HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CYTOMEL safely and effectively. See full prescribing information for CYTOMEL.
CYTOMEL® (liothyronine sodium) tablets, for oral use
Initial U.S. Approval: 1956
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
CYTOMEL is an L-triiodothyronine (T3) indicated for:
Limitations of Use:
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Tablets: 5 mcg, 25 mcg, 50 mcg (3)
Uncorrected adrenal cortical insufficiency (4)
WARNINGS AND PRECAUTIONS
Most common adverse reactions for CYTOMEL are primarily those of hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash (6)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See full prescribing information for drugs that 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 CYTOMEL (7)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION.
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
- Thyroid hormones, including CYTOMEL, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.
- In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.
- Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects [see Adverse Reactions (6), Drug Interactions (7.7), and Overdosage (10)].
2 DOSAGE AND ADMINISTRATION
5 WARNINGS AND PRECAUTIONS
6 ADVERSE REACTIONS
Adverse reactions associated with CYTOMEL therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5.4) and 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 and cramps
Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest
Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests
Dermatologic: hair loss, flushing
Endocrine: decreased bone mineral density
Reproductive: menstrual irregularities, impaired fertility
Adverse Reactions in Pediatric Patients
Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving thyroid replacement therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in pediatric patients with resultant compromised adult height.
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.
7 DRUG INTERACTIONS
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics
Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g. absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to CYTOMEL (see Tables 1 – 4).
|Potential impact: Concurrent use may reduce the efficacy of CYTOMEL by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.|
|Drug or Drug Class||Effect|
|Bile Acid Sequestrants
Ion Exchange Resins
|Bile acid sequestrants and ion exchange resins are known to decrease thyroid hormones absorption. Administer CYTOMEL at least 4 hours prior to these drugs or monitor TSH levels.|
|Drug or Drug Class||Effect|
Estrogen-containing oral contraceptives
Heroin / Methadone
|These drugs may increase serum thyroxine-binding globulin (TBG) concentration.|
|Androgens / Anabolic Steroids
Slow-Release Nicotinic Acid
|These drugs may decrease serum TBG concentration.|
|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%.|
Furosemide (>80 mg IV)
Hydantoins Non-Steroidal Anti-inflammatory Drugs
|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 increased 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 thyroid hormones, and total and FT4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.|
|Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of thyroid hormones, resulting in increased CYTOMEL requirements.|
|Drug or Drug Class||Effect|
|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 thyroid hormones.|
|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, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a 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).|
|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.|
7.2 Antidiabetic Therapy
Addition of CYTOMEL therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when CYTOMEL is started, changed, or discontinued [see Warnings and Precautions (5.5)].
7.3 Oral Anticoagulants
CYTOMEL 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 CYTOMEL dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.
7.4 Digitalis Glycosides
CYTOMEL may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides.
7.5 Antidepressant Therapy
Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and CYTOMEL 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 central nervous system stimulation. CYTOMEL may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on CYTOMEL may result in increased CYTOMEL requirements.
Concurrent use of ketamine and CYTOMEL may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.
Concurrent use of sympathomimetics and CYTOMEL 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.
7.8 Tyrosine-Kinase Inhibitors
Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients.
7.9 Drug-Laboratory Test Interactions
Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.
8 USE IN SPECIFIC POPULATIONS
Experience with liothyronine use in pregnant women, including data from post-marketing studies, have not reported increased rates of major birth defects or miscarriages (see Data). There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and CYTOMEL dosage adjusted during pregnancy (see Clinical Considerations). There are no animal studies conducted with liothyronine during pregnancy. CYTOMEL should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Disease-associated maternal and/or embryo/fetal risk
Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development.
Dose adjustments during pregnancy and the postpartum period
Pregnancy may increase CYTOMEL requirements. Serum TSH levels should be monitored and the CYTOMEL dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the CYTOMEL dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3)].
Limited published studies report that liothyronine is present in human milk. However, there is insufficient information to determine the effects of liothyronine on the breastfed infant and no available information on the effects of liothyronine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CYTOMEL and any potential adverse effects on the breastfed infant from CYTOMEL or from the underlying maternal condition.
8.4 Pediatric Use
The initial dose of CYTOMEL varies with age and body weight. Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters [see Dosage and Administration (2.3, 2.4)].
In pediatric patients in whom a diagnosis of permanent hypothyroidism has not been established, discontinue thyroid hormone for a trial period, but only after the child is at least 3 years of age. Obtain serum TSH, T4, and T3 levels at the end of the trial period, and use laboratory test results and clinical assessments to guide diagnosis and treatment, if warranted [see Dosage and Administration (2.6)].
Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, initiate thyroid hormone immediately upon diagnosis. Thyroid hormone is generally continued for life in these patients.
Closely monitor infants during the first 2 weeks of thyroid hormone therapy for cardiac overload, arrhythmias, and aspiration from avid suckling.
Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment is associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation, and may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature [see Dosage and Administration (2.6) and Adverse Reactions (6)].
Acquired Hypothyroidism in Pediatric Patients
Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.
Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height [see Adverse Reactions (6)].
8.5 Geriatric Use
Because of the increased prevalence of cardiovascular disease among the elderly, initiate CYTOMEL at less than the full replacement dose [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with thyroid hormone overtreatment in the elderly.
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5.4) and Adverse Reactions (6)]. In addition, confusion and disorientation may occur. Cerebral embolism, seizure, shock, coma, and death have been reported. Symptoms may not necessarily be evident or may not appear until several days after ingestion.
Reduce the CYTOMEL dose or temporarily discontinued if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient's medical status.
For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.
CYTOMEL tablets contain the active ingredient, liothyronine (L-triiodothyronine or LT3), a synthetic form of a thyroid hormone liothyronine in sodium salt form. It is chemically designated as L-Tyrosine, O-(4-hydroxy-3-iodophenyl)-3,5-diiodo-, monosodium salt. The molecular formula, molecular weight and structural formula of liothyronine sodium are given below.
CYTOMEL tablets contain liothyronine sodium equivalent to liothyronine in 5 mcg, 25 mcg, and 50 mcg. Inactive ingredients consist of calcium sulfate, corn starch, gelatin, stearic acid, sucrose and talc.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins.
The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.
The onset of activity of liothyronine sodium occurs within a few hours. Maximum pharmacologic response occurs within 2 or 3 days.
T3 is almost totally absorbed, 95 percent in 4 hours. The hormones contained in the natural preparations are absorbed in a manner similar to the synthetic hormones.
Liothyronine sodium (T3) is not firmly bound to serum protein. The higher affinity of levothyroxine (T4) for both thyroid-binding globulin and thyroid-binding prealbumin as compared to triiodothyronine (T3) partially explains the higher serum levels and longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium with minute amounts of free hormone, the latter accounting for the metabolic activity.
The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3. T3 is further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.
16 HOW SUPPLIED/STORAGE AND HANDLING
CYTOMEL tablets (round, white to off-white) are supplied as follows:
|Strength||Tablet Markings||NDC – bottles of 100|
|5 mcg||Debossed with KPI on one side and 115 on the other side||60793-115-01|
|25 mcg||Scored and debossed with KPI on one side and 116 on the other side||60793-116-01|
|50 mcg||Scored and debossed with KPI on one side and 117 on the other side||60793-117-01|
17 PATIENT COUNSELING INFORMATION
Dosing and Administration
- Instruct patients that CYTOMEL should only be taken as directed by their healthcare provider.
- Instruct patients to notify their healthcare provider should they become pregnant or breastfeeding or are thinking of becoming pregnant, while taking CYTOMEL.
- Inform patients that the liothyronine in CYTOMEL is intended to replace a hormone that is normally produced by the thyroid gland. Generally replacement therapy is to be taken for life.
- Inform patients that CYTOMEL should not be used as a primary or adjunctive therapy in a weight control program.
- Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations.
- Instruct patients to notify their healthcare provider of any other medical conditions, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while taking CYTOMEL. If patents are taking anticoagulants (blood thinners), their clotting status should be checked frequently.
- Instruct patients to notify their physician or dentist if they are taking CYTOMEL prior to any surgery.
- Instruct patients to notify their healthcare provider if they experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event [see Adverse Reactions (6)].
- Inform patients that partial hair loss may occur rarely during the first few months of CYTOMEL therapy; this is usually temporary [see Adverse Reactions (6)].