Prescription Drugs

CLINICAL PHARMACOLOGY Sodium Iodide is readily absorbed from the gastrointestinal tract. Following absorption, the iodide is distributed primarily within the extracellular fluid of the body. It is concentrated and organified by the thyroid, and trapped but not organified by the stomach and salivary glands. It is also promptly excreted by the kidneys.

CLINICAL PHARMACOLOGY Pharmacokinetics Absorption Following oral administration, Sodium Iodide I-131 is readily absorbed from the gastrointestinal tract. Distribution Following absorption, the iodide is primarily distributed within the extra-cellular fluid of the body. It is trapped by the thyroid. The thyroid uptake of iodide is usually increased in hyperthyroidism and in goiter with impaired hormone synthesis, decreased in hypothyroidism, and normal to decreased in hypothyroidism receiving iodine. It should be noted that the uptake of radioactive iodide is a function of stable iodide concentration in the serum and the functional state of the thyroid. The iodine concentrating mechanism of the thyroid, termed the iodide trap or pump, accounts for an iodide concentration of some 25 times plasma levels, but may increase as much as 500 times under certain conditions. It is also concentrated by the stomach, choroid plexus, and salivary glands, but is not protein-bound. Metabolism Trapped iodide is oxidized to iodine and organically incorporated so rapidly that the iodide trap of the thyroid contains less than 0.2 % free iodide in comparison to the organically bound iodine. This process results in further concentration of iodine in the thyroid gland to about 500 times that in the blood. The iodinated organic compounds chiefly consist of thyroxine (T4) and triiodothyronine (T3), which are bound by thyroglobulin in the follicular colloid. T4 and T3 are released by enzymatic proteolysis of thyroglobulin into the blood where they are specifically bound and transported by plasma thyroid binding proteins. These reactions are primarily under the control of anterior pituitary gland release of thyroid stimulating hormone (TSH) and hypothalamic thyroid release factor (TRF). Excretion Sodium Iodide I-131 is excreted by the kidneys. The normal range of urinary excretion is 37 to 75 % of the administered dose, varying with the thyroid and renal function of the patient. Pharmacodynamics Stimulation of radioiodide uptake may be achieved by the administration of thyrotropin or placing the patient on a low iodine diet prior to treatment. Palliative effects may be seen in patients with papillary and/or follicular carcinoma of the thyroid. Radioiodide will not be taken up by giant cell and spindle cell carcinoma of the thyroid or by amyloid solid carcinomas.

SODIUM IODIDE I 131 (sodium iodide, i-131) Capsule DESCRIPTION Sodium Iodide 131 (Na 131I) for diagnostic use is supplied for oral administration in opaque white gelatin capsules. The capsules are available in a strength of 3.7 megabecquerels (100 microcuries) iodine I-131 at the time of calibration. Sodium Iodide I 131 (sodium iodide i 131 (sodium iodide i 131 capsules) capsules) Capsules are prepared by absorbing a solution of carrier-free sodium iodide I-131 into inert fillers. The iodine I-131 utilized in the preparation of the capsules contains not less than 99% iodine I-131 at the time of calibration. Physical Characteristics Iodine I-131 decays by beta and associated gamma emissions with a physical half-life of 8.04 days.1 The principle beta emissions and gamma photons are listed in Table 1. Table 1. Principal Radiation Emission Data Radiation Mean Percent Per Disintegration Energy (keV) Beta-1 2.12 69.4 Avg. Beta-3 7.36 96.6 Avg. Beta-4 89.3 191.6 Avg. Gamma-7 6.05 284.3 Gamma-14 81.2 364.5 Gamma-17 7.26 637.0 External Radiation The specific gamma ray constant for iodine I-131 is 2.27 R/hr-mCi at 1 cm. The first half-value thickness of lead (Pb) for iodine I-131 is 0.24 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 2. For example, the use of 4.6 cm of Pb will decrease the external radiation exposure by a factor of about 1,000. Table 2. Radiation Attenuation by Lead Shielding* Shield Thickness (Pb), cm Coefficient of Attenuation 0.24 0.5 0.95 10-1 2.6 10-2 4.6 10-3 6.5 10-4 *Data supplied by Oak Ridge Associated Universities, Radiopharmaceutical Internal Dose Information Center, Oak Ridge, TN, 1987. To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the date of calibration are shown in Table 3. Table 3. Physical Decay Chart, Iodine I-131, Half Life 8.04 Days Days Fraction Remaining Days Fraction Remaining 0* 1.000 16 0.252 1 0.917 17 0.231 2 0.842 18 0.212 3 0.772 19 0.194 4 0.708 20 0.178 5 0.650 21 0.164 6 0.596 22 0.150 7 0.547 23 0.138 8 0.502 24 0.126 9 0.460 25 0.116 10 0.422 26 0.106 11 0.387 27 0.098 12 0.355 28 0.089 13 0.326 29 0.082 14 0.299 30 0.075 15 0.274 *Calibration Day 1Kocher, David C., “Radioactive Decay Data Tables,” DOE/TIC 11026, page 133 (1981).

HICON™ Kit for the Preparation of Sodium Iodide I 131 Capsules and Solution USP Therapeutic – Oral DESCRIPTION HICON™ is a kit which provides a solution of Sodium Iodide I-131 with a radioconcentration of 37 gigabecquerels/mL (1,000 millicuries/mL). Each mL of the concentrated solution contains 37 GBq of no-carrier-added Sodium Iodide I-131, < 2 mg of Disodium Edetate Dihydrate USP as a stabilizer, < 4.4 mg of Sodium Thiosulfate Pentahydrate USP as a reducing agent, and < 40 mg of Dibasic Sodium Phosphate Anhydrous USP. The pH of the solution is between 7.5 and 9.0. The concentrated solution provided with HICON™ is intended for use in the preparation of capsules and solution of varying strengths for oral administration for therapy. Sodium Iodide I 131 Solution USP is designated chemically as Na 131I (MW 153.99, CAS 7790-26-3). Hard gelatin capsules provided for the preparation of the Sodium Iodide I-131 final dosage form contain approximately 300 mg of Dibasic Sodium Phosphate Anhydrous USP as the absorbing buffer. Physical Characteristics Iodine I-131 decays by beta emission and associated gamma emission with a physical half-life of 8.04 days.1 Photons that are useful for detection and imaging are listed in Table 1. Table 1 : Principal Radiation Emission Data Radiation Mean % per Disintegration Mean Energy (keV) Beta-4 (average) 89.3 191.6 Gamma-14 81.2 364.5 1Kocher, David C., “Radioactive Decay Data Tables”, DOE/TIC-11026, (1981) p. 133. External Radiation The specific gamma-ray constant for iodine I-131 is 15.8 μC•kg-1•MBq-1•hr-1 (2.27 R/mCi-hr) at 1 cm. The first half-value thickness of lead (Pb) for iodine I-131 is 0.24 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 2. For example, the use of 2.55 cm of Pb will decrease the external radiation exposure by a factor of about 1,000. Table 2 : Radiation Attenuation by Lead Shielding Shield Thickness (Pb) cm Coefficient of Attenuation 0.24 0.5 0.89 10-1 1.6 10-2 2.55 10-3 3.73 10-4 To correct for physical decay of iodine I-131, the fractions that remain at selected intervals after the time of calibration are shown in Table 3. Table 3 : Physical Decay Chart: Iodine I-131, Half-Life 8.04 Days Days Fraction Remaining Days Fraction Remaining Days Fraction Remaining 0* 1.000 11 .388 22 .151 1 .918 12 .356 23 .138 2 .842 13 .327 24 .127 3 .773 14 .300 25 .116 4 .709 15 .275 26 .107 5 .651 16 .253 27 .098 6 .597 17 .232 28 .090 7 .548 18 .213 29 .083 8 .503 19 .195 30 .076 9 .461 20 .179 10 .423 21 .164 *Calibration time

INDICATIONS Sodium Iodide I 131 (sodium iodide i 131 (sodium iodide i 131 capsules) capsules) is indicated for use in performance of the radioactive iodide (RAI) uptake test to evaluate thyroid function. Diagnostic doses may also be employed in localizing metastases associated with thyroid malignancies. DOSAGE AND ADMINISTRATION The suggested oral dosage ranges employed in the average patient (70 kg) for diagnostic procedures for thyroid function are as follows: Thyroid Uptake: 0.185 to 0.555 megabecquerels (5 to 15 microcuries) Scintiscanning:1.85 to 3.7 megabecquerels (50 to 100 microcuries) Localization of extra-thyroidal metastases: 37 megabecquerels (1000 microcuries). Waterproof gloves should be used during the entire handling and administration procedure. The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. Radiation Dosimetry The estimated absorbed radiation doses2 to an average (70 kg) euthyroid (normal functioning thyroid) patient from an oral dose of 3.7 megabecquerels (100 microcuries) of iodine I-131 are shown in Table 4. Table 4. Absorbed Radiation Doses Tissue Absorbed radiation doses for 3.7 megabecquerels (100 Microcuries) Thyroid Uptake 5% 15% 25% mGy rads mGy rads mGy rads Thyroid 260 26.0 800 80.0 1300 130.0 Stomach Wall 1.7 0.17 1.6 0.16 1.4 0.14 Red Marrow 0.14 0.014 .20 0.020 0.26 0.026 Liver 0.20 0.020 0.35 0.035 0.48 0.048 Testes 0.08 0.008 0.09 0.009 0.09 0.009 Ovaries 0.14 0.014 0.14 0.014 0.14 0.014 Total Body 0.24 0.024 0.47 0.047 0.71 0.071 2MIRD DOSE ESTIMATE REPORT No. 5. Summary of Current Radiation Dose Estimates to Humans from 123I, 124I, 125I, 126I, 130I, 131I, and 132I Sodium Iodide. J. Nucl. Med., 16, No. 9, 857-60 (1975). HOW SUPPLIED Catalog Number 300. Sodium Iodide I 131 (sodium iodide i 131 (sodium iodide i 131 capsules) capsules) Diagnostic Capsules are supplied in a strength of 3.7 megabecquerels (100 microcuries) at time of calibration. The capsules are packaged in plastic vials containing 5, 10, or 15 capsules per vial. Storage And Handling Sodium Iodide I 131 (sodium iodide i 131 (sodium iodide i 131 capsules) capsules) Diagnostic capsules should be stored at controlled room temperature 20-25°C (68-77°F) [See USP]. Storage and disposal of Sodium Iodide I 131 (sodium iodide i 131 (sodium iodide i 131 capsules) capsules) Diagnostic Capsules should be controlled in a manner that is in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide. The U.S. Nuclear Regulatory Commission has approved distribution of this radiopharmaceutical to persons licensed to use byproduct material listed in Section 35.100, and to persons who hold an equivalent license by an Agreement State. Revised 1/2003. Mallinckrodt Inc., St. Louis, MO 63134.

INDICATIONS Therapeutic doses of Sodium Iodide I 131 Solution USP prepared with HICON™ are indicated for the treatment of hyperthyroidism and selected cases of carcinoma of the thyroid. DOSAGE AND ADMINISTRATION The concentrated Sodium Iodide I 131 Solution USP provided with HICON™ must not be used for direct administration to patients. It must be diluted and prepared as described in the Drug Handling And Dosage Form Preparation section. The recommended dosage for orally administered Sodium Iodide I 131 Solution USP is based on the thyroid gland uptake as well as the size of the gland. Thyroidal uptake and size should be determined by the physician prior to treatment and may be useful in calculating the therapeutic dose to be administered to the individual patient. Recommended dosages of orally administered Sodium Iodide I-131 are: Disease Therapy Antihyperthyroid Therapy: Oral dose of 148 to 370 megabecquerels (4 to 10 millicuries). Toxic nodular goiters and other serious thyroid conditions may require larger dosages. Antineoplastic – Ablation of normal thyroid tissue: Initial oral dose of 1.1 to 3.7 gigabecquerels (30 to 100 millicuries). Subsequent ablation of metastases with oral dose of 3.7 to 7.4 giga-becquerels (100 to 200 millicuries). General Dosing Information Patients should be adequately hydrated before and after administration of radioiodide to assure rapid urinary elimination of the iodide that is not absorbed by the thyroid gland. Radiation Dosimetry Following administration of Sodium Iodide I-131, about 40 percent of the activity has an effective half-life of 0.34 days and 60 percent has an effective half-life of 7.61 days. On this basis, the estimated absorbed radiation dose to an average adult (70 kg) from an oral dose of 370 MBq (10 mCi) of Sodium Iodide I-131 is shown in Table 4. Table 4 : Absorbed Radiation Doses I-131 Tissue mGy/370 MBq Rads/10 mCi Thyroid 350,000 350,000 Testes 92 9.2 Ovaries 93 9.3 Whole body 160 16.0 Method of Calculation: A Schema for Absorbed-Dose Calculations for Biologically Distributed Radionuclides, MIRD Pamphlet No. 1, J Nucl Med Suppl, 1:7, 1968. Drug Handling And Final Dosage Form Preparation Drug Handling The concentrated Sodium Iodide I 131 Solution USP provided with HICON™ should not be used after the expiration date stated on the container label. The solution should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should not be used if cloudy, discolored, or found to contain particulate matter. However, it is well known that glass tends to darken in the presence of high radioactivity. Care should be taken to minimize radiation exposure to the patient consistent with proper patient management and to insure minimum radiation exposure to occupational workers. Waterproof gloves should be used during the entire handling and administration procedure. Adequate shielding should be maintained during the life of the product. Preparation of Dilute Sodium Iodide I 131 Solution USP Using the calibration date and radionuclidic concentration on the label of the product vial, calculate the required volume to produce the necessary dose in MBq or mCi. Using a shielded syringe, remove the required volume. Using the shielded syringe, transfer the required volume to a suitably shielded receiving vial. Add diluent solution to the receiving vial to produce a final dose of the desired volume. The recommended diluent is Purified Water USP containing 0.2 % Sodium Thiosulfate USP as a reducing agent. The use of acidic diluents may cause the pH to drop below 7.5 and stimulate the volatilization of Iodine I-131 hydriodic acid. The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. The finished preparation should not be used after the expiration date stated on the container label. Preparation of Sodium Iodide I 131 Capsules USP 1. The kit includes one large gelatin capsule and one small gelatin capsule for each dose prepared. Each large capsule is empty and each small capsule contains approximately 300 mg of Dibasic Sodium Phosphate Anhydrous USP as the absorbing buffer. 2. Using the calibration date and radionuclidic concentration on the label of the product vial, calculate the required volume to produce the necessary dose in MBq or mCi. 3. Open one LARGE capsule by pulling apart the capsule into two pieces as illustrated below: 4. Insert an unopened SMALL capsule into the bottom half of the empty large capsule as illustrated below: 5. With an appropriate syringe, withdraw the required volume of Sodium Iodide I 131 Solution USP (maximum 150 μL) from the vial as illustrated below: 6. Inject into the center of the SMALL capsule through the top as illustrated below: 7. Slip the upper half of the large capsule over the bottom half to completely cover the small capsule and push down gently until locked as illustrated below: 8. After dispensing, the patient dose should be measured in a suitable radioactivity calibration system immediately prior to administration. 9. Store the capsule in a suitable polypropylene container and place inside a lead pot until use. The capsule should be used within seven days. HOW SUPPLIED Each HICON™ kit of 9.25 GBq (250 mCi) includes: a blister package of ten small hard gelatin capsules each containing approximately 300 mg of Dibasic Sodium Phosphate Anhydrous USP as absorbing buffer. a blister package of ten empty large hard gelatin capsules. a 1 mL vial containing 0.25 mL of Sodium Iodide I 131 Solution USP, therapeutic oral solution containing approximately 9.25 GBq (250 mCi) at time of calibration. Each HICON™ kit of 18.5 GBq (500 mCi) includes: two blister packages of ten small hard gelatin capsules each containing approximately 300 mg of Dibasic Sodium Phosphate Anhydrous USP as absorbing buffer. two blister packages of ten empty large hard gelatin capsules. a 1 mL vial containing 0.5 mL of Sodium Iodide I 131 Solution USP, therapeutic oral solution containing approximately 18.5 GBq (500 mCi) at time of calibration. Each HICON™ kit of 37 GBq (1,000 mCi) includes: four blister packages of ten small hard gelatin capsules each containing approximately 300 mg of Dibasic Sodium Phosphate Anhydrous USP as absorbing buffer. four blister packages of ten empty large hard gelatin capsules. a 1 mL vial containing 1 mL of Sodium Iodide I 131 Solution USP, therapeutic oral solution containing approximately 37 GBq (1,000 mCi) at time of calibration. Each mL of the aqueous product that comes with HICON™ contains: 37 gigabecquerels of Sodium Iodide I-131 < 2.0 mg of Disodium Edetate Dihydrate USP < 4.4 mg of Sodium Thiosulphate Pentahydrate USP < 40 mg of Dibasic Sodium Phosphate Anhydrous USP Complete assay data are available on the container. Storage The Sodium Iodide I 131 Solution USP provided with HICON™ should be stored between 2° C and 25° C (36° F and 77° F). NDC 65174-880-25 (for 250 mCi vial size) NDC 65174-880-50 (for 500 mCi vial size) NDC 65174-880-00 (for 1,000 mCi vial size) Manufactured by: Jubilant DraxImage Inc., Kirkland, Québec, Canada.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE No information provided. CONTRAINDICATIONS None.

OVERDOSE In the treatment of hyperthyroidism, over-dosage may result in hypothyroidism, the onset of which may be delayed. Appropriate replacement therapy is recommended if hypothyroidism occurs. Radiation absorbed doses to various tissues for any administered dose may be calculated by reference to Table 4 (Absorbed Radiation Doses I-131). (SeebCONTRAINDICATIONS, WARNINGS, PRECAUTIONS sections). CONTRAINDICATIONS Patients with vomiting and diarrhea should not receive radio-iodide and concurrent antithyroid therapy should be discontinued 3 to 4 days before administration of radioiodide. Sodium Iodide I-131 is contraindicated in women who are, or who may become pregnant. (See Pregnancy section and Nursing section).

SIDE EFFECTS Although rare, reactions associated with the administration of iodine containing radiopharmaceuticals for diagnostic use include, in decreasing order of frequency, nausea, vomiting, chest pain, tachycardia, itching skin, rash and hives. DRUG INTERACTIONS No information provided.

SIDE EFFECTS Adverse events associated with the class of Sodium Iodide I-131 drug product include hypersensitivity reactions, radiation toxicities, and metabolic events. Immediate adverse reactions typically are related to hypersensitivity; e.g., anaphylaxis, rash, hives, bronchospasm, and other allergic events. Radiation adverse events are related to the dose include the following: Bone marrow depression, leukopenia, thrombocytopenia, acute leukemia, anemia, blood dyscrasia, chromosomal abnormalities, radiation sickness, and death. Delayed radiation toxicity includes radiation thyroiditis, gastritis and sialadentis. Metabolic adverse events include hypothyroidism and exaggerated hyperthyroidism due to radiation thyroiditis. Tenderness and swelling of the neck, pain on swallowing, sore throat and cough may occur about the 3rd day after treatment. Drug Abuse And Dependence Patients administered Sodium Iodide I 131 Solution USP are not at risk for developing chemical dependency. DRUG INTERACTIONS No information provided.

WARNINGS None. PRECAUTIONS General The uptake of radioiodide will be affected by recent intake of stable iodine in any form, or by the use of thyroid, anti-thyroid and certain other drugs. Accordingly, the patient should be questioned carefully regarding previous medication and procedures involving radiographic contrast media. The expiration date is not later than two months from the date of manufacture. The calibration date and the expiration date are stated on the container label. As in the use of any radioactive material, care should be taken to minimize radiation exposure to the patient, consistent with proper patient management, and to insure minimum radiation exposure to occupational workers. Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to evaluate carcinogenic potential, mutagenic potential, or whether this drug affects fertility in males or females. Pregnancy Category C Animal reproduction studies have not been conducted with Sodium Iodide I 131 (sodium iodide i 131 (sodium iodide i 131 capsules) capsules) Diagnostic Capsules. It is also not known whether Sodium Iodide I 131 (sodium iodide i 131 (sodium iodide i 131 capsules) capsules) Diagnostic Capsules can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Iodide I 131 (sodium iodide i 131 (sodium iodide i 131 capsules) capsules) Diagnostic Capsules should be given to a pregnant woman only if clearly needed. Ideally, examinations using radiopharmaceutical drug products – especially those elective in nature – of women of childbearing capability should be performed during the first ten days following the onset of menses. Nursing Mothers Radioiodine is excreted in human milk during lactation. Therefore, formula feedings should be substituted for breast feedings. Pediatric Use Safety and effectiveness in pediatric patients have not been established.

WARNINGS Sodium Iodide I-131 is not usually used for the treatment of hyperthyroidism in patients under 30 years of age unless circumstances preclude other methods of treatment. PRECAUTIONS General The recent intake of stable iodine in any form, or the use of thyroid or anti-thyroid drugs will affect the uptake of radioiodide. Accordingly, the patient should be questioned carefully regarding previous medication and procedures involving radiographic contrast media. Metabolic interactions Hyperthyroidism and thyrotoxic cardiac disease may be aggravated by radiation thyroiditis. Pre-treatment and posttreatment with antithyroid agents and/or beta-blockers, such as propranolol should be considered. Low serum chlorides or nephrosis may increase thyroid uptake of Sodium Iodide I-131. Renal function impairment may decrease excretion of radio-iodide and increase the amount of radiation exposure. Radiopharmaceuticals should be used only by nuclear physicians and/or radiopharmacists who are qualified by training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides (See Drug Handling And Final Dosage Form Preparation section). As in the use of any radioactive material, care should be taken to minimize radiation exposure to the patient consistent with proper patient management and to assure minimum radiation exposure to occupational workers. Carcinogenesis Experiments in animals with Sodium Iodide I-131 have demonstrated that radioiodide administration can induce thyroid adenomas and carcinomas. However, studies in humans have shown no conclusive evidence of thyroid carcinoma in hyperthyroid patients treated with Sodium Iodide I-131. Mutagenesis Mutagenic effects have not been clearly established in clinical studies of patients treated with Sodium Iodide I-131. However, chromosomal changes have been reported in laboratory studies. Impairment of Fertility A follow-up study of 627 women treated for differentiated thyroid carcinoma with Sodium Iodide I-131 revealed no evidence of fertility impairment. Pregnancy Category X See CONTRAINDICATIONS section. Sodium Iodide I-131 may cause fetal harm to the thyroid gland when administered to a pregnant woman. Radioiodide crosses the placenta and may cause severe and irreversible hypothyroidism in the neonate; the fetal thyroid begins to concentrate iodine during approximately the 12th week of gestation. The possibility of pregnancy should be assessed in women of childbearing potential. To avoid the possibility of fetal exposure to radiation, in those circumstances where the patient's pregnancy status is uncertain, a pregnancy test should be performed. Radioiodide therapy for the treatment of thyroid disease in women of childbearing age should only be performed when appropriate contraceptive measures have been taken or when pregnancy testing is negative. Adequate and well controlled studies have not been performed in animals. Nursing Mothers Sodium Iodide I-131 is distributed into breast milk and may reach concentrations equal to or greater than concentrations in maternal plasma. Formula feeding should be substituted for breast feeding until radiation levels have substantially decreased. Pediatric Use Safety and efficacy in pediatric patients have not been established. (See WARNINGS section). Geriatric Use Adequate and well controlled studies on the relationship of age to the effect of radioiodide have not been performed in geriatric population. This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.