Thyrolar

Statement from Forest Laboratories Re: Availability of Thyrolar:

[Posted 5/18/2012] U.S. Pharmacopeia, an official public standards-setting authority for all prescription and over-the-counter medicines and other health care products manufactured or sold in the United States, has mandated new specifications for a component used in the manufacturing of Thyrolar. As a result, all strengths of Thyrolar are currently on long-term back order while Forest makes the modifications necessary to meet these new specifications.

Forest is working diligently to complete these modifications. In the meantime, patients should speak with their physician regarding appropriate treatment for their condition, and check for future updates on the availability of Thyrolar through the Forest product availability toll-free hotline at (866) 927-3260.

Dosage Forms & Strengths

Each 60 mg tablet will replace approximately 60-65 mg (1 grain) of desicated thyroid

Liothyronine sodium (T3) is approximately 4 times as potent as levothyroxine (T4)

tablet, T3/T4

• Thyrolar 1/4 (15mg): 3.1/12.5mcg
• Thyrolar 1/2 (30mg): 6.25/25mcg
• Thyrolar 1 (60mg): 12.5/50mcg
• Thyrolar 2 (120mg): 25/100mcg
• Thyrolar 3 (180mg): 37.5/150mcg

Hypothyroidism

1 tab of Thyrolar 1/2 daily; follow with increments of 1 tab of Thyrolar 1/4 q2-3wk

Lower starting dose of 1 tab recommended in long-standing myxedema, especially if cardiovascular impairment suspected where extreme caution recommended

Maintenance: 1 tab Thyrolar 1 to 1 tab Thyrolar 2 per day; failure to respond to tab Thyrolar 3 may suggest lack of compliance or malabsorption

Adjust dose within the first 4 weeks of therapy after proper clinical laboratory evaluations where serum levels of T4 bound and free TSH are measured

Administer before breakfast

Dosage Forms & Strengths

Each 60 mg tablet will replace approximately 60-65 mg (1 grain) of desicated thyroid

Liothyronine sodium (T3) is approximately 4 times as potent as levothyroxine (T4)

tablet, T3/T4

• Thyrolar 1/4 (15mg): 3.1/12.5mcg
• Thyrolar 1/2 (30mg): 6.25/25mcg
• Thyrolar 1 (60mg): 12.5/50mcg
• Thyrolar 2 (120mg): 25/100mcg
• Thyrolar 3 (180mg): 37.5/150mcg

Congenital Hypothyroidism

0-6 months: 3.1/12.5 to 6.25/25 PO;

6-12 months: 6.25/25 to 9.35/37.5 PO;

1-5 years: 9.35/37.5-12.5/50 mcg PO;

6-12 years: 12.5/50-18.75/75 mcg PO;

>12 years: >18.75/75 mcg PO;

Administration: Before breakfast

Frequency Not Defined

Arrhythmias

Increased blood pressure

Chest pain

Palpitation

Anxiety

Headache

Urticaria

Changes in menstrual cycle

Insomnia

Hyperhydrosis pruritus

Tachycardia

Nervousness

Tremor

Cramps

Increased appetite

Weight loss

Diarrhea

Some hair loss may occur during the first few months of starting this drug. This effect is usually temporary as your body adjusts to this medication. If this effect persists or worsens, tell your doctor or pharmacist promptly.Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor immediately if any of these unlikely but serious effects of high thyroid hormone levels occur: diarrhea, bone pain, headache, mental/mood changes (e.g., nervousness, mood swings), shaking (tremor), sensitivity to heat, increased sweating, tiredness.Seek immediate medical attention if any of these rare but very serious effects of high thyroid hormone levels occur: chest pain, fast/pounding/irregular heartbeat, seizures, swelling of the ankles/feet.A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Before taking liotrix, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: increased thyroid hormones (thyrotoxicosis), a heart attack (acute myocardial infarction), adrenal gland problem (e.g., uncorrected adrenal insufficiency).Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart disease (e.g., coronary artery disease, irregular heartbeat), high blood pressure, diabetes, other hormone disorders (e.g., decreased pituitary hormone).If you have diabetes, this medication may increase your blood sugar levels. Check your blood glucose levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms of high blood sugar, such as increased thirst and urination. Your anti-diabetic medication or diet may need to be adjusted.Before having surgery, tell your doctor or dentist that you are taking this medication.Caution is advised when using this drug in the elderly because they may be more sensitive to the effects on the heart caused by high thyroid hormone level.Current information shows that this drug may be used during pregnancy. Tell your doctor if you are pregnant or if you become pregnant because your dose may need to be adjusted.Small amounts of this medication pass into breast milk. Consult your doctor before breast-feeding.

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: androgens/anabolic steroids, beta blockers (e.g., propranolol), "blood thinners" (e.g., warfarin), corticosteroids (e.g., dexamethasone), cytokines (e.g., interferon-alpha, interleukin-2), digoxin, drugs affecting liver enzymes that remove liotrix from your body (such as phenobarbital, rifamycins including rifabutin, certain anti-seizure medicines including carbamazepine/phenytoin), drugs that can decrease thyroid hormone levels (e.g., amiodarone, medications containing iodide/iodine, lithium), estrogen-containing products (including birth control pills), growth hormones, medications for depression (e.g., maprotiline, tricyclic antidepressants such as amitriptyline, SSRIs such as sertraline), theophylline.Certain medications (cholestyramine, colestipol, antacids, sucralfate, simethicone, iron, sodium polystyrene sulfonate, calcium carbonate, orlistat) can decrease the amount of liotrix that is absorbed by your body . If you are taking any of these drugs, separate them from this medication by at least 4 hours.Check the labels on all your medicines (e.g., cough-and-cold products, diet aids) because they may contain ingredients such as decongestants or caffeine that could increase your heart rate or blood pressure. Ask your pharmacist about using those products safely.This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

The steps in the synthesis of the thyroid hormones are controlled by thyrotropin (Thyroid Stimulating Hormone, TSH) secreted by the anterior pituitary. This hormone's secretion is in turn controlled by a feedback mechanism effected by the thyroid hormones themselves and by thyrotropin releasing hormone (TRH), a tripeptide of hypothalamic origin. Endogenous thyroid hormone secretion is suppressed when exogenous thyroid hormones are administered to euthyroid individuals in excess of the normal gland's secretion.

The mechanisms by which thyroid hormones exert their physiologic action are not well understood. These hormones enhance oxygen consumption by most tissues of the body, increase the basal metabolic rate, and the metabolism of carbohydrates, lipids, and proteins. Thus, they exert a profound influence on every organ system in the body and are of particular importance in the development of the central nervous system.

The normal thyroid gland contains approximately 200 mcg of levothyroxine (T4) per gram of gland, and 15 mcg of triiodothyronine (T3) per gram. The ratio of these two hormones in the circulation does not represent the ratio in the thyroid gland, since about 80 percent of peripheral triiodothyronine comes from mon-odeiodination of levothyroxine. Peripheral monodeiodination of levothyroxine at the 5 position (inner ring) also results in the formation of reverse triiodothyronine (T3), which is calorigenically inactive.

Triiodothyronine (T3) levels are low in the fetus and newborn, in old age, in chronic caloric deprivation, hepatic cirrhosis, renal failure, surgical stress, and chronic illnesses representing what has been called the "low triiodothyronine syndrome."

Pharmacokinetics

Animal studies have shown that T4 is only partially absorbed from the gastrointestinal tract. The degree of absorption is dependent on the vehicle used for its administration and by the character of the intestinal contents, the intestinal flora, including plasma protein, soluble dietary factors, all of which bind thyroid and thereby make it unavailable for diffusion. Only 41 percent is absorbed when given in a gelatin capsule as opposed to a 74 percent absorption when given with an albumin carrier.

Depending on other factors, absorption has varied from 48 to 79 percent of the administered dose. Fasting increases absorption. Malabsorption syndromes, as well as dietary factors (children's soybean formula, concomitant use of anionic exchange resins such as cholestyramine) cause excessive fecal loss. 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.

More than 99 percent of circulating hormones are bound to serum proteins, including thyroid-binding globulin (TBg), thyroid-binding prealbumin (TBPA), and albumin (TBa), whose capacities and affinities vary for the hormones. The higher affinity of levothyroxine (T4) for both TBg and TBPA 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.

Deiodination of levothyroxine (T4) occurs at a number of sites, including liver, kidney, and other tissues. The conjugated hormone, in the form of glucuronide or sulfate, is found in the bile and gut where it may complete an enterohepatic circulation. Eighty-five percent of levothyroxine (T4) metabolized daily is deiodinated.

In the U.S.

• Euthroid
• Thyrolar

Available Dosage Forms:

• Tablet

Therapeutic Class: Thyroid Supplement

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Do not run out of Thyrolar.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.
• If you are 65 or older, use Thyrolar with care. You could have more side effects.
• Use with care in children. Talk with the doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Thyrolar Tablets (Liotrix Tablets, USP) are available in five potencies coded as follows:

Composition
Name	(T3/T4 per tablet)	Color	Armacode®	NDC
Thyrolar-1/4	3.1 mcg/ 12.5 mcg	Violet/White	YC	0456-0040-01
Thyrolar-1/2	6.25 mcg/ 25 mcg	Peach/White	YD	0456-0045-01
Thyrolar-1	12.5 mcg/ 50 mcg	Pink/White	YE	0456-0050-01
Thyrolar-2	25 mcg/ 100 mcg	Green/White	YF	0456-0055-01
Thyrolar-3	37.5 mcg/ 150 mcg	Yellow/White	YH	0456-0060-01

Supplied in bottles of 100, two-layered compressed tablets.

Tablets should be stored at cold temperature, between 36˚F and 46˚F (2˚C and 8˚C) in a tight, light-resistant container.

Note: (T3 liothyronine sodium is approximately four times as potent as T4 thyroxine on a microgram for microgram basis.)

FOREST PHARMACEUTICALS, INC.
A Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045

Rev. January 2010
RMC #1436

© 2010 Forest Laboratories, Inc.

Synthetic thyroid agent; combination preparation containing tetraiodothyronine (levothyroxine, T4) sodium and triiodothyronine (liothyronine, T3) sodium.a b c d j

Contraindications

• Untreated thyrotoxicosis.b j

• AMI uncomplicated by hypothyroidism.j

• Uncorrected adrenal insufficiency.b j

• Known hypersensitivity to any ingredient in the formulation.b j (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Unlabeled Uses

Should not be used for the treatment of obesity or for weight loss either alone or with other therapeutic agents.b j k r In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.b j r Larger doses may produce serious or life-threatening toxicity, particularly when given in conjunction with sympathomimetic amines (e.g., anorectic agents).b j r

Should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.b j k r

Sensitivity Reactions

Hypersensitivity to thyroid hormone is not known to occur.b However, hypersensitivity reactions to inactive ingredients of thyroid hormone products have been reported and include urticaria, pruritus, rash, flushing, angioedema, abdominal pain, nausea, vomiting, diarrhea, fever, arthralgia, serum sickness, and wheezing.j

Major Toxicities

Effects on Bone Mineral Density

Increased markers of bone turnover.d

General Precautions

Therapy Monitoring

Thyroid agents have a narrow therapeutic index.j Avoid undertreatment or overtreatment, which may result in adverse effects on growth and development in pediatric patients, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, GI function, and glucose and lipid metabolism.j

Periodically perform appropriate laboratory tests (e.g., serum TSH, total or free T4, total T3) and clinical evaluations to monitor adequacy of therapy.a b c j

Preexisting Cardiovascular Disease

Use with extreme caution.b j (See Patients with Cardiovascular Disease under Dosage and Administration.) Patients with CHD should be monitored closely during surgical procedures due to increased risk of arrhythmias.j

Associated Endocrine Disorders

Hypopituitarism, adrenal insufficiency, and other endocrine disorders such as diabetes mellitus and diabetes insipidus are characterized by signs and symptoms which may be diminished in severity or obscured by hypothyroidism.j Thyroid agents may aggravate the intensity of previously obscured symptoms in patients with endocrine disorders, and appropriate adjustment of therapy for these concomitant disorders may be required.b j

In patients with secondary or tertiary hypothyroidism, consider possibility of additional hypothalamic/pituitary hormone deficiencies and treat if diagnosed.q

Chronic autoimmune thyroiditis may occur in association with other autoimmune disorders (e.g., adrenal insufficiency, pernicious anemia, type 1 diabetes mellitus.)e f

Patients with concomitant adrenal insufficiency should be treated with replacement corticosteroids prior to initiation of thyroid agents.j Failure to do so may precipitate an acute adrenal crisis due to increased metabolic clearance of corticosteroids when the thyroid agent is initiated.j

Patients with diabetes mellitus may require increased dosages of antidiabetic agents when treated with thyroid agents.b j

Specific Populations

Pregnancy

Category A.b

During pregnancy, serum free T4 levels may decrease and serum TSH levels increase to values outside the normal range.d q Elevations in serum TSH may occur at 4 weeks’ gestation;q monitor TSH levels during each trimester (or every 6 weeks) and adjust liotrix dosage accordingly.d e k Reduce dosage to pre-pregnancy level immediately after delivery, since postpartum TSH concentrations are similar to preconception levels; measure serum TSH concentrations 6–8 weeks postpartum.q

Lactation

Although thyroid hormones are distributed minimally into human milk, exercise caution when administering to a nursing woman.b However, adequate replacement dosages generally are needed to maintain normal lactation.o q

Pediatric Use

The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development.b j Initiate therapy immediately upon diagnosis.b j Maintain therapy for life, unless transient hypothyroidism is suspected.b j

Neonates with suspected hypothyroidism should receive thyroid agent therapy pending results of confirmative tests.j If a positive diagnosis cannot be made on the basis of laboratory findings but there is a strong clinical suspicion of congenital hypothyroidism, initiate replacement therapy to achieve euthyroidism until the child is 1–2 years of age.j During the first 2 weeks of therapy, closely monitor infants for cardiac overload, arrhythmias, and aspiration resulting from avid suckling.j Evaluate infant’s clinical response to therapy about 6 weeks after initiation of thyroid agent therapy and at least at 6 and 12 months of age and yearly thereafter.j

When transient hypothyroidism is suspected, temporarily discontinue therapy for 2–8 weeks to reassess the condition when the child is >3 years of age.b j m If the diagnosis of permanent hypothyroidism is confirmed, reinstitute full replacement therapy.j However, if serum concentrations of free T4 and TSH are normal, discontinue thyroid agent therapy and monitor carefully;b j repeat thyroid function tests if manifestations of hypothyroidism develop.j

In pediatric patients with transient severe hypothyroidism, reduce replacement dose by half for 30 days to reassess condition.m If, after 30 days, serum TSH >20 mU/L, consider the hypothyroidism permanent and reinstitute full replacement therapy.m However, if serum TSH has not increased, temporarily discontinue thyroid agent therapy for another 30 days, then repeat serum free T4 and TSH measurements.m Reinstitute or discontinue replacement therapy based on laboratory findings.m

Monitor patients closely to avoid undertreatment or overtreatment.j Undertreatment may result in poor school performance (due to impaired concentration and slowed mentation) and reduced adult height.j Overtreatment may result in craniosynostosis in infants and accelerate aging of bones, resulting in premature epiphyseal closure and compromised adult stature.j m

Treated children may manifest a period of catch-up growth, which may be adequate in some cases to achieve normal adult height.j In children with severe or long-standing hypothyroidism, catch-up growth may not be adequate to achieve normal adult height.j

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving thyroid agents.j

Geriatric Use

Because of the increased risk of cardiovascular disease among geriatric patients, liotrix therapy should not be initiated at the full replacement dose.b j k (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Adverse reactions result from overdosage and resemble manifestations of hyperthyroidism,a b j including fatigue,b j weight loss,j increased appetite,j heat intolerance,j fever,j excessive sweating,b j headache,b j hyperactivity,j nervousness,j anxiety,b j irritability,j emotional lability,j insomnia,b j tremor,b j muscle weakness,j palpitations,b j tachycardia,j arrhythmias,b j increased heart rate and BP,b j heart failure,j angina,j AMI,j cardiac arrest,j diarrhea,j vomiting,j abdominal cramps,j elevations in liver function test results,j hair loss,b j flushing,j decreased bone mineral density,j menstrual irregularities,j and impaired fertility.j

Storage

Oral

Tablets

Tight, light-resistant containers at 2–8°C.a b

Caution is recommended.

Excreted into human milk: Yes

Comments:
-This drug is a mixture of levothyroxine (T4) and liothyronine (T3) which are normal components of human milk.
-Limited data on exogenous replacement doses of T4 show no adverse effects on nursing infants.
-Dose requirements may be increased in the postpartum period compared to pre-pregnancy requirements in women with Hashimoto's thyroiditis.