FDA Advisory Committee for Pharmaceutical Science—March 13, 2003 Carlos R. Hamilton, Jr. MD, FACE American Association of Clinical Endocrinologists—Vice President The University of Texas Health Science Center—Houston, Executive Vice-President for Clinical Affairs

American Association of Clinical Endocrinologists A professional organization representing over 4000 physicians specializing in the care of patients with disorders of the endocrine system and with metabolic diseases. These are the specialists called on by our colleagues for care of patients with thyroid and other glandular disorders. Hence we have an acute awareness of the effects of thyroid replacement medication.

3 Significant Clinical Effects May Result from Mild Degrees of either Over-Replacement (Hyperthyroidism) or Under-Replacement (Hypothyroidism) of Thyroid Hormone in Treated Patients Hyperthyroidism Irregular or rapid heart rhythm Accelerated osteo- porosis Muscle weakness and weight loss Psychiatric symptoms etc. Hypothyroidism Premature ischemic heart disease High cholesterol Abnormal weight gain Menstrual changes Fatigue and lethargy etc.

4 Measurement of the Serum TSH Level is the Gold Standard for Evaluating Effective Levels of Circulating Thyroid Hormone Much more precise and sensitive than measurement of the actual thyroid hormone (L-thyroxine or T-3). TSH (thyroid stimulating hormone or thyrotropin) is produced by the pituitary gland and increases when the effective thyroid levels are lower than ideal and decreases when thyroid levels are excessive. Serum TSH level is very sensitive to changes in effective thyroid hormone blood levels and is the most accurate guide to finding the optimal dosage of thyroid hormone medication for a particular patient.

5 Dosage Changes of as Little as 12.5 to 25 Micrograms of Oral L-Thyroxine Daily Have Significant Effects on Serum TSH These changes, whether from change in dose or brand, can have important clinical effects on our patients. Excessive amounts can cause symptoms and effects of hyperthyroidism. Sub-optimal amounts can cause symptoms and effects of hypothyroidism.

6 Effects of L-Thyroxine Dosage Changes on Serum TSH Levels Carr D, et al. Fine Adjustment of Thyroxine Replacement Dosage: Comparison of the Thyrotropin Releasing Hormone Test Using a Sensitive Thyrotropin Assay with Measurement of Free Thyroid Hormones and Clinical Assessment. Clinical Endocrinology, 1998, 28:

7 Importance of these Observations for the Management of Patients Requiring Thyroid Hormone Replacement When the dosage, source or brand of thyroid hormone replacement is changed, one should re- check serum TSH levels in 6-8 weeks to verify the effectiveness of the new preparation. Changes from one brand or manufacturer of L- thyroxine should be followed by a re-check of serum TSH to verify their equivalence. When the same dose and source of thyroid is used, one needs to re-check only at yearly intervals. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hyperthyroidism and Hypothyroidism. Endocrine Practice 8:457, 2002.