SODIUM IODIDE I-131: 372 Adverse Event Reports & Safety Profile

11 DESCRIPTION

11.1 Chemical Characteristics Sodium Iodide I-131 Solution, a radioactive therapeutic agent, provides a concentrated solution of sodium iodide I-131 with a radioconcentration of 37,000 MBq/mL (1,000 mCi/mL). Each mL of the concentrated solution contains 37,000 MBq of no-carrier-added sodium iodide I-131, disodium edetate dihydrate USP as a stabilizer, sodium thiosulfate pentahydrate USP as a reducing agent, and dibasic sodium phosphate anhydrous USP. The pH of the concentrated solution is between 7.5 and 10. The concentrated solution provided with Sodium Iodide I-131 Solution is used for the preparation of sodium iodide I-131 capsules or sodium iodide I-131 solution of varying strengths for oral administration for therapy. Sodium iodide I-131 solution is designated chemically as Na 131 I and has a molecular weight of 153.99 g/mol. Hard gelatin capsules, provided for the preparation of the sodium iodide I-131 capsules final dosage form, contain approximately 300 mg of dibasic sodium phosphate anhydrous USP as the absorbing buffer.

11.2 Physical Characteristics Iodine I-131 decays by beta emission and associated gamma emission with a physical half-life of 8.02 days. The principal radiation emissions are listed in Table 5.

Table

5 Principal Radiation Emission Data from Decay of Sodium Iodide I 131 Radiation Mean % per Disintegration Mean Energy (keV) Beta-1 2.1%

69.4 Beta-3 7.2%

96.6 Beta-4 89.4%

191.6 Gamma-7 6.1%

284.3 Gamma-14 81.2%

364.5 Gamma-18 7.1% 637.0

11.3 External Radiation The specific gamma-ray constant for iodide I 131 is 4.26 × 10 -13 C·m 2 ·kg -1 ·MBq -1 ·s -1 (2.2 R·cm 2 /mCi·hr). The first half-value thickness of lead (Pb) for iodide I 131 is 0.27 cm. A range of values for the relative attenuation of the radiation emitted by iodide I 131 that results from interposition of various thicknesses of Pb is shown in Table 6. For example, the use of 2.59 cm of Pb will decrease the external radiation exposure by a factor of about 1,000.

Table

6 Radiation Attenuation of Iodine I 131 by Lead Shielding Shield Thickness (Pb) cm Coefficient of Attenuation 0.27 0.5 0.56 0.25 0.99 10 -1 2.59 10 -2 4.53 10 -3 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 7.

Table

7 Physical Decay Chart: Iodine I-131 Half-Life 8.02 days *Calibration time Days Fraction Remaining Days Fraction Remaining Days Fraction Remaining 0* 1.000 11 .386 22 .149 1 .917 12 .354 23 .137 2 .841 13 .325 24 .126 3 .772 14 .298 25 .115 4 .708 15 .274 26 .106 5 .649 16 .251 27 .097 6 .595 17 .230 28 .089 7 .546 18 .211 29 .082 8 .501 19 .194 30 .075 9 .459 20 .178 10 .421 21 .163

AND USAGE Sodium Iodide I 131 Capsules Diagnostic is indicated for use in adults for: Assessment of thyroid function using radioactive iodine (RAI) uptake test Imaging the thyroid (scintigraphy)

Sodium

Iodide I 131 Capsules Diagnostic is a radioactive diagnostic agent indicated for the assessment of thyroid function and for thyroid imaging.

AND ADMINISTRATION The concentrated sodium iodide I 131 solution USP provided with HICON ® must be diluted. ( 2.2 )

See Full Prescribing

Information for important administration instructions and dilution and preparation instructions for sodium iodide l 131 capsules or oral solution. ( 2.2 , 2.4 ) The recommended dose is based on the thyroid gland uptake as well as the size of the gland: Treatment of Hyperthyroidism: Recommended dosage is 148 MBq to 370 MBq (4 mCi to 10 mCi). ( 2.3 ) Treatment of Thyroid Carcinoma: Recommended dosage is 1,110 MBq to 3,700 MBq (30 mCi to 100 mCi). ( 2.3 )

2.1 Radiation Safety HICON ® is a radioactive drug. Handle with appropriate safety measures to minimize radiation exposure to the patient and healthcare workers <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 )]</span> : Use only by, or under the direction of, physicians who are qualified by specific training and experience in the safe use and handling of radioactive materials, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals. Use waterproof gloves when handling and administering the product. Maintain adequate shielding during the life of the product. Measure patient dose with a suitable radioactivity calibration system immediately prior to administration.

2.2 Important Administration Instructions Do not directly administer the concentrated sodium iodide I 131 solution USP provided with HICON ® to patients. The concentrated sodium iodide I 131 solution USP must be diluted and prepared prior to administration <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> . Obtain a pregnancy test in females of reproductive potential prior to administration to verify the absence of pregnancy <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 , 8.3 )]</span> . Instruct patients to fast at least 2 hours before and 2 hours after administration to ensure absorption. Instruct patients to hydrate before and after administration of sodium iodide I 131 and to void frequently to enhance urinary elimination of the radioiodide that is not absorbed by the thyroid gland <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . Instruct patients to maintain a low-iodide diet two weeks prior to radioiodide administration and continue for several days during the uptake or imaging process <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 ) and Drug Interactions ( 7 )]</span> . Instruct patients to discontinue the anti-thyroid therapy three days before administration of sodium iodide I 131 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 ) and Drug Interactions ( 7 )]</span> . For patients with a history of renal impairment, evaluate renal function for therapeutic planning and consider dosimetry <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> . Obtain a complete blood count within one month of therapy. If patients show leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity, while delivering less than 2 Gy to the bone marrow <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

2.3 Recommended Dosage and Administration Individualization of Therapy The recommended dose for orally administered sodium iodide I 131 capsules or solution 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. Treatment of Hyperthyroidism The recommended dose is 148 MBq to 370 MBq (4 mCi to 10 mCi) administered orally. Toxic nodular goiter may require a larger dose. Treatment of Thyroid Carcinoma The recommended dose is 1,100 MBq to 3,700 MBq (30 mCi to 100 mCi) administered orally. For subsequent ablation of metastases, the recommended dose is 3,700 MBq to 7,400 MBq (100 mCi to 200 mCi) administered orally.

2.4 Dilution and Preparation Instructions Drug Handling Wear waterproof gloves throughout the entire handling and administration procedure. Make all transfers of radioactive solutions with an adequately shielded syringe or remote handling equipment and maintain adequate shielding around the vial during the useful life of the radioactive product. Preparation of Dilute Sodium Iodide I 131 Solution Using the calibration date and radionuclide 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 the solution diluent 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. Acidic diluents should not be used as they may cause the pH to drop below 7.5 and stimulate the volatilization of Iodine I 131 hydriodic acid. Present the dose in a shielded container for administration to the patient with a straw. Preparation of Sodium Iodide I 131 Capsules HICON ® 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. Using the calibration date and radionuclide concentration on the label of the product vial, calculate the required volume to produce the necessary dose in MBq or mCi. Open one LARGE capsule supplied with HICON ® by pulling apart the capsule into two pieces as illustrated below: Insert an unopened SMALL capsule supplied with HICON ® into the bottom half of the empty LARGE capsule as illustrated below: With an appropriate syringe, withdraw the required volume of sodium iodide I 131 solution USP (maximum 150 microliters) from the vial as illustrated below: Inject into the center of the SMALL capsule through the top as illustrated below and wait for 30 seconds to allow the solution to be absorbed by the absorbing buffer: 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: Measure the patient dose in a suitable radioactivity calibration system immediately prior to administration. Prepared capsules may be stored in a suitable polypropylene container and placed inside a lead pot until use, within seven days. image description image description image description image description image description

2.5 Radiation Dosimetry The biokinetic modeling and radiation dose distributions associated with thyroid uptake of iodide I 131 depend on dietary intake of stable iodide and presume normal production of thyroid hormone.

Table

1 shows a range of uptake percentages in an average adult (73.7 kg reference model).

Table

1 is not intended to be used for treatment planning. For a thyroid blocked from iodide uptake in the production of hormones, the effective half-life of iodide I 131 is approximately 1.4 hours; for “low” to “high” uptake, the effective half-life of I 131 ranges from approximately 80 hours to 90 hours.

Table

1 Table 1 is not intended for treatment planning. - Absorbed dose per unit activity sodium iodide I 131 administered orally (mGy/MBq) in adult (73.7 kg reference model)

Organ

Thyroid uptake of I 131 (% administered activity A 0 ) 24 h after oral administration Blocked thyroid (0% A 0 ) Low uptake These columns are not applicable to estimate organ or effective doses in patients following thyroidectomy. In patients with thyroid cancer following thyroidectomy, organ and effective doses can be estimated from the "blocked"-thyroid-uptake values. (16% A 0 ) Medium uptake (26% A 0 ) High uptake (36% A 0 )

Adrenals

0.044 0.051 0.055

0.059 Bone surfaces 0.03 0.089 0.12

0.16 Brain 0.021 0.093 0.13

0.17 Breast 0.02 0.038 0.048

0.058 Gallbladder wall 0.037 0.043 0.046

0.049 Gastrointestinal tract Esophagus 0.024 0.1 0.14

0.19 Stomach wall 0.87 0.77 0.71

0.66 Small intestine wall 0.035 0.033 0.032

0.032 Colon wall 0.14 0.14 0.14 0.14 (Upper large intestine wall) 0.12 0.12 0.12 0.12 (Lower large intestine wall) 0.17 0.17 0.17

0.16 Heart wall 0.062 0.089 0.1

0.12 Kidneys 0.27 0.27 0.27

0.27 Liver 0.05 0.093 0.12

0.14 Lungs 0.053 0.1 0.13

0.15 Muscles 0.026 0.084 0.12

0.15 Ovaries 0.038 0.037 0.036

0.035 Pancreas 0.06 0.064 0.066

0.068 Red marrow 0.031 0.072 0.095

0.12 Salivary glands 0.27 0.22 0.19

0.16 Skin 0.019 0.043 0.057

0.071 Spleen 0.064 0.069 0.072

0.075 Testes 0.025 0.024 0.023

0.22 Thymus 0.024 0.1 0.14

0.19 Thyroid 2.2 280 These values presume unimpeded production of thyroid hormone and may not be applicable to estimate thyroid dose and effective dose in patients who have had previous treatment with I 131 for hyperthyroidism. 430 580 Urinary bladder wall 0.54 0.45 0.39

0.34 Uterus 0.045 0.042 0.04

0.038 Remaining organs 0.029 0.084 0.11

0.15 Effective dose per administered activity (mSv/MBq) 0.28 14 22 29

HICON ® is contraindicated in: Patients with vomiting and diarrhea [see Warnings and Precautions ( 5.7 )] . Patients with thyroid malignancies shown to have no iodide update, which include the majority of medullary or anaplastic carcinomas. Patients receiving concurrent anti-thyroid therapy [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 )] . Pregnancy [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] . Lactation [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.2 )] . Patients with vomiting and diarrhea. ( 4 ) Patients with thyroid malignancies shown to have no iodide uptake. ( 4 ) Patients receiving concurrent anti-thyroid therapy. ( 4 ) Pregnancy. ( 4 ) Lactation. ( 4 )

REACTIONS The following clinically significant adverse reactions are described below and elsewhere in labeling: Radiation-induced Thyroiditis [see Warnings and Precautions ( 5.1 )] . Radiation-induced Toxicities [see Warnings and Precautions ( 5.2 )] .

Hypersensitivity

Reactions [see Warnings and Precautions ( 5.3 )] . Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] .

Increased Radiation

Exposure to Breast Tissue with Lactation [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.2 )] .

Transient

Infertility [see Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.3 )] .

Radiation

Exposure to Other Individuals [see Warnings and Precautions ( 5.7 )] . Risk of Decreased Effectiveness of Therapy [see Warnings and Precautions ( 5.8 )] . Common adverse reactions reported with therapeutic doses of sodium iodide I 131 include local swelling, radiation sickness, sialadenitis, salivary gland dysfunction, bone marrow depression, lacrimal gland dysfunction, hypothyroidism, hyperthyroidism, thyrotoxic crisis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Jubilant DraxImage Inc., dba Jubilant Radiopharma TM at 1-888-633-5343 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Postmarketing Experience The following adverse reactions have been reported during post-approval use of sodium iodide I 131 (Table 3). 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.

Table

3 Postmarket Adverse Reactions by System Organ Class System Organ Class In alphabetical order Symptoms Cardiac disorders Chest pain, tachycardia Congenital, familial and genetic disorders Chromosomal abnormalities, congenital hypothyroidism Endocrine disorders Hyperthyroidism, hypoparathyroidism, hypothyroidism, thyrotoxic crisis Eye disorders Lacrimal gland dysfunction Gastrointestinal disorders Gastritis, nausea, salivary gland dysfunction, sialadenitis, vomiting General disorders and administration site conditions Local swelling of thyroid or sites of iodide avid tumor Hematologic and lymphatic disorders including fatalities Anemia, blood dyscrasia, bone marrow depression, leukopenia, thrombocytopenia Immune system disorders Bronchospasm Neoplasms benign, malignant and unspecified (including cysts and polyps) Acute leukemia, solid cancer Nervous system disorders In patients with iodide-avid brain metastases Cerebral edema, headache Respiratory, thoracic and mediastinal disorders In patients with iodide-avid lung metastases Pulmonary fibrosis, radiation pneumonitis Skin and subcutaneous tissue disorders Hives, itching, rash

AND PRECAUTIONS Radiation-induced thyroiditis may cause or worsen hyperthyroidism. Consider pre-treatment with anti-thyroid medications. ( 5.1 ) Multiple non-thyroid radiation toxicities, including hematopoietic suppression: Individualize dose and monitor for toxicity. ( 5.2 ) Embryo-Fetal toxicity: May cause severe and irreversible hypothyroidism in the neonate. Verify pregnancy status in females of reproductive potential prior to initiating treatment. Females and males of reproductive potential should use effective contraception. ( 5.4 , 8.1 , 8.3 ) Radiation exposure to breast tissue with lactation: Sodium iodide I 131 concentrates in the breast of lactating women. Discontinue breast feeding at least 6 weeks prior to therapy. ( 5.5 , 8.2 )

5.1 Radiation-induced Thyroiditis Sodium iodide I 131 may cause thyroiditis with gland enlargement and release of thyroid hormone, which may cause or aggravate hyperthyroidism, thyroid storm and thyrotoxic cardiac disease <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . When treating hyperthyroidism, consider pre-treatment anti-thyroid medication to help deplete the thyroid hormone content within the gland. Discontinue the anti-thyroid medication at least three days before administration of sodium iodide I 131 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Consider a beta-blocker pre or post-treatment to minimize the risk of hyperthyroidism and thyroid storm. Thyroiditis may cause gland enlargement resulting in tenderness and swelling of the neck, pain on swallowing, sore throat, and cough; which may occur approximately the third day after sodium iodide I 131 administration. Consider management with pain-reliever or anti-inflammatory medications.

5.2 Radiation-induced Toxicities Sodium Iodide I 131 may cause radiation induced toxicities <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> : Dose-dependent fatalities (bone marrow suppression, malignancy). Dose-dependent hematopoietic suppression which manifests as a transient thrombocytopenia or neutropenia 3 to 5 weeks following sodium iodide I 131 administrations, may lead to increased susceptibility to infections or bleeding. Salivary gland toxicity: sialadenitis, xerostomia. Lacrimal gland toxicity: conjunctivitis, xerophthalmia, and epiphora. Increased risk of developing new solid tumors and leukemias. Obtain a complete blood count within one month of therapy. If patients show leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity, while delivering less than 2 Gy to the bone marrow. Advise good hydration for one week following sodium iodide I 131 administration and stimulate salivary flow via a sialagogue (e.g. sugar-free candy or gum, pilocarpine, and ascorbic acid) to reduce radiation exposure to the salivary glands. Advise patients to void frequently after administration of radioiodide to enhance excretion.

5.3 Hypersensitivity Reactions Hypersensitivity reactions including anaphylaxis may occur in patients who receive sodium iodide I 131. Although iodide is not considered an allergen, hypersensitivity reactions may occur in relation with excipients or chemical component of the capsule, such as sodium thiosulfate. Obtain and document an allergy history, particularly a sulfite allergy. Emergency resuscitation equipment and personnel should be immediately available <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> .

5.4 Embryo-Fetal Toxicity HICON ® is contraindicated in pregnancy because sodium iodide I 131 crosses the placenta and fetal exposure can lead to neonatal hypothyroidism. Multiple reports in the published literature describe hypothyroidism in the neonates following in utero exposure to sodium iodide I 131. Some cases of neonatal hypothyroidism were severe and irreversible. Verify pregnancy status of females of reproductive potential prior to initiating HICON ® treatment. Advise females and males of reproductive potential to use effective contraception during treatment with HICON ® and for at least 6 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

5.5 Increased Radiation Exposure to Breast Tissue with Lactation HICON ® is contraindicated in lactating women because sodium iodide I 131 concentrates in the breast via the increased expression of the sodium iodide symporter in breast tissue with lactation. The literature describes moderate to marked radioiodine uptake in the breast tissue for 5 to 32 weeks post cessation of breast feeding. Advise lactating women to discontinue breast feeding at least 6 weeks prior to administration of sodium iodide I 131 to allow sufficient time for involution to occur and to avoid excess concentration of sodium iodide I 131 in breast tissue. Consider administration of drugs to suppress lactation. Consider diagnostic scintigraphy before administration of sodium iodide I 131 to assess the persistence of uptake by breast tissue. If sodium iodide I 131 is administered in the postpartum period, the lactating mother should not breastfeed the infant <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.2 )]</span> .

5.6 Transient Infertility Transient dose-related impairment of testicular function in men and transient ovarian insufficiency in women has been reported after sodium iodide I 131 therapy. Sperm banking for men may be considered prior to administration of HICON ® for thyroid carcinoma <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span>.

5.7 Radiation Exposure to Other Individuals Household Contacts Instruct patients to follow radiation safety precautions after receiving HICON ® to minimize the radiation contamination of other persons or the environment. Patients should avoid close contact with others, especially pregnant women and children, and take care to avoid contamination of other persons or the environment with body fluids. Patients and Healthcare Providers HICON ® contributes to a patient’s overall long-term cumulative radiation exposure, which is associated with an increased risk of cancer. Follow safe handling and administration to minimize radiation exposure to the patient and healthcare providers.

5.8 Risk of Decreased Effectiveness of Therapy Certain food or drugs may alter the thyroid uptake of sodium iodide I 131 and diminish its effectiveness. Recent intake of stable iodide in any form, or the use of thyroid or anti-thyroid drugs may diminish thyroid uptake of sodium iodide I 131 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

INTERACTIONS Concomitant use of bone marrow depressants may enhance the depression of the hematopoietic system caused by the use of large doses of sodium iodide I 131 [see Warnings and Precautions (5.2 )] . Many drugs and iodide-containing foods interfere with the accumulation of radioiodide by the thyroid. Review the patients history, current medications, and recent diagnostic tests prior to the administration of sodium iodide I 131 [see Warnings and Precautions (5.8) ] . Advise patients to maintain a low-iodide diet two weeks prior to radioiodide administration and continue for several days during the uptake or imaging process and to discontinue taking the following products before they undergo the procedure as shown in Table 4.

Table

4 Pharmaceuticals/OTCs/Agents Blocking Radioiodine Uptake Type of Medication Recommended time of withdrawal Thionamide medications (e.g., propylthiouracil, methimazole, carbimazole) 3 days Multivitamins containing iodide 10 days Natural or synthetic thyroid hormones triiodothyronine thyroxine 2 weeks 4 weeks Iodide-containing foods: iodized salt, dairy products, egg yolks, seafood, turkey and liver 2 weeks Kelp, agar, carrageenan, Lugol solution 3 weeks Saturated solution of potassium iodide 3 weeks Topical iodide (e.g., surgical skin preparation) 3 weeks Intravenous radiographic contrast agents Water soluble Lipophilic 2 months 6 months Amiodarone 6 months Many drugs and iodine-containing foods interfere with the accumulation of radioiodide by the thyroid. Instruct patients to maintain a low-iodide diet (2 weeks) and discontinue anti-thyroid therapy (3 days) before administration. ( 5.8 , 7 )