LEVOTHYROXINE SODIUM

Levothyroxine Sodium for Injection contains synthetic crystalline levothyroxine (L-thyroxine) sodium salt. Levothyroxine sodium, USP has a molecular formula of C 15 H 10 I 4 NNaO 4 , a molecular weight of 798.85 g/mol (anhydrous), and the following structural formula: Levothyroxine Sodium for Injection is a sterile, preservative-free lyophilized powder consisting of the active ingredient, levothyroxine sodium, USP and the excipients mannitol and sodium hydroxide for pH adjustment in single-dose amber glass vials. Levothyroxine Sodium for Injection is available at three dosage strengths: 100 mcg per vial, 200 mcg per vial and 500 mcg per vial. Image

Levothyroxine sodium for injection is indicated for the treatment of myxedema coma. Important Limitations of Use: The relative bioavailability between levothyroxine sodium for injection and oral levothyroxine products has not been established. Caution should be used when switching patients from oral levothyroxine products to levothyroxine sodium for injection as accurate dosing conversion has not been studied. Levothyroxine sodium is an L-thyroxine product. Levothyroxine (T 4 ) sodium for injection is indicated for the treatment of myxedema coma. ( 1 ) Important Limitations of Use: The relative bioavailability of this drug has not been established. Use caution when converting patients from oral to intravenous levothyroxine. ( 1 )

An initial intravenous loading dose of levothyroxine sodium for injection between 300 mcg to 500 mcg followed by once daily intravenous maintenance doses between 50 mcg and 100 mcg should be administered, as clinically indicated, until the patient can tolerate oral therapy. ( 2.1 ) Reconstitute the lyophilized levothyroxine sodium for injection by aseptically adding 5 mL of 0.9% sodium chloride injection, USP. Shake vial to ensure complete mixing. Reconstituted drug product is preservative free. Use immediately after reconstitution. Discard any unused portion. ( 2.3 ) Do not add to other IV fluids. ( 2.3 ) 2.1 Dosage An initial intravenous loading dose of levothyroxine sodium for injection between 300 mcg to 500 mcg, followed by once daily intravenous maintenance doses between 50 mcg and 100 mcg, should be administered, as clinically indicated, until the patient can tolerate oral therapy. The age, general physical condition, cardiac risk factors and clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of levothyroxine sodium for injection. Levothyroxine sodium for injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 days to 10 days in hypothyroid patients. Daily administration of levothyroxine sodium for injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable. For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state. Relative bioavailability between levothyroxine sodium for injection and oral levothyroxine products has not been established. Based on medical practice, the relative bioavailability between oral and intravenous administration of levothyroxine sodium for injection is estimated to be from 48% to 74%. Due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly. 2.2 Dosing in the Elderly and in Patients with Cardiovascular Disease Intravenous levothyroxine may be associated with cardiac toxicity-including arrhythmias, tachycardia, myocardial ischemia and infarction or worsening of congestive heart failure and death—in the elderly and in those with underlying cardiovascular disease. Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations. 2.3 Reconstitution Directions Reconstitute the lyophilized levothyroxine sodium for injection by aseptically adding 5 mL of 0.9% sodium chloride injection, USP only. Shake vial to ensure complete mixing. The resultant solution will have a final concentration of approximately 20 mcg per mL, 40 mcg per mL and 100 mcg per mL for the 100 mcg, 200 mcg and 500 mcg vials, respectively. Reconstituted drug product is preservative free and is stable for 4 hours. Discard any unused portion. DO NOT ADD LEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

None. None. ( 4 )

Excessive doses of levothyroxine can predispose to signs and symptoms compatible with hyperthyroidism. The signs and symptoms of thyrotoxicosis include, but are not limited to: exophthalmic goiter, weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac arrhythmias, angina pectoris, tremors, insomnia, heat intolerance, fever and menstrual irregularities. Excessive doses of L-thyroxine can predispose to signs and symptoms compatible with hyperthyroidism. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., synthesis, secretion, catabolism, protein binding and target tissue response) and may alter the therapeutic response to levothyroxine sodium for injection. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs (see Section 12.3 ). Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding and target tissue response) and may alter the therapeutic response to levothyroxine sodium for injection. ( 7 , 12.3 ) 7.1 Antidiabetic Therapy Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed or discontinued. 7.2 Oral Anticoagulants Levothyroxine increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the levothyroxine sodium for injection dose is increased. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments. 7.3 Digitalis Glycosides The therapeutic effects of digitalis glycosides may be reduced by levothyroxine. Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. 7.4 Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. 7.5 Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. 7.6 Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. 7.7 Drug-Laboratory Test Interactions Changes in thyroxine binding globulin (TBG) concentration must be considered when interpreting levothyroxine and triiodothyronine values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free levothyroxine index. Pregnancy, infectious hepatitis, estrogens, estrogen containing oral contraceptives and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly and after androgen or corticosteroid therapy. Familial hyper or hypo thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9,000.

16.2 Storage and Handling Protect from light and store dry product at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Reconstituted drug product is preservative free. Discard any unused portion. This container closure is not made with natural rubber latex. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Please address medical inquiries to, [email protected] or Tel.: 1-877-993-8779.