KIT FOR THE PREPARATION OF INDIUM IN 111 PENTETREOTIDE

Indium In 111 pentetreotide is the 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 Pentetreotide 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 of 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 labeling yield is presented at the end of this package insert (see RECOMMENDED METHOD FOR DETERMINATION OF RADIOLABELING YIELD OF INDIUM In 111 PENTETREOTIDE INJECTION). Structure 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* 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 From Radiopharmaceutical Internal Dosimetry Information Center, Oak Ridge Associated Universities, Oak Ridge, TN 37831-0117, February 1985. 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.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 indium In 111 pentetreotide kit for kit Injection. 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, 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. Radiation Dosimetry The estimated radiation doses 2 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. 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 † Equivalent 13.03 1.30 26.06 2.61

None known.

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 : Hypersensitivity reactions, predominantly rash, pruritus, less frequently angioedema or features of anaphylaxis

Storage 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.