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Thyroid Dysfunction: Pharmaceutical Considerations

Combined T4/T3 Therapy Summary of Studies. Bunevicius. N Engl J Med. 1999 Feb 11;340(6):424-9. Bunevicius. Int J Neuropsychopharmacol. 2000 Jun;3(2):167-174. Walsh et al. J Clin Endocrinol Metab. 2003 Oct;88(10):4543-50. Sawka et al. J Clin Endocrinol Metab. 2003 Oct;88(10):4551-5. Clyde. JAMA. 200

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Thyroid Dysfunction: Pharmaceutical Considerations

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    1. Thyroid Dysfunction: Pharmaceutical Considerations

    2. Combined T4/T3 Therapy Summary of Studies

    3. T3 and T4 / T3 Therapy T3 has a very short half-life Liothyronine Synthetic T3 is more biologically active that LT4 No indication for the use of T3 alone Thyroid extract Porcine-derived T4 and T3

    4. Brand Chemistry Manufacturing Controls Labeling Testing Preclinical/Clinical Bioavailability Generic Chemistry Manufacturing Controls Labeling Testing Bioequivalence FDA Considerations for Approval: Brand and Generic The FDA looks at a number of processes and characteristics before approving either a generic or branded product. This list hits some of the key points. The brand drug’s preclinical and bioavailability studies are used to determine the generic’s BE.The FDA looks at a number of processes and characteristics before approving either a generic or branded product. This list hits some of the key points. The brand drug’s preclinical and bioavailability studies are used to determine the generic’s BE.

    5. Definition of a Generic Drug A drug product that is the same as brand drug in: Active ingredient Strength Dosage form Route of administration Quality Therapeutic effect

    6. Therapeutic Equivalents: Assumptions Pharmaceutical Equivalent + Bioequivalence = Therapeutic Equivalence When administered under conditions specified in the labeling, expected to have the same: Clinical effect Safety profile

    7. Bioequivalence

    8. Area Under the Curve (AUC) Measure of extent of absorption of drug into blood plasma

    9. Pharmacokinetic Profile of a Reference Drug

    10. Comparison of PK Profiles to Determine Bioequivalence

    11. FDA Requirements for Bioequivalence FDA Requirements for Bioequivalence. The rate and extent of absorption between a drug being tested and the reference drug is compared statistically using characteristics of concentration-time curves, such as AUC and Cmax. For a drug to be approved as bioequivalent to the reference drug, its AUC and Cmax values must fall within a 90% confidence interval (CI), or between 80% and 125%, of the reference drug values. In the example shown on this slide, Product A is bioequivalent to the reference drug. Its AUC value falls within 80% to 125% of the reference drug. Product B is not bioequivalent to the reference drug. Its AUC value falls outside of 80% to 125% of the reference drug.1 Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003. FDA Requirements for Bioequivalence. The rate and extent of absorption between a drug being tested and the reference drug is compared statistically using characteristics of concentration-time curves, such as AUC and Cmax. For a drug to be approved as bioequivalent to the reference drug, its AUC and Cmax values must fall within a 90% confidence interval (CI), or between 80% and 125%, of the reference drug values. In the example shown on this slide, Product A is bioequivalent to the reference drug. Its AUC value falls within 80% to 125% of the reference drug. Product B is not bioequivalent to the reference drug. Its AUC value falls outside of 80% to 125% of the reference drug.1 Reference 1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.

    12. FDA Coding System for Therapeutic Equivalence Products receive “AB” ratings to signify bioequivalence or “BX” ratings to signify inequivalence. If a product receives an AB rating, pharmacists may change to another AB-rated drug

    13. Does a –20% to +25% difference in absorption have an effect on therapeutic outcomes?

    15. What’s Unique About LT4? Thyroxine is an endogenous hormone and accounts for 70% of the AUC In dosage form proportionality studies, the average contribution of endogenous thyroxine to AUC was 69% (range 52%-88%). Data on file, Abbott Laboratories, Study M01-324. In dosage form proportionality studies, the average contribution of endogenous thyroxine to AUC was 69% (range 52%-88%). Data on file, Abbott Laboratories, Study M01-324.

    18. Equivalence of Thyroxine Formulations

    19. The Blakesley Study

    20. Current BE standards cannot detect the difference between LT4 doses that differ by as much as:

    21. Study Design N=36 LT4 doses administered Regimen A: 600 mg (12 x 50 mg Synthroid) Regimen B: 450 mg (9 x 50 mg Synthroid) Regimen C: 400 mg (8 x 50 mg Synthroid) The same Synthroid lot was used for all regimens Followed FDA criteria for determining BE

    23. Equivalence of Thyroxine Formulations

    24. Equivalence of Thyroxine Formulations Sandoz Study Results

    25. Implications of Sandoz Study Results Despite the absorption difference of ~12.5% between Synthroid and the generic, they are considered bioequivalent

    26. LT4 Dosage Strengths in 1982

    30. What Happens at the Pharmacy?

    31. 3 Generic, 3 Reference, Several Brand Names Substitution Approved Drug Products With Therapeutic Equivalence Evaluations. 24th edition Cumulative Supplement 7. Center for Drug Evaluation and Research, FDA July 2004 www.fda.gov/cder/orange/supplement/cspreface.htm. Approved Drug Products With Therapeutic Equivalence Evaluations. 24th edition Cumulative Supplement 7. Center for Drug Evaluation and Research, FDA July 2004 www.fda.gov/cder/orange/supplement/cspreface.htm.

    32. Approved LT4 Products

    33. Practical Advice Pick one LT4 brand for your patient, and do not allow generic substitution by protecting the prescription. Confirm the LT4 brand the patient is taking at each visit. Obtain serum TSH 8-12 weeks after LT4 dose or brand changes. Consider brand substitution among the list of explanations for deviation of the TSH from the therapeutic goal range.

    34. Professional Associations Guidance to Physicians and Patients June 24, 2004

    35. Given the multiple sources of variation in the effects of a dose of the drug, there is no good reason to introduce another one by substituting a generic that could be switched without the prescriber’s knowledge from one refill to the next.

    36. Internet References American Association of Clinical Endocrinologists www.aace.com American Thyroid Association www.thyroid.org Thyroid Manager www.thyroidmanager.org Thyroid Today www.thyroidtoday.com National Cancer Institute www.cancer.gov (search “thyroid”) www.thyroidpharmacovigilance.net/

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