Pentetreotide

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 ). Structural Formula 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 ). From Radiopharmaceutical Internal Dosimetry Information Center, Oak Ridge Associated Universities, Oak Ridge, TN 37831-0117, February 1985. 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 . 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) Hours Fraction Remaining Hours Fraction Remaining -72 2.100 0 Calibration time 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

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

HOW SUPPLIED The Octreoscan kit (NDC 69945-050-40) is supplied with the following components: 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. Before 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. 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 0.02 N 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. In addition, the kit also contains the following items: (1) a 25 G x 5/8” needle (B-D, Monoject) used to transfer Indium In 111 Chloride Solution to the Octreoscan Reaction Vial, (2) pressure sensitive label, and (3) a package insert. Storage The Octreoscan kit 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.

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

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 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. 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. Since indium In 111 pentetreotide is eliminated primarily by renal excretion, use in patients with impaired renal function should be carefully considered. 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 ). 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. 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. 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. As with any other radioactive material, appropriate shielding should be used to avoid unnecessary radiation exposure to the patient, occupational workers, and other persons. 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. 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.

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.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

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.