Levothyroxine Bioequivalence, Therapeutic Equivalence, and Generic Levothyroxine Substitution

1
Levothyroxine Bioequivalence, Therapeutic
Equivalence, and Generic Levothyroxine
Substitution
2
FDA Considerations for Approval Brand and
Generic

• Brand
• Chemistry
• Manufacturing
• Controls
• Labeling
• Testing
• Preclinical/Clinical
• Bioavailability

• Generic
• Chemistry
• Manufacturing
• Controls
• Labeling
• Testing
• Bioequivalence

Food and Drug Administration Web site. Glossary
of Terms. Available at http//www.fda.gov/cder/d
rugsatfda/glossary.htm. Accessed February 16,
2006.
3
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

Food and Drug Administration Web site.
Productivity Documentation in the Division of
Bioequivalence. Available at http//www.fda.gov/c
der/mapp/5210-3.pdf. Accessed February 16,
2006. Food and Drug Administration Web site.
Glossary of Terms. Available at
http//www.fda.gov/cder/drugsatfda/glossary.htm.
Accessed February 16, 2006.
4
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

5
Bioequivalence
6
Bioavailability (BA)
The measure of the rate and extent of a drugs
absorption

• AUC
• Area under the plasma-time curve
• Measure of extent of absorption
• Cmax
• Maximum concentration
• Measure of rate of absorption

Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/ob/docs/preface/ecpreface.htmStatistical20Crite
ria20for20Bioequivalence. Accessed February 16,
2006.
7
Pharmacokinetic Profile of a Reference Drug
Reference Formulation
Concentration
Time
Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/ob/docs/preface/ecpreface.htmStatistical20Crite
ria20for20Bioequivalence. Accessed February 16,
2006.
8
Comparison of PK Profiles to Determine
Bioequivalence
Test Formulation (Generic) Reference Formulation
The AUC and Cmax of the generic must meet 80 -
125 of the brand in order to be deemed BE
Concentration
Time
Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/ob/docs/preface/ecpreface.htmStatistical20Crite
ria20for20Bioequivalence. Accessed February 16,
2006.
9
FDA Requirements for Bioequivalence
Pharmacokinetic Reference Range
80
100
125
Product ABioequivalent

• Product A is bioequivalent to the reference drug
• Product B is not

Reference Drug
Product BNot Bioequivalent
Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/ob/docs/preface/ecpreface.htmStatistical20Crite
ria20for20Bioequivalence. Accessed February 16,
2006.
10
Bioequivalence andTherapeutic Equivalence

• Some clinicians may infer from current
  bioequivalence standards that
• A 20 to 25 difference in absorption (Cmax,
  AUC) has no effect on therapeutic outcomes

Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/orange/obannual.pdf. Accessed February 16, 2006.
11
The Orange BookSubstitution of Drugs at the
Pharmacy
12
FDA Coding Systemfor Therapeutic Equivalence

• A
• Drug products that are considered to be
  therapeutically equivalent to other
  pharmaceutically equivalent products
• B
• Drug products not considered to be
  therapeutically equivalent to other
  pharmaceutically equivalent products

Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/ob/docs/preface/ecpreface.htmTherapeutic
Equivalence-Related Terms. Accessed February 16,
2006.
13
AB-Rated Products

• Generic has met bioequivalence requirements
• Actual or potential bioequivalence problems have
  been resolved through appropriate scientific
  testing
• Pharmacists may change to AB rated equivalent
  product without physician consultation
  (Substituting an unprotected Rx is actually the
  law in some states)
• Physicians may restrict substitution by
  protecting prescription
• Do not substitute
• Dispense as written
• Placement of signature

Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/ob/docs/preface/ecpreface.htmTherapeutic
Equivalence-Related Terms. Accessed February 16,
2006. National Institute of Health Care
Management Foundation Web site. A Primer Generic
Drugs, Patents and the Pharmaceutical
Marketplace. Available at http//www.nihcm.org/Ge
nericsPrimer.pdf. Accessed on February 16, 2006.
14
FDA Policy on Drug Substitution

• The FDA has prepared a list of drugs that are
  bioequivalent they can be substituted for each
  other
• These drugs are listed in a Federal publication
  called Approved Drug Products With Therapeutic
  Equivalence Evaluations, known as the Orange Book
• The FDA does not recommend substituting drugs
  that have not been determined to be bioequivalent

Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/ob/docs/preface/ecpreface.htmTherapeutic
Equivalence-Related Terms. Accessed February 16,
2006.
15
What Is Uniqueabout Levothyroxine?

• Thyroxine is an endogenous hormone
• The FDA prefers PK trials in normal volunteers
• Protocol
• Normal volunteers
• 600 mcg, single dose, fasting
• Monitor for 48 hours
• Measure T4 and T3
• Take samples at -30, -15, and 0 minutes
• Simple baseline correction required

Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/ob/docs/preface/ecpreface.htmStatistical20Crite
ria20for20Bioequivalence. Accessed February 16,
2006.
16
Whats Unique About Thyroxine?

• LT4 has a narrow therapeutic index
• Thyroxine is an endogenous hormone produced by
  the thyroid gland and accounts for 70 of the AUC

17
Narrow Therapeutic Index (NTI)Clinical View

• Drugs with small difference between therapeutic
  and toxic dose
• Require careful dose titration, monitoring
• LT4 considered NTI by FDA
• Should BE/TE assessment of NTI agents be
  different than other drugs?
• Would a 20-25 potential difference in
  bioavailability alter the therapeutic effects of
• Warfarin, Digoxin, Phenytoin, Cyclosporin,
  Levothyroxine, Lithium

Food and Drug Administration Web site. The FDA
Process for Approving Generic Drugs. Available
at http//www.fda.gov/cder/ogd/02-10_BCBS_gjb/sld
041.htm. Accessed February 16, 2006.
18
Suboptimal Thyroxine Therapy Impact of Small
Thyroxine Dose Changes
1
0
Above-normal TSH
Normal TSH range
8
Below-normal TSH
TSH
6
mU/L
4
2
1
0.2
.
-
50
-25

2
5
50
Optimum
75
T4 (?g/day) Dose
Carr D, et al. Clin Endocrinol. 198828325-333.
19
The Dong Study
20
Equivalence of Thyroxine Formulations Dong Study

• Comparison of 4 LT4 (Synthroid, Levoxyl, and 2
  generics)
• 24 subjects
• 6-week blinded crossover trial
• Standard FDA bioequivalence criteria
• None of the products were bioequivalent when
  adjusted for baseline thyroxine levels (3/13/03
  methodology)

Dong B, et al. JAMA. 19972771205-1213.
21
Equivalence of Thyroxine Formulations
TSH Out of Range
0 59 42 55 54
Baseline
Period 4
Period 2
Period 1
Period 3
Mayor GH, et al. Am J Ther. 19952417-432.
22
The Blakesley Study
23
Current BE standards cannot detect the difference
between LT4 doses that differ by as much as
?

• 7.5
• B. 10
• C. 12.5
• D. 15

24
Study Design

• 36 healthy volunteers (18M, 18F)
• Fasting, open-label, randomized, three-period,
  crossover 42 to 54 days between periods
• 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

Blakesley V, et al. Thyroid. 200414191-200.
25
Study Results

• T4 profiles with a correction for endogenous
  hormone

Blakesley V, et al. Thyroid. 200414191-200.
26
Results
RELATIVE BIOAVAILABILITY
90 Confidence Interval
PHARACOKINETIC PARAMETER
REGIMENS
.5 .6 .7 .8 .9 1.0 1.1 1.2 1.25 1.3 1.4 1.5
0.890 0.968 0.927 0.982 0.757 0.888 0.672
0.779
450 mg Dose vs. 600 mg Dose
Uncorrected Cmax Uncorrected AUC48
Corrected Cmax Corrected AUC48
Uncorrected Cmax Uncorrected AUC48
0.967 1.050 0.997 1.055 0.979 1.145 1.008
1.165
450 mg Dose vs. 400 mg Dose
Corrected Cmax Corrected AUC48
Blakesley V, et al. Thyroid. 200414191-200.
1.25
Range of Bioequivalence
.8
27
Equivalence of Thyroxine Formulations Sandoz
Study Results
AUC0-48
.6
.8
1.0
1.25
1.4
Sandoz L-T4 vs. Synthroid
Sandoz L-T4 vs. Levoxyl
.8
1.25
Range of Bioequivalence
Food and Drug Administration Web site.
Levothyroxine Sodium, Supplement to Petition for
Reconsideration Docket No. 211030387).
Available at http//www.fda.gov/ohrms/dockets/dai
lys/04/oct04/100504/03p-0387-let00005-vol5.pdf.
Accessed February 16, 2006.
28
Implications of Sandoz Study Results

• Conclusion
• Pharmacokinetic parameters of generic
  levothyroxine (Sandoz) differed from those of
  Synthroid by as much as 12.5
• Nevertheless, on the basis of FDA criteria for
  bioequivalence, Sandoz levothyroxine was labeled
  bioequivalent to both Synthroid and Levoxyl

Food and Drug Administration Web site.
Levothyroxine Sodium, Supplement to Petition for
Reconsideration Docket No. 211030387).
Available at http//www.fda.gov/ohrms/dockets/dai
lys/04/oct04/100504/03p-0387-let00005-vol5.pdf.
Accessed February 16, 2006.
29
Current FDA Bioequivalence Standards Cannot
Distinguish a 12.5 Dose Difference
Difference of Blakesley V, et al. Thyroid. 200414191-200.
30
What Happens at the Pharmacy?
31
Approved LT4 Products
Prescriptions that are not protected are likely
to be substituted at the pharmacy
Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations 25th ed. Cumulative Supplement 3.
Center for Drug Evaluation and Research, FDA.
March 2005. Available at http//www.fda.gov/cder
/orange/supplement/cspreface.htm. Accessed
February 16, 2006.
32
Professional GuidanceJune 24, 2004

• Joint statement from
• American Thyroid Association
• Endocrine Society
• American Association of Clinical Endocrinologists
• Concerned about current BE standards and harm to
  patients following a preparation switch at the
  pharmacy

The American Thyroid Association Web site. ATA,
TES, and AACE express disappointment and concern
for the health of millions of thyroid patients
after FDA announces decision to approve generic
substitutes for levothyroxine product. Available
at http//www.thyroid.org/professionals/advocacy/0
4_06_24_fda.html. Accessed February 16, 2006.
33
Professional GuidanceJune 24, 2004

• Physicians should
• Alert patients that preparation may be switched
  at pharmacy
• Encourage patients to ask to remain on the same
  preparation at every pharmacy refill
• Make sure patients understand the need to have
  their TSH retested and dosing readjusted every
  time their levothyroxine preparation is switched

The American Thyroid Association Web site. ATA,
TES, and AACE express disappointment and concern
for the health of millions of thyroid patients
after FDA announces decision to approve generic
substitutes for levothyroxine product. Available
at http//www.thyroid.org/professionals/advocacy/0
4_06_24_fda.html. Accessed February 16, 2006.
34
Practical Advice

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

Singer et al. JAMA. 1995273808-812