Levothyroxine Sodium

LEVOTHYROXINE SODIUM- levothyroxine sodium injection, solution
Fresenius Kabi USA, LLC

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

Thyroid hormones, including Levothyroxine Sodium Injection, should not be used for the treatment of obesity or for weight loss.

Larger doses may produce serious or even life threatening manifestations of toxicity. (6,10)

1 INDICATIONS AND USAGE

Levothyroxine Sodium Injection is indicated for the treatment of myxedema coma.

Limitations of Use:

Not recommended as a substitute for oral levothyroxine sodium because the relative bioavailability of Levothyroxine Sodium Injection to oral levothyroxine sodium has not been established and there is a risk of inaccurate dose conversion.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

  • Consider the age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms when determining the starting and maintenance dosages of Levothyroxine Sodium Injection.
  • Start with lower doses in elderly patients and in patients with underlying cardiovascular disease [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].
  • The recommended loading dose of Levothyroxine Sodium Injection is 300 mcg to 500 mcg administered intravenously.
  • The recommended maintenance dose of Levothyroxine Sodium Injection is 50 mcg to 100 mcg administered intravenously daily until the patient can tolerate oral therapy.

2.2 Administration Instructions

  • Administer Levothyroxine Sodium Injection as an intravenous injection at a rate not to exceed 100 mcg per minute.
  • Do not add Levothyroxine Sodium Injection to intravenous fluids.
  • Inspect Levothyroxine Sodium Injection visually prior to injection. It should appear clear and colorless, solution free of visible particulates. Do not use if particulate matter or coloration is seen.
  • Discard any unused portion.

3 DOSAGE FORMS AND STRENGTHS

Levothyroxine Sodium Injection is clear, colorless solution supplied as:

  • 100 mcg per 5 mL (20 mcg per mL) single-dose vial

4 CONTRAINDICATIONS

Uncorrected adrenal insufficiency [see Warnings and Precautions (5.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease

Overtreatment with Levothyroxine Sodium Injection may cause arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death, particularly in patients with cardiovascular disease and in elderly patients. Start with lower doses in elderly patients and in patients with underlying cardiovascular disease and monitor patients after administration of Levothyroxine Sodium Injection for cardiac adverse reactions.

5.2 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency

Chronic autoimmune thyroiditis, which can lead to myxedema coma, may occur in association with other autoimmune disorders such as adrenal insufficiency. Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency [see Contraindications (4)]. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with Levothyroxine Sodium Injection.

5.3 Worsening of Diabetic Control

Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control [see Drug Interactions (7.2)].

6 ADVERSE REACTIONS

Adverse reactions associated with levothyroxine are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5), Overdosage (10)]. They include the following:

  • General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating
  • Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia
  • Musculoskeletal: tremors, muscle weakness, muscle spasm
  • Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest
  • Respiratory: dyspnea
  • Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests
  • Dermatologic: flushing, rash

Seizures have been reported rarely with the institution of levothyroxine therapy.

Hypersensitivity Reactions

Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

7 DRUG INTERACTIONS

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

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 Injection (see Tables 13).

Table 1: Drugs That May Alter T4 and Triiodothyronine (T3 ) Serum Transport Without Effecting Free Thyroxine (FT4 ) Concentration (Euthyroidism)
Drug or Drug Class Effect
ClofibrateEstrogen-containing oral contraceptivesEstrogens (oral)Heroin / Methadone5-FluorouracilMitotaneTamoxifen These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic SteroidsAsparaginaseGlucocorticoidsSlow-Release Nicotinic Acid These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs:CarbamazepineFurosemide (> 80 mg IV)HeparinHydantoinsNon-Steroidal Anti-inflammatory Drugs- Fenamates These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.
Table 2: Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements.
Drug or Drug Class Effect
PhenobarbitalRifampin Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5′-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.
Table 3: Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3 , leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class Effect
Beta-adrenergic antagonists(e.g., Propranolol > 160 mg/day) In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state.
Glucocorticoids(e.g., Dexamethasone ≥ 4 mg/day) Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs:Amiodarone Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.
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