Generic Name: Levothyroxine
Common Brand Name: Synthroid (Abbott Laboratories — U.S.)
Popularity: Seventh most commonly prescribed drug between 2002 — 2007 (U.S.)
Class: Synthetic thyroid hormone
Treatment Uses — Hypthyroidism and secondary conditions (specifically caused by hypothyroidism) including amenorrhea (disappearance of normal menstrual cycle), peripheral arterial disease, urticaria, carpal tunnel syndrome, cardiomyopathy, and myxedema coma. Treatment and prevention of goiter and thyroid nodules. Potential benefit in refractory depression. Intra-amniotic administration to accelerate fetal maturation in premature deliveries has been effective. While beneficial in animals suffering from acute renal failure, levothyroxine had no beneficial effect on humans with acute renal failure and was actually associated with higher mortality. Studies using levothyroxine to increase cardiac performance in patients with cardiomyopathy have shown no benefits. Carpal tunnel syndrome is associated with hypothyroidism — patients treated with levothyroxine have less severe symptoms. There is no evidence to suggest that treatment with levothyroxine reduces carpal tunnel symptoms in patients with normal thyroid function. Levothyroxine is used to suppress production of thyroid stimulating hormone (TSH) in patients with thyroid cancers. Use of thyroid hormones alone, or in combination with other drugs, for treatment of obesity is ineffective and potentially dangerous.
Hypothyroidism is a common condition, affecting more than 5 million Americans, with an incidence approaching 0.5 percent of the population. Up to 2 percent of the population may have subclinical hypothyroidism. Occurrence is more common in women and the elderly, and with advancing age, affects 2 to 3 percent of women. Up to 5 percent of women develop hypothyroidism during the first year following childbirth (sometimes mistaken for postpartum depression). Amiodarone induced hypothyroidism occurs in 14 to 18 percent of patients and is seen more often in iodine-sufficient areas than in iodine-deficient locales. Discontinuation of amiodarone will usually restore normal thyroid function and when this is not feasible, treatment with levothyroxine is also effective. Despite the critical role of the thyroid gland in regulating metabolism, growth and development, and maturity of central nervous system tissue and bone, signs and symptoms of hypothyroidism are vague and easily confused with other conditions, except when severe. Myxedema coma (unconsciousness with severe hypothermia) is a life-threatening hypothyroidism complication usually seen only in colder climates.
Dosing and Administration — Initial adult oral dosing is 1.7 micrograms per kilogram per day. Typical maintenance doses range from 100 — 200 micrograms once daily. It would be unusual for an adult to require more than 200 mcg per day. Note that 1 microgram is the equivalent of 0.001 milligram, or 1/1000th of a milligram. In healthy adults, levothyroxine is normally started at 75 mcg daily and increased slowly based on blood thyroid stimulating hormone (TSH) levels.
Children and infants’ higher metabolic rates require higher doses of levothyroxine. These range from 2 micrograms per kilogram daily for preteens to a high of 15 micrograms per kilogram daily for newborns. Monitoring and dose adjustment is similar to guidelines for adults.
TSH levels lag behind thyroid hormone levels, making the full effect of levothyroxine dose adjustments difficult to appreciate for at least four weeks and sometimes up to eight weeks. Hence, dose adjustments based on TSH levels are recommended at six to eight week intervals. Once stable TSH levels are achieved in adults, the levothyroxine dose typically remains adequate until the person reaches their 60s or 70s, absent significant weight changes. Despite this, most prescribers tend to recheck TSH levels annually.
Levothyroxine is best taken as a single dose one-half to one hour before breakfast every day. Taking with food can interfere with absorption. It is acceptable to crush levothyroxine tablets and dissolve in 1 — 2 tablespoons of water or sprinkle over a small amount of applesauce or cereal if taken immediately. This option is helpful for pediatric patients or adults with swallowing difficulties. Antacids, iron, and calcium supplements should be spaced at least four hours before or after taking levothyroxine. Several studies of once weekly dosing (using slightly more than seven times the daily dose) have shown results similar to daily dosing without adverse side effects in healthy adults and teenagers. The small size of these studies is insufficient to wholeheartedly endorse weekly dosing.
Intravenous (IV) and intramuscular (IM) formulations of levothyroxine are available and initiated at 50 percent of the established oral dose, according to manufacturers prescribing information. Other recommendations differ and, in real life practice when only one or two days oral dosing will be missed (such as recovery from major surgical procedures), many prescribers simply give the previous oral dose intravenously. The long half-life and distribution of levothyroxine in the body in all likelihood make it unnecessary to provide the drug by alternate routes for up to a week in patients who are unable to take it orally.
Lower initial doses are recommended in the elderly or persons with cardiovascular disease because thyroid hormone replacement can rapidly increase resting heart rates and blood pressure. In this population, a daily starting dose of 25 mcg is preferred, increasing by 25 to 50 mcg steps until TSH levels normalize. Final dosages will often be roughly 20 percent lower than used with middle aged adults. Annual TSH monitoring is appropriate in the older population.
In overdoses, hemodialysis is not helpful. Efforts to decrease gastric absorption are warranted (gastric lavage, emesis, activated charcoal, etc.). Seizures were reported in a child who ingested 18 milligrams of levothyroxine. Keep in mind that symptoms of thyroid hormone overdose are unlikely to become evident for several days. Expert consultation for management of sympathetic and endocrine effects is helpful. Plasmapheresis and charcoal hemoperfusion have been helpful in cases of continued deterioration despite conventional treatments.
Pharmacology/Pharmacokinetics/Stability — Following oral administration, about 50 to 80 percent of an oral dose is actually absorbed, and reaches peak serum levels within two to four hours of ingestion. Therapeutic effects are seen within three to five days, and last for seven to 10 days. Levothyroxine is converted by the liver to a metabolite (T3) that accounts for most of its thyroid activity. About 50 percent is excreted in feces and the remaining 50 percent in urine. When given intravenously, effects are seen within six to eight hours and peak in one day.
Older studies found significant differences in the bioavailability between different brands of levothyroxine, probably because the drug was made from thyroid glands of cows. Modern day levothyroxine is synthetically manufactured and more recent studies fail to show significant differences when patients are switched from one brand to another. Nonetheless, experts in the field strongly caution against switching between brands without considering differing bioavailabilities (amount of drug released into the body). Consultation with a knowledgeable pharmacist or prescriber is warranted when changing between brands of levothyroxine.
Thyroid hormones do not readily cross the placental barrier and are considered safe for use during pregnancy. Of note, untreated maternal hypothyroidism is associated with significantly higher rates of pregnancy complications including spontaneous abortion, pre-eclampsia, stillbirth, and premature delivery. Levothyroxine should be continued during pregnancy and TSH levels monitored each trimester and six to eight weeks postpartum. Increased doses may be required due to higher estrogen levels experienced during pregnancy.
Small quantities of levothyroxine are detected in human breast milk. Risk to infants is minimal and the American Academy of Pediatrics considers this medication safe for breastfeeding. Note that small quantities of thyroxine are naturally present in breastmilk of nursing mothers not taking levothyroxine.
While the exact mechanism of action is unknown, of the thyroid hormones available, levothyroxine most closely simulates normal thyroid secretion, and is identical to T4 secreted by the thyroid gland.
Levothyroxine tablets are typically very small, come in a variety of colors and strengths depending on the manufacturer, and should be stored at room temperature (77 F) but remain stable when briefly kept at extremes between 59-86 F. They should be protected from light and moisture. The parenteral form of levothyroxine (IV/IM) is a vial of lyophilized powder for reconstitution with 0.9 percent sodium chloride injection. Although stable for up to 48 hours following reconstitution, it should be used immediately and any remaining drug discarded.
Cautions and Warnings — Thyroid hormones, including levothyroxine, should never be used to treat obesity or for weight loss. Normal therapeutic doses are ineffective for inducing weight loss in euthyroid patients (patients with a normally functioning thyroid gland). Doses exceeding normal can easily be toxic and lead to life threatening side effects, particularly when given with other commonly used weight loss drugs.
Important Side Effects and Interactions — Most adverse reactions to levothyroxine result from therapeutic overdosage and resemble signs and symptoms of hyperthyroidism. These would include increased appetite, weight loss, fever, hyperactivity, insomnia, tremors, tachycardia, hypertension, diarrhea, hair loss, flushed skin, and menstrual irregularities, among others. EMS providers evaluating patients with tachycardias should include therapeutic overdosage of levothyroxine among potential causes considered. Carefully evaluate medication containers to determine if more than one brand of levothyroxine is being taken simultaneously. In thyroid patients with lethargy and bradycardia, underdosage should be considered.
Information from the manufacturer suggests that levothyroxine may decrease bone mineral density, especially in older women. Attention to TSH levels and using the lowest effective dose of levothyroxine can help minimize this risk.
While hypersensitivity to levothyroxine itself has not been known to occur, patients have experienced hypersensitivity to inactive ingredients used in manufacturing levothyroxine. Persons allergic to iodine or yellow food dye, or sensitive to lactose or corn starch should consult their pharmacist to select a brand or strength of levothyroxine free from the offending ingredient.
There are 79 drugs reported to interact with levothyroxine. Soybean, soy formula, and soy protein are the most frequently reported. Infants treated with levothyroxine who were fed soy containing formula required an average 20 percent increase in thyroid hormone dose. Similar findings would be expected for dietary supplements containing soy. Suggestions that this effect can be minimized or eliminated by separating medication and soy administration times are not evidence based. People taking levothyroxine should avoid soy dietary products or have their TSH levels closely monitored until stable.
EMS providers should be aware that there have been anecdotal reports of ketamine inducing serious hypertension and tachycardia in patients taking levothyroxine. The manufacturer advises using ketamine with caution. These reports are not substantiated in peer reviewed drug literature.
Women starting estrogen therapy may need to increase their dose of levothyroxine, as may women who become pregnant (due to the high estrogen state of pregnancy). Patients taking oral anticoagulants should have their clotting times closely monitored when adding or withdrawing treatment with thyroid hormones as these tend to increase anticoagulant effects. Patients taking digoxin may require increased doses when also taking levothyroxine. Documentation of interactions between levothyroxine and other medications is weak at best.
Average Costs — U.S.
50 mcg tablet/75 mcg tablet/125 mcg tablet (generic)
Patient cost: $0.21/0.28/0.31 each*
Large Hospital cost: $0.11/0.12/0.14 each
*($4.00 at Wal Mart® and Target for 1 month or $10.00 for 90 day supply)
References
- MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed July, 2008).
- Albany Medical Center Pharmacy, Albany, New York.
- American Thyroid Association: www.thyroid.org.
