Precise Dosing of Levothyroxine

Release Date: June 1, 2007

Expiration Date: June 30, 2009 

FACULTY:

John B. Tourtelot, RPh, MD
Assistant Clinical Professor of Medicine
University of South Florida
Tampa, FL

FACULTY DISCLOSURE STATEMENTS:

John B. Tourtelot has served on the speakers' bureaus of Abbott Laboratories and Sanofi-Aventis.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

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Pharmacists
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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities. GOAL:
To understand the use of levothyroxine, with emphasis on the importance of the precise dosing of this hormone.

OBJECTIVES: 

After completing this article, the pharmacist will be able to:

  1. Review the clinical significance of levothyroxine's narrow therapeutic range.
  2. Explain the FDA's criteria for determining bioequivalence and therapeutic equivalence of drugs.
  3. List current guidelines for the treatment of thyroid disorders utilizing levothyroxine products.
  4. Describe the role of clinicians in managing and monitoring patients undergoing therapy with levothyroxine.


Thyroid hormones are necessary throughout life. In utero, these potent biochemicals are essential for normal development and must be in adequate concentrations throughout childhood. Early defects lead to mental retardation. Cretinism occurs in severe cases in which the thyroid gland does not develop (thyroid agenesis). This may be prevented if treatment is initiated soon after birth. In childhood, the thyroid influences adequate linear growth and timely sexual maturation. It interacts with every organ system and plays a crucial role in metabolism.1

BACKGROUND

Thyroid hormone levels are maintained by an intricate feedback system, which involves the hypothalamus, pituitary gland, thyroid gland, and receptors found on most cells (FIGURE 1). The hypothalamus produces thyrotropin-releasing hormone (TRH), which is transported on nerve endings to the portal capillary system of the anterior pituitary.2 This tripeptide is highly concentrated in the paraventricular nuclei and the median eminence. Its production is based on an inverse relationship to the amount of active thyroid hormones in circulation and is also influenced by neuroendocrine modulation from higher centers of the brain. External environmental factors such as temperature also affect its synthesis and release. This negative feedback system results in the pulsatile secretion of TRH, which in turn regulates the synthesis, and secretion of thyroid-stimulating hormone (TSH). TSH production and release is also modulated by the active thyroid hormones. When these serum concentrations are low, TSH promotes biosynthesis and secretion of the two bioactive thyroid hormones thyroxine (T4) and triiodothyronine (T3). Thyroxine is the major product of the thyroid gland and much of it is later deiodinated in extrathyroidal tissue to form T3. The liver, thyroid, and kidneys have the highest concentration of the type I deiodinase. Another form of this enzyme, type II deiodinase, is found in the brain, pituitary, and skin.2,3

Each component of the hypothalamic-pituitary-thyroid axis can be evaluated. The serum TSH concentration can be accurately measured utilizing an immunoradiometric assay and is often the starting point for an evaluation of thyroid function. Over the last decade, this test has improved significantly. The third-generation tests can detect levels as low as 0.01 mU/L and are capable of diagnosing even the mildest hyperthyroid and hypothyroid states.4-6 These assays are 10 times more sensitive in detecting TSH in comparison to the second-generation assays. In spite of the fact that it is an indirect measure of thyroid function, it is utilized clinically for several reasons. It is very sensitive to minuscule changes in the free T4 levels. A two-fold change in the free T4 level can cause a 100-fold change in the TSH level. This virtually eliminates the necessity for a TRH stimulation test. It is available at most clinical laboratories and can usually be completed in two to 24 hours. The cost and quality of the test various significantly from lab to lab and it is advisable for the clinician to be aware of these limitations when interpreting the results and advising patients.7

Figure1

CAUSES OF THYROID DYSFUNCTION

Thyroid dysfunction ranging from hypothyroidism (deficient activity of the thyroid gland) to hyperthyroidism (excessive functional activity of the thyroid gland) can be triggered by abnormalities emanating from any one of these components of the hypothalamic-pituitary-thyroid axis ( TABLE 1).8 For instance, if the thyroid is unable to synthesize thyroid hormones due to destruction of the follicular cells, the resultant condition will be hypothyroidism. This common condition is often triggered by an autoimmune process and is termed Hashimoto's thyroiditis. In this disorder, the TSH level will be elevated in response to the low levels of thyroxine and triiodothyronine. No matter how high this level rises, it will be unable to stimulate the damaged thyroid gland sufficiently. In another form of hypothyroidism, central hypothyroidism, the pituitary is unable to produce enough TSH resulting in insufficient thyroxine levels. Abnormalities may arise from either the hypothalamus or the pituitary. Etiologies include tumors, surgery, irradiation, head trauma, infections, vascular lesions, and medications.

Hyperthyroidism has several etiologies, some of which are transient, but more often are chronic and require definitive treatment. Grave's disease is an autoimmune disease which commonly presents with hyperthyroidism. In this condition, the thyroid gland is overactive and results in an elevated thyroxine level and a suppressed TSH. The diagnosis is often confirmed with a nuclear medicine radioactive iodine uptake scan of the thyroid. It is then treated by surgical thyroidectomy, radioactive iodine, or medical treatment with a thioamide (propylthiouracil or methimazole). Treatment often results in hypothyroidism requiring thyroid hormone replacement for life. Hyperthyroidism can be life threatening and must be treated to avoid complications such as osteoporosis, atrial fibrillation, and acute myocardial infarction. If a thioamide is considered, it should be limited to 12 to 18 months of therapy and monitored very closely for severe life threatening complications associated with these medications, including hepatitis and aplastic anemia.9

Table 1
Common Causes of Thyroid Dysfunction8
Hyperthyroidism
Amiodarone
Excess thyroid replacement
Grave's disease
Toxic multinodular goiter
Toxic thyroid nodule
Transient or postpartum thyroiditis
Hypothyroidism
Amiodarone
Autoimmune/Hashimoto's thyroiditis
IFN-alpha
Inadequate thyroid replacement
Iodine deficiency
I-131 treatment for thyroiditis/thyroid cancer
Lithium
Previous thyroid surgery
Radiation
Transient or postpartum thyroiditis
Trauma to head/neck
Congenital Hypothyroidism
Inborn errors of thyroid hormone synthesis
Peripheral resistance to thyroid hormone
Thyroid agenesis

DIAGNOSING THYROID DYSFUNCTION

Symptoms associated with thyroid dysfunction are often nonspecific ( TABLE 2) and commonly encountered during a routine physical exam or follow-up appointment.3 It is not unusual for some of these complaints to be overlooked by the patient and only mentioned if questioned very specifically during the consultation or on the review of systems. Fatigue, cold intolerance, weight gain, and depression are often revealed. Older patients may discount the significance of these nonspecific symptoms and believe that they are due to the aging process. On physical exam, the patient suffering from hypothyroidism may exhibit signs of dry skin, thinning hair, goiter, and delayed recovery phase of the deep tendon reflexes. Symptoms of depression and hypothyroidism may overlap (e.g., constipation, diminished concentration, depressed mood, sleep disturbances, increased weight, and fatigue) and require that underlying etiologies be actively sought out. It is also important to realize that patients who suffer from thyroid dysfunction are predisposed to affective disorders, which may require additional treatment with antidepressive medications.8,10

Table 2
Symptoms and Signs Associated with Thyroid Dysfunction2
SYMPTOMS
Hypothyroidism Hyperthyroidism
Fatigue
Cold intolerance
Constipation
Depression
Weight gain
Fatigue
Heat intolerance
Diarrhea
Anxiety (depression)
Weight loss (or gain)
SIGNS
Hypothyroidism Hyperthyroidism
Hypertension (diastolic)
Dry skin
Diminished recovery phase of deep tendon (Achilles) reflexes
Slow pulse
Myxedema
Ptosis
Hypertension (systolic)
Oily skin (acne)
Hyperreflexia
Rapid pulse
Tremor
Exophthalmos

If thyroid dysfunction is suspected, a serum TSH level should be obtained. If signs and symptoms are sug gestive of an overactive thyroid and the TSH level is suppressed, the patient is likely hyperthyroid. Elderly patients who are hyperthyroid sometimes present with a confusing constellation of signs and symptoms, which are more suggestive of hypothyroidism. These patients will have a suppressed TSH level. A free T4 and T3 level will help determine the cause of the abnormality. This condition is termed apathetic hyperthyroidism. If the TSH level is elevated, with hypothyroid symptoms, a free T4 level should be evaluated in order to determine the severity. An elevated TSH and a normal free T4 level would be classified as subclinical hypothyroidism or mild thyroid dysfunction. Treatment should be considered, especially if the patient is symptomatic.

Newborn children are screened for thyroid dysfunction just after birth. This is mandated by law and is the standard of care. Screening for thyroid dysfunction should be considered in all adults beginning at the age of 35 and every five years thereafter. Women are especially at risk, but men should also be checked since this is a cost-effective method for detecting and treating these relatively common disorders. Patients at higher risks for thyroid disease (i.e., postirradiation of the face and neck, family history of thyroid disease) should be screened more frequently.11

Thyroid auto-antibodies are sometimes helpful in determining the etiology and its predicted course. Thyroid peroxidase antibodies are present in 90% to 100% of the patients with Hashimoto's thyroiditis. They are also present in 20% of the general population and typically are used to support a diagnosis, rather than for screening. These patients are sometimes evaluated in cases of postpartum thyroiditis and silent thyroiditis. It is not necessary to check for antibodies in most cases, especially if the patient is clearly hypothyroid with other evidence as to its etiology.

When evaluating and treating thyroid abnormalities, especially when the levels are in the subclinical range, it is important to understand that population-based normal values are broadly distributed. Individual thyroid function variation is often reflected by much narrower ranges. Serum free T4 levels (by direct dialysis) normally range from 0.8 to 2.7 ng/dL, and free T3 levels (by tracer dialysis) normally range from 210 to 440 pg/dL. Normal TSH (ICMA) levels range from 0.4 to 5.5 mU/L.

One longitudinal study looked at individual thyroid function tests, which were repeated monthly over a period of one year. TSH, T4, T3, and free T4 index (FTI) levels were measured. It was noted that "high individuality causes laboratory reference ranges to be insensitive to changes in test results that are significant for the individual." Individuals in the study showed unique levels within 25% variation for T4, T3, and FTI. The TSH varied within 50%. The individual reference for T3 and T4 was approximately half the width of the population-based reference range. This emphasizes the importance of the TSH level especially if it is outside of the population-based normal range. One would expect the TSH level to be abnormal if the T4 or T3 was outside of the individual's normal range.12

CASE STUDY #1

A 72-year-old man was seen for a routine follow-up exam for hypertension and to obtain a refill for his ramipril prescription. He had been on this medication for over five years without a dosage adjustment and his blood pressure readings were always less than 120/70. He was also taking an aspirin tablet daily. His cholesterol had been excellent without medical therapy. He was not taking any other medications except for a daily multivitamin. He had been seen twice a year by a physician and has only been hospitalized once in his life for an appendectomy. He has always been active, never smoked tobacco products, and drinks one glass of wine with dinner.

He answered "no" when he was asked if he had any complaints. He was then asked more specifically if he had noticed a change in his energy level or change in his weight. This time he answered "yes," he had gained 10 pounds over the last six months and stated that he needed to walk more. He went on to say that his energy level has been a little low but attributed it to his age. He continued to talk and brought up his wife's death, which occurred two years previously. He felt that he may be "a little down," but he did not consider himself depressed. He noted that his family was in the area and he had an excellent support system. On further questioning, he answered "yes" to complaints of constipation, cold intolerance, and dry skin.

Physical Exam

His physical exam was significant for an elevated blood pressure reading of 140/94. His weight was 188 pounds, his temperature was 97.1 ยบF, the hair on his extremities was sparse, his skin was dry, and he had an enlarged thyroid (goiter). A complete blood count (CBC), comprehensive chemistry, urine analysis (UA), lipid panel, and a TSH level were ordered. His TSH was 11 mU/L, his low-density lipoprotein cholesterol (LDL-C) was 164, his high-density lipoprotein cholesterol (HDL-C) was 38, his glucose was 88, and his CBC and chemistry were normal. Based on these results, you could start a low dose of levothyroxine or repeat the TSH level and complete the workup with a free T4 level and thyroid peroxidase antibodies.

Results

His thyroid peroxidase antibodies were 140, TSH was 15.2 mU/L, and his free T4 was 0.7 ng/dL. At his follow-up appointment, he was started on a brand-specific levothyroxine at a dose of 25 mcg daily. He received information on the importance of taking his medication on an empty stomach in the morning and discussed the goals of treatment, precautions, and a follow-up plan (TABLE 3).13 He was instructed to have a TSH level completed in six weeks.

Table 3
Patient Information Regarding Levothyyroxine13
Notify physician regarding:
Any allergies to medications
If pregnant, breastfeeding, or contemplating pregnancy
If experiencing other medical conditions (i.e., cardiac, diabetes, clotting disorders, adrenal, or pituitary problems)
If on other medications or nutritional supplements, or if surgery is scheduled
Take your medication:
In the morning, 30 minutes to one hour prior to breakfast, preferably with a full glass of water. Agents such as iron, calcium, and antacids can decrease the absorption of levothyroxine and should not be taken within four hours of each other. Do not switch brands of levothyroxine or discontinue or change the amount you take or how often you take it, unless directed to do so by your physician. Notify your physician if you 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.
TSH monitoring:
For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage or brand of levothyroxine changed, the serum TSH concentration should be measured after eight to 12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every six to 12 months, depending on the clinical situation, and whenever there is a change in the patient's status.

Discussion

Once it is clear that a patient has a chronic form of primary hypothyroidism, treatment should be considered. In this patient's case, the enlarged thyroid and thyroid auto-antibodies were both consistent with chronic autoimmune thyroiditis (Hashimoto's thyroiditis). He was symptomatic with signs on his physical exam, consistent with mild hypothyroidism. Other causes of his symptoms were considered and evaluated with a CBC, urine analysis, and a comprehensive chemistry. His abnormal lipid panel, at least in part; may also be due to his thyroid dysfunction. One study has shown a direct correlation between TSH elevations and the mean total cholesterol levels.14 The goal of therapy is to eliminate symptoms and to normalize the TSH level.

Treatment options include levothyroxine, triiodothyronine, desiccated thyroid, combination products (levothyroxine and triiodothyronine) and others (TABLE 4 ).15

Table 4
Thyroid Products15
Levothyroxine (T4)
Brand names include Euthyrox, Levothroid, Levoxyl, Synthroid, Unithroid, and several generic products
Liothyronine (T3)
Brand names includes Cytomel and Triostat
Liotrix (combination of T4 and T3)
Brand names include Euthroid and Thyrolar
Thyroid USP
Brand names include Armour Thyroid, S-P-T, Thyrar, and Thyroid Strong

LEVOTHYROXINE

Most experts in the field of clinical thyroidology agree that levothyroxine is the drug of choice for treatment of hypothyroidism. Levothyroxine acts as a reservoir for the active thyroid hormone, T3. Its long half-life makes it especially suitable for daily administration. As it is a sodium salt, 80% of the dose is absorbed when taken orally on an empty stomach. By acting as a pro-hormone, it does not impede other components of the thyroid axis, allowing for the deiodinase enzyme to function appropriately. Manufacturers are able to produce it in several different strengths, differing by as little as 9%. The American Association of Clinical Endocrinologists (AACE), the Endocrine Society, and the American Thyroid Association (ATA) all have guidelines recommending the use of levothyroxine treatment for most patients suffering from chronic hypothyroidism.9,16

The initial dosage of levothyroxine for adults is dependent on several clinical issues. Infants and children have different requirements for thyroid replacement. The dosage, on a microgram per kilogram basis, is higher and must be replaced in a timely manner to avoid irreversible consequences. This topic will not be discussed here and the following dosage recommendations are to be considered only for patients over the age of 18. If the patient is between 18 and 50 years old and in relatively good health without any risks for coronary heart disease (CAD), the initial dose for overt hypothyroidism is based on the complete replacement dose.

Most patients will require between 1.6 to 1.8 mcg of levothyroxine per kilogram of ideal body weight. A woman weighing 110 lbs (50 kg) could be started on 75 or 88 mcg daily. If the patient is not in good health with evidence of CAD, the initial dose could be as low as 12.5 to 25 mcg/day, and titrated very cautiously. Patients over the age of 50, even without a documented history of ischemic heart disease, should be started on a low dose of levothyroxine and monitored closely.13

In a prospective, randomized, double-blind study, the starting dose of levothyroxine was evaluated by comparing two dosage regimens. A total of 75 patients were enrolled into the study. One group began on a traditional low starting dose (25 mcg), adjusting the dose every six to eight weeks until their laboratory studies were in the euthyroid (normal) range. The other group began therapy at a much higher dose of 1.6 mcg/kg/day. As expected, this group became euthyroid, based on laboratory studies, at a much faster rate. In spite of these differences, patients in both groups symptomatically improved, on average, at the same rate. Clinical effectiveness was assessed based on signs and symptoms and quality-of-life scores during treatment. There were no complaints of palpitations, chest pain, or cardiac events documented during the study. The authors concluded that there was evidence to suggest that it was safe to treat older patients (without documented heart disease) with a full replacement dose on initiation of therapy.17 One might also conclude, since there was no difference in the rate of clinical improvement, it would be prudent to slowly titrate the dosage upward, to avoid cardiac dysfunction. Many experts in this field, at least for now, plan to continue taking a cautious approach in treating older patients even if there is no documented cardiac history.18

The chronicity of the hypothyroid state should also be considered prior to initiating thyroid replacement therapy. If the patient has been severely hypothyroid for several months, the initial dose should be reduced initially to avoid the possibility of an exaggerated response leading to anxiety and even psychosis.10 Patients who have undergone treatment for Grave's disease (radioactive I-131 treatment or surgery) may require less than the total replacement dose due to residual thyroid tissue. These patients may require several dosage adjustments after initiating therapy.

In some situations, triiodothyronine is given for a short period to alleviate symptoms of severe hypothyroidism while allowing levothyroxine to reach steady state. This treatment strategy would be considered for a patient who has recently had a total thyroidectomy followed by radioactive iodine treatment for a differentiated (papillary or follicular) thyroid cancer. These patients are often profoundly hypothyroid after being off thyroid replacement for six to eight weeks. The dosage initially ranges from 10 to 25 mcg, given twice a day. After two to three weeks of treatment, the dose is tapered down and discontinued within four to six weeks as the levothyroxine effect takes over.

Once levothyroxine treatment has been initiated, the dosage should be adjusted every four to eight weeks until the patient becomes euthyroid. The goal of therapy depends on the clinical situation. In elderly and younger patients with symptomatic heart disease, TSH levels should be maintained within the mid to upper range of normal. In healthy young patients, a TSH in the lower range of normal should be considered. A goal of 1 to 1.5 mU/L would be a reasonable starting point. Clinical progress should be evaluated at each appointment as the patient transitions from hypothyroidism to the euthyroid state. Changes in the signs and symptoms often lag behind the laboratory values. Clinicians should counsel patients on the goals of therapy as well as the time frame to expect to notice changes. Each patient should be well advised regarding symptoms of overtreatment or hyperthyroidism (TABLE 2).

DIFFERENTIATED THYROID CANCER

There is evidence to suggest a relationship between the magnitude of TSH suppression to the clinical consequences of treated differentiated thyroid cancer. In clinical practice, experts in the field often advocate suppressive therapy, although the treatment goals may vary somewhat. Keeping in mind that this issue is not completely resolved, the ATA has made recommendations based on current evidence and expert opinion.19 The goal of thyroxine suppressive therapy depends on the clinical course of the cancer and the overall health of the patient (TABLE 5).

CASE STUDY #2

A 38-year-old woman was recently diagnosed with papillary thyroid cancer. She had a total thyroidectomy, revealing a 4.5-centimeter papillary thyroid cancer. The pathologist noted it to be an aggressive tall cell variant. Three cervical lymph nodes were positive for the cancer. Five weeks after her surgery, while withholding thyroid replacement, she received 200 millicuries (mCi) of radioactive I-131. She had just completed her nuclear medicine posttreatment scan, which revealed metastasis to the lungs. At that time she was very tired, depressed, and was gaining weight. She had constipation and severe cold intolerance. She was unable to drive or work due to poor concentration and fatigue. On physical exam, she was tearful with a depressed affect. Significant findings included the surgical site on the lower aspect of her neck that appeared to be healing well. She had very dry skin, brittle nails, trace edema, and delayed Achilles reflexes. Laboratory studies revealed a TSH level of 65 mU/L and a serum sodium level of 125 meq/dL. She also had a mild normocytic anemia. The rest of her studies were in the normal range, although a lipid panel was not obtained. It was apparent that she was very depressed and frustrated. She said, "I have accepted the diagnosis of cancer, but I just feel terrible. I had no idea how important my thyroid was."

Next Steps

Levothyroxine suppressive therapy was initiated. Her lean body weight was 140 pounds, so she was given a prescription for 137 mcg of a brand-specific (non-generic) levothyroxine sodium preparation. She was instructed and given information regarding her prescription (TABLE 3). She was also given a prescription for triiodothyronine at a dose of 20 mcg twice a day. She was instructed to take her first dose in the morning and her second dose every day no later than about 3 PM, preferably at 2 PM. She was also given instructions to taper down her dose after two to three weeks or if she starts having symptoms of over-replacement (hyperthyroidism). Her TSH level was scheduled to be checked in four weeks.

Discussion

This woman was very symptomatic. Her TSH level was significantly elevated, with anemia and hyponatremia. The first priority was to rapidly relieve the symptoms she was experiencing and to suppress her TSH level. This was a situation in which triiodothyronine could be administered for a few weeks to allow the levothyroxine to reach steady state. Triiodothyronine has a relatively short onset of action and duration of activity, in comparison to levothyroxine. Symptoms of fatigue and diminished concentration often improve soon after initiating this medication. A month's supply of 5-mcg tablets is usually prescribed to enable convenient dosage adjustments based on symptoms. The dosage may also be adjusted based on the patients work schedule. It is important to emphasize this medication could be discontinued at any time and it is only being prescribed to accelerate the recovery time.

The levothyroxine dose was based on 1 mcg per pound, which is slightly higher than a replacement dose of 0.8 mcg per pound. In this case, due to the aggressive form of cancer, the goal of therapy was to completely suppress her TSH (below 0.1 mU/L) but not to the point of overt, symptomatic hyperthyroidism (TABLE 5 ). This requires a fine balance to avoid complications associated with subclinical hyperthyroidism, including atrial fibrillation and osteoporosis. It is important that the patient be well informed regarding the goals of therapy and the importance of close follow-up appointments to assess for the safety and effectiveness of her treatment. The patient should have a clear understanding of symptoms associated with hypo- and hyperthyroidism. Realistic expectations should be addressed and reinforced at each appointment, since clinical improvement can be slow and frustrating. It is also important for the clinician to be aware of drug interactions and other clinical situations that may affect the pharmacokinetics of this hormone (TABLE 6 ).13

Table 5
Levothyroxine Doing (Adults)13
General Principles (as noted in the product insert)
The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of levothyroxine to achieve these goals depends on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medications, and the specific nature other conditions being treated.
Replacement Therapy in Overt Hypothyroidisma
Adult Patients Starting Dose TSH Goal
Under age 50b 1.7 mcg/kg/day 1 to 2
Over age 50 25-50 mcg/day Mid-normal range
With heart disease 12.5-25 mcg/day Mid-normal range
Replacement Therapy in Subclinical Hypothyroidism
Adult Patients Starting Dose TSH Goal
Under age 50c 1.0 mcg/kg/day 1 to 2
Over age 50 25-50 mcg/day Mid-normal range
With heart disease 12.5-25 mcg/day Mid-normal range
Suppressive Therapy for Differentiated Thyroid Cancer19
1. If the patient has persistent disease, the serum TSH should be maintained below 0.1 mU/L as long as it can be safely administered.
2. If the patient is free of disease, but at high risk for recurrence or metastasis, the TSH should be kept between 0.1 and 0.5 mU/L for five to 10 years.
3. Those at low risk and free of disease may be titrated to TSH levels in the low normal range of 0.3 to 2.0 mU/L.

a Myxedema should not be treated initially with oral replacement therapy and intravenous levothyroxine is often recommended.
b Patients under age 50 in otherwise good health and without risks for heart disease.
c Requirements for subclinical hypothyroidism are often less than the full replacement dose needed in overt hypothyroidism.

 

Table 6
Changes in Steady State Resulting in Low Levothyroxine Levels
(Increasing TSH Level)13

Suboptimal/subtherapeutic dosing
Poor compliance
Increased biliary excretion
Pregnancy
Formulation switch
Decreased residual gland function
Dietary interference with absorption
Malabsorption syndromes
  Cirrhosis, jejunoileal bypass, short bowel syndrome
Drugs that increase hepatic metabolism of thyroid hormone
  Carbamazepine, hydantoins, phenobarbital, rifampin
Drugs that may decrease T4 absorption
  Aluminum hydroxide, calcium carbonate, cation
  exchange resin, cholestyramine, ferrous sulfate,
  sucralfate
Drugs that reduce thyroid hormone secretion
  Aminoglutethimide, amiodarone, iodide, lithium,
  methimazole, propylthiouracil, sulfonamides, tolbutamide

CASE STUDY #2: FOLLOW-UP APPOINTMENT

The patient returned six weeks later. She complained of feeling irritable with heat intolerance. She was also having trouble sleeping. She discontinued the triiodothyro-nine one week prior to her visit, after tapering over a period of two weeks. For the first adjustment, she reduced the dose to 10 mcg twice a day, and continued to taper down until she reached her last dosage of 5 mcg daily, prior to work. She continued on this low daily dose for five days before discontinuing. Her free T4 level, which was checked just prior to her appointment, was 1.9 ng/dL and her TSH level was 0.9 mU/L. She recalled the symptoms of hyperthyroidism and was sure that her dose of levothyroxine was too high. Her physical exam revealed a fine bilateral hand tremor and an elevated pulse. Her skin looked improved and her Achilles (deep tendon) reflex no longer demonstrated a delay in the recovery phase.

Next Steps

It is recommended to hold her levothyroxine for three days and then restart it at a slightly lower dose of 137 mcg every other day on odd days, alternating with 125 mcg every other day on even days of the month. A TSH and free T4 level was ordered, with a follow-up appointment in six weeks. She was instructed to have her laboratory studies completed in the morning and not to take her levothyroxine until after she had her blood drawn.

Discussion

Her hypothyroid state had resolved. She was now having symptoms of hyperthyroidism due to overreplacement of her brand-specific levothyroxine. This is not an uncommon situation, especially during the initiation of treatment and underscores the importance of close follow-up appointments and laboratory studies. The triiodothyronine is not likely contributing to her symptoms since her last dose was a week ago and she was on a very low dosage prior to discontinuing. If she were to remain on this dose, her TSH level would likely continue to drop. By holding the dose for a few days, her symptoms will resolve more rapidly while reaching a new steady state level.

Her next TSH level was 0.05 mU/L, with a free T4 of 1.4 ng/dL (subclinical hyperthyroidism). She said that she felt much better and was not having any significant complaints. Her concentration was back to normal and she was working at her profession as an accountant. She had gained 15 pounds during her original treatment phase, but she was able to return to her original weight after improving her diet and increasing her exercise over a period of three months. After she lost 15 pounds, her dose was dropped to 125 mcg daily. Her levels were rechecked and she remained stable at that dose for several years. There was no evidence of cancer recurrence or metastasis.

CASE STUDY #2: FIVE YEARS LATER

The patient continued on a brand-specific levothyroxine for several years. There had been no changes in her dosage and she was not having any other medical problems. She had a TSH level checked every six to twelve months. She started taking calcium and vitamin D supplements during perimenopause. She understood the significance of the drug interaction between calcium and levothyroxine and was very careful to space the two drugs by at least four hours.

At her last appointment, she was having symptoms of mild fatigue and depression. She also had gained 5 pounds since her last appointment in spite of exercising and dieting. Her TSH level was 5.5 mU/L with a free T4 level in the low-normal range. Her skin was dry. Various factors that could affect the absorption or metabolism of levothyroxine were methodically reviewed (TABLE 6 ). She brought in her medication and stated it looked a little different although the color was the same. The pharmacist was called and confirmed that the appropriate strength had been given, although the manufacturer was different. The pharmacist apologized for not informing her health care provider earlier so a TSH level could have been checked. He further stated this was the second change over the last six months.

Next Steps

She was clearly having symptoms due to the change in her thyroid levels. She was now in the subclinical hypothyroid range. With her history of an aggressive thyroid cancer, her TSH level needed to be significantly lower.

Her dose was increased slightly, and there was to be no substitution of the brand-specific levothyroxine, which she was on previously. She was given a prescription for the same strength 125 mcg daily on Monday through Saturday, and an additional half tablet on Sundays. This is the equivalent to 133 mcg daily. She was instructed to see the physician in six weeks with a repeat TSH and free T4 level to be drawn prior to her appointment.

Discussion

After seeing the patient and reviewing her record, the physician debated on increasing the dose, not knowing if her metabolism or absorption rate had changed and thus affected the free T4 level, or if the change in the drug itself was the cause. After careful review of her chart, the physician recalled that she had always been very compliant with taking her levothyroxine as directed. She was taking calcium and confirmed she was not taking the levothyroxine at the same time. She also reminded the physician that her TSH levels were normal, subsequent to initiating her calcium supplements. With some patients it is not always this clear and other factors must be considered. Compliance and absorption issues are always high on the list. The physician decided on using the same strength at a slightly higher dosage. This would make it easier to adjust the dose in six weeks if the problem was due to the change in the product itself.

CASE STUDY #2: SIX WEEKS LATER

At her follow-up appointment, the patient was feeling much better, although not quite back to normal. She also noted having a few palpitations recently. Her TSH level was 0.6 mU/L and her free T4 level was 1.7 ng/dL. The T4 was a little high and her physician was fairly confident that her TSH level would continue to drop. Her physical exam was unremarkable except that the fine tremor had returned. She was instructed to reduce the dosage by a half tablet per week and to recheck her TSH level in eight weeks.

Discussion

Levothyroxine can be affected by several factors (TABLE 6 ). Each of theses factors should be considered at the time of the original consult and reviewed at each subsequent appointment. The patient should have a clear understanding regarding the best time to take her dose as well as possible drug interactions and how comorbid conditions could affect her levels. The pharmacist should reinforce these issues with patients. Patients should check for any changes in their medications and talk to their pharmacist if they have any concerns. Unfortunately, patients do not always notice subtle changes in their medications and physicians must depend on pharmacists to ensure that the patient is receiving the appropriate drug and pertinent information to go with it. If a change in the manufacturer is necessary, a TSH level should be rechecked within eight weeks. The health care providers must be kept aware of any changes in the treatment regimen so appropriate laboratory studies can be ordered.

Consequences of a change in the TSH steady state due to a change in levothyroxine bioavailability (in this case due to the change in the product) include:
1) associated symptoms;
2) loss of thyroid cancer suppression;
3) additional laboratory studies (in this case, two TSH levels and a T4 level) to readjust her levothyroxine dose;
4) time spent on the phone, determining the cause;
5) additional appointments (in this case, two);
6) cost to insurance company and the patient; and
7) potential liability if a complication occurs (i.e., hyperthyroidism, hypothyroidism resulting in a cancer recurrence).

A recent study has shown that symptoms are not always evident when subtle changes in the dose have occurred.20 The problems associated with this case probably could have been avoided by a simple phone call.

Levothyroxine preparations differ. The US Food and Drug Administration (FDA) recognizes this and determines, by pharmacokinetic studies, if one product can be substituted for another.21,22 Unfortunately, the criteria the FDA uses is based only on pharmacokinetic data and does not take into account the pharmacodynamic effects of the drug. Free T4 levels are measured after supra-physiologic doses of levothyroxine are given to healthy volunteers. 23 These levels are checked, prior to reaching steady state and without regard to the TSH level. This is odd because the TSH level is clearly the best indicator of thyroid function, just as the INR level is used to titrate the dose of warfarin. Both are very sensitive measures of biologic activity.

When two preparations are compared by measuring the T4 levels, the FDA considers the two drugs to be bioequivalent if the area under the curve (AUC) and C-max fall within 80% to 125% of the reference drug. When patients are treated with levothyroxine, dosage adjustments are often less than 10%. In fact, if you review all of the strengths available that are approved by the FDA, you will note that they differ by as little as 9%.21,22

One study compared two brand name products.24,25 The AUC was evaluated utilizing the FDA method stated above. One product was 12.5% more bioavailable than the other. The FDA considered the two to be bio-equivalent based on the above criteria. The data suggest that they are not the same. That does not mean one is better than the other, only different, and may impact the clinical care of a patient.

Consider, for example, a situation in which an elderly patient is on levothyroxine product A at a dose of 150 mcg daily. On a routine follow-up appointment, he states that he is starting to have symptoms of mild anxiety and heat intolerance. His TSH level is 0.9 mU/L. Because his symptoms are suggestive of hyperthyroidism and he may be susceptible to adverse cardiovascular complications, his dose would be reduced, likely to 137 mcg. As mentioned earlier, elderly patients should be cautiously followed, keeping their TSH levels in the mid-normal range. If he is given product B, which is more bioavailable, he could actually end up taking a higher dose than the original 150 mcg strength.

It should be clear that even if the FDA considers two products bioequivalent, they are not necessarily clinically equivalent.21,22,26-28 The AACE, ATA, and the Endocrine Society each have voiced their concerns regarding the importance of having their patients on brand-specific preparations to avoid unnecessary complications associated with changes in their thyroid levels. 16

SUMMARY

The evaluation and treatment of thyroid dysfunction requires that health care providers work together to coordinate the care of our patients. After the diagnosis has been confirmed from biochemical studies, treatment with levothyroxine is often initiated. As previously described, the initial dosage must first be titrated at six- to eight-week intervals and then monitored on a regular basis to ensure that safe therapeutic levels are maintained. With time, patients' clinical issues (e.g., age, comorbid conditions) will likely change and further adjustments in therapy will need to take place. The pharmacists who are administering the medications play a vital role in ensuring that patients are receiving the most appropriate medications without unnecessary product changes.

References

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