listed include a correction for a maximum of 0.1% indium In-114m radiocontaminant at calibration. to the average adult (70 kg) from intravenous administration of 111 MBq (3 mCi) and 222 MBq (6 mCi) are presented in Table 4. These estimates were calculated by Oak Ridge Associated Universities using the data published by Krenning, et al. E.P. Krenning, W.H. Bakker, P.P.M. Kooij, W.A.P. Breeman, H.Y. Oei, M. de Jong, J.C. Reubi, T.J. Visser, C. Bruns, D.J. Kwekkeboom, A.E.M. Reijs, P.M. van Hagen, J.W. Koper, and S.W.J. Lamberts, “Somatostatin Receptor Scintigraphy with Indium-111-DTPA-D-Phe-1-Octreotide in Man: Metabolism, Dosimetry and Comparison with Iodine-123-Try-3-Octreotide,” The Journal of Nuclear Medicine, Vol. 33, No. 5, May 1992, pp. 652-658. Table 4. Estimated Absorbed Radiation Doses after Intravenous Administration of Indium In 111 Pentetreotide Assumes 4.8 hour voiding interval and International Commission on Radiological Protection (ICRP) 30 model for the gastrointestinal tract calculations. 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 rem/3 mCi mSv/222 MBq rem/6 mCi Effective Dose Estimated according to ICRP Publication 53. Equivalent 13.03 1.30 26.06 2.61

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.

CONTRAINDICATIONS None known.

ADVERSE REACTIONS 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 Octreoscan. 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: Hypersensitivity reactions, predominantly rash, pruritus, less frequently angioedema or features of anaphylaxis.

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.