Sodium Iodide I 131

HICON ® is indicated for the treatment of hyperthyroidism and selected cases of thyroid carcinoma. HICON ® is a radioactive therapeutic agent indicated for the treatment of hyperthyroidism and selected cases of carcinoma of the thyroid.

HICON ® is available in 1 mL size, clear vials containing a colorless, aqueous, concentrated Sodium Iodide I 131 Solution USP [9,250 MBq (250 mCi), 18,500 MBq (500 mCi), and 37,000 MBq (1,000 mCi) at time of calibration] for the preparation of sodium iodide I 131 capsules, therapeutic or sodium iodide I 131 solution, therapeutic. Refer to Table 2 for the radioactivity and volume in each vial. Large gelatin capsules (empty) and small gelatin capsules containing approximately 300 mg of dibasic sodium phosphate anhydrous as the absorbing buffer are supplied along with HICON ® for the preparation of sodium iodide I 131 capsules, therapeutic. Table 2 HICON ® Concentrated Sodium Iodide I 131 Solution USP Total Radioactivity At time of calibration / Via l Solution Volume (mL) / Vial 9,250 MBq (250 mCi) 0.25 18,500 MBq (500 mCi) 0.5 37,000 MBq (1,000 mCi) 1 Vials: Sodium Iodide I 131 Solution [9,250 MBq (250 mCi), 18,500 MBq (500 mCi), and 37,000 MBq (1,000 mCi) at time of calibration] for the preparation of sodium iodide I 131 capsules, therapeutic or sodium iodide I 131 solution, therapeutic.

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 )

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 [see Adverse Reactions (6) ] . 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 [see Drug Interactions (7) ]. 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 [see Adverse Reactions (6) ] : 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 [see Adverse Reactions (6) ] .

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 [see Use in Specific Populations ( 8.1 , 8.3 )] .

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 [see Use in Specific Populations ( 8.2 )] .

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 [see Use in Specific Populations ( 8.3 )].

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 [see Drug Interactions ( 7 )] .

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

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 patient’s 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 pharmacologic agents are known to interact with radioiodide. See Full Prescribing Information complete list. ( 5.8 , 7 )

Pregnancy. ( 4 ) Lactation. ( 4 ) Females and Males of Reproductive Potential: May impair fertility in females and males. ( 5.6 , 8.3 )

8.1 Pregnancy Risk Summary HICON ® is contraindicated in pregnancy because fetal exposure can lead to neonatal hypothyroidism, which in some cases is severe and irreversible [See Warnings and Precautions ( 5.4 )] . Data from the published literature describe reports of neonatal thyroid abnormalities after fetal exposure; including agenesis of the thyroid and hypothyroidism (see Clinical Considerations, Data) . No animal reproductive studies have been conducted. Clinical Considerations Fetal/ Neonatal Adverse Reactions A fetus exposed to sodium iodide I 131 can develop neonatal hypothyroidism. Delay in diagnosis of neonatal hypothyroidism after exposure to sodium iodide I 131 in utero can result in severe sequelae such as cognitive impairment and delayed bone age. Monitor thyroid function in any infant born after in utero exposure to sodium iodide I 131. Data Human Data Sodium iodide I 131 crosses the placenta and the fetal thyroid begins to concentrate iodide during the 10 th to 12 th week of gestation. In literature reports of maternal exposures to sodium iodide I 131 at doses of 333 MBq to 8,325 MBq (9 mCi to 225 mCi) during 4 to 26 weeks gestational age, the most common adverse outcomes were hypothyroid infants and children.

8.2 Lactation Risk Summary HICON ® is contraindicated during lactation because I 131 concentrates in the breast during lactation via the increased expression of the sodium iodide symporter in breast tissue and can lead to hypothyroidism in the infant through breastfeeding. If sodium iodide I 131 is administered postpartum, breastfeeding should not be restarted for the remainder of the postpartum period. In addition, to minimize the absorbed radiation dose to the breast tissue, breastfeeding and breast-pumping should be discontinued for at least 6 weeks before administration of sodium iodide I 131 [see Data and Warnings and Precautions ( 5.5 )] . Infants exposed to sodium iodide I 131 through breast milk are at risk for development of hypothyroidism because sodium iodide I 131 is distributed into breast milk and may reach concentrations equal to or greater than concentrations in maternal plasma (see Data) . Data Published literature describes sodium iodide I 131 transfer into breast milk and uptake by the thyroid of the breastfed infant. The amount of sodium Iodide I 131 detected in the breast milk at 36 to 48 hours after administration is 1% to 27% of the injected dose (with injected doses between 1.1 MBq (0,0297 mCi) to 5,143 MBq (139 mCi)).

8.3 Female and Males of Reproductive Potential HICON ® is contraindicated in pregnancy because of the risk of fetal hypothyroidism [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.1 )] . Pregnancy Testing Obtain a pregnancy test in females of reproductive potential and verify the absence of pregnancy within 24 hours prior to administration of treatment [see Dosage and Administration ( 2.2 )] . Contraception Advise females and males of reproductive potential to use effective contraception during treatment with HICON ® and for at least six months after the last dose of HICON ® . Infertility Females Fertility may be impaired with HICON ® treatment. Transient amenorrhea and ovarian insufficiency have been observed after sodium iodide I 131 therapy in females. The literature describes reports of transient menstrual cycle irregularities, including amenorrhea, and ovarian failure in females treated with cumulative doses of 1,000 MBq to 59,000 MBq (27 mCi to 1,595 mCi) sodium iodide I 131. In a published literature analysis, the effects on fertility occurred in up to 30% of women treated with sodium iodide I 131, and may resolve 12 months after treatment. Males Fertility may be impaired with HICON ® treatment. Discuss sperm banking for males who are expected to receive a high cumulative dose of sodium iodide I 131. Transient dose-related impairment of testicular function after sodium iodide I 131 therapy has been reported in the published literature. The literature describes reports of males treated with sodium iodide I 131 at doses of 370 MBq to 22,000 MBq (10 mCi to 595 mCi) resulting in transiently impaired testicular function (including spermatogenesis). The risk of persistent testicular dysfunction increases after administration of repeated or high cumulative radioiodide exposure.

8.4 Pediatric Use The safety and effectiveness of HICON ® have not been established in pediatric patients. Pediatric patients are at an increased lifetime risk for malignancy from radiation exposure.

8.5 Geriatric Use Clinical experience has not identified differences in safety or effectiveness in geriatric patients compared to younger patients. However, elderly patients are more likely to have decreased renal function and radiation exposure is greater in patients with impaired renal function [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 ) ].

8.6 Renal Impairment HICON ® is primarily excreted by the kidneys. Renal function impairment decreases excretion of sodium iodide I 131 and increases the radiation exposure and risk of radiation toxicity. For patients with a history of renal impairment, evaluate renal function for therapeutic planning and consider dosimetry. Sodium Iodide I 131 is dialyzable. Hemodialysis can be used to reduce total body radiation exposure [see Clinical Pharmacology ( 12.3 )].

Iodide is actively transported by the sodium-iodide symporter (NIS) protein, in thyroid follicular cells. Iodide is concentrated in follicular cells to levels up to 50 times higher than in the plasma. Iodide is metabolically oxidized by thyroid peroxidase to iodinium (I + ) which in turn iodinates tyrosine residues of thyroglobulin (tri or tetra-iodinated tyrosine). The beta emission of I 131 is responsible for the therapeutic effect.