1. The Need for Precise L-Thyroxine Dosing James V. Hennessey M.D. Associate Professor of Medicine Brown Medical School Current, pending and past affiliations: Speakers Bureau: Abbott, Forest Pharmaceuticals Research Support: Knoll, King Pharmaceuticals

2. Indications for L-Thyroxine Primary Hypothyroidism (> 95% of cases) –Principle dose titration parameter: TSH –Recommended target range: 0.5 - 2.0 mIU/L Suppression therapy for Thyroid Cancer –Principle dose titration parameter: TSH –Recommended target range: 0.1- < 0.4 mIU/L Other experts recommend < 0.1 for high risk patients Demers and Spencer NACB Guidelines 2003 Mazzaferri 2000 Singer et al. 1995

3. Individual TSH normal Range 16 caucasian men 24-52 yrs (median 38) 15 no Hx Thyroid Dz, goiter nor medication Blood samples: –monthly (0900-1200) –stored frozen –analyzed random order in same assay run Participants Andersen et al. 2002 JCEM 87:1068-72 Mean +/- 2SD =1.27 (0.16 - 2.39)

4. Subclinical Thyroid Disease Definition: High or low TSH while T4 and T3 remain within laboratory reference range Both Subclinical Hypo and Hyperthyroidism are associated with physiologic and biochemical abnormalities as well as increased risk of certain diseases. Brent & Larsen 2000

5. Adverse Effects of Thyroxine Rx Excess: Overt (symptomatic) Thyrotoxicosis Subclinical Thyrotoxicosis –Excess bone loss Postmenopausal women –Cardiac arrhythmias or dysfunction increased pulse rates increased cardiac wall thickness increased cardiac contractility increased risk of atrial fibrillation Brent & Larsen 2000

6. EQUIVALENCY OF TWO THYROXINE PREPARATIONS PATIENTS ON LT4: 34 CLINICALLY EUTHYROID PATIENTS –25 WITH 1º HYPOTHYROIDISM –9 - GOITER SUPPRESSION INDICATION Rx:LEVOTHROID (L), SYNTHROID (S) –6 WEEK PERIOD THEN CROSSED OVER EVAL: TFT’s, TRH STIMULATION Hennessey et al. 1985 Ann Intern Med 102:770-773

7. Levothroid® or Synthroid® TT4 AND FTI  g/dL Hennessey et al. 1985 Ann Intern Med 102:770-773

8. Levothroid® or Synthroid® TT3 AND FT3I Hennessey et al. 1985 Ann Intern Med 102:770-773 ng//dL

9. Levothroid® or Synthroid® TRH RESULTS * * ** P S Hennessey et al. 1985 Ann Intern Med 102:770-773

10. ASSESSMENT OF LT4 INTERCHANGEABILITY 31 PATIENTS (6 MEN, 25 WOMEN) –“LONG-STANDING 1 0 HYPOTHYROID” STABLE LT4 Rx > 6 WKS @ ENTRY 23/31 SYNTHROID (S) TO LEVOXINE 8/31 LEVOXINE (L) TO SYNTHROID TFT’s @ BASELINE AND FOUR MONTHS AFTER SWITCH Escalante et al.1995

11. INTERCHANGEABILITY RESULTS

12. ASSESSMENT OF LT4 INTERCHANGEABILITY RESULTS: 6/24 (24%) EUTHROID ON Synthroid WERE THYROTOXIC ON Levoxine 2/21 (9.5%) EUTHYROID ON Levoxine WERE THYROTOXIC ON Synthroid 8/31 (26%) HAD CHANGE IN BASAL TSH CLASSIFICATION Escalante et al.1995

13. L-T4 BIOEQUIVALENCE: NAME BRAND VS. GENERIC PATIENTS: –24 HYPOTHYROID PATIENTS 16 HASHIMOTO’S THYROIDITIS 8 POST SURGICAL OR 131-I TREATMENT –22 IN FINAL ANALYSIS SETTING: –UCSF DEPT. CLINICAL PHARMACOLOGY Dong et al 1997

14. L-T4 BIOEQUIVALENCE TREATMENT RAMDOMIZATION: –PREV. EUTHYROID ON 0.1 OR 0.15 mg/d Rx for min 6 weeks prior to study entry BLOCK ASSIGNMENT 4 CROSSOVER SCHEMES (6 weeks each) –A Levoxyl  –B Pharm. Basics (Geneva) –C Pharm. Basics (Rugby) –D Synthroid  Dong et al 1997

15. 24 HOUR TFT PROFILES Mayor et al 1995

16. TSH PROFILES Dong et al 1997

17. Data derived from Mayor et al. 1995, Dong et al. 1997

18. References Andersen et al. 2002 –Narrow Individual Variations in Serum T4 and T3 in Normal Subjects: A Clue to the Understanding of Subclinical Thyroid Disease. JCEM 2002; 87:1068-72. Brent and Larsen 2000 –Treatment of Hypothyroidism: The Thyroid, Eighth Edition, 2000. Braverman & Utiger eds. pp.853-860. Dong et al. 1997 –Bioequivalence of generic and brand levothyroxine products in the treatment of hypothyroidism. JAMA 1997; 277:1205-1213. Escalante et al.1995 – Assessment of Interchangeability of Two Brands of Levothyroxine Preparations with a Third-Generation TSH Assay. Am J Med. 1995; 98:374-378 Hennessey et al. 1985 –The equivalency of two L-thyroxine Preparations. Ann Intern Med. 1985; 102:770-773.

19. References Mazzaferri 2000 –Carcinoma of Follicular Epithelium: Radioiodine and Other Treatment and Outcomes: The Thyroid, Eighth Edition. Braverman & Utiger eds. pp.904-929. Mayor et al. 1995 –Limitations of Levothyroxine Bioequivalence Evaluation: Analysis of an attempted Study. Am J Therapeutics 1995; 2:417-432. Singer et al. 1995 –Treatment Guidelines for Patients With Hyperthyroidism and Hypothyroidism JAMA 273:808-812. Singer et al. 1996 –Treatment Guidelines for Patients With Thyroid Nodules and Well-Differentiated Thyroid Cancer. Archives of Internal Medicine 156:2165-2172.