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Frequently Asked Questions

Are all levothyroxine products created equal?

For over 50 years, levothyroxine has been the drug of choice for the treatment of hypothyroidism.1-3 Of the top 200 generic drugs in 2007, it was ranked 4th with close to 50 million prescriptions filled annually, while Synthroid (levothyroxine sodium, Abbott) was ranked 5th among the top 200 brand name drugs with over 25 million prescriptions filled annually.4,5 Levothyroxine is a synthetic form of endogenous thyroxine, which is excreted from the thyroid gland.1,6 At average daily doses of 0.075 to 0.1 mg (women) and 0.1 to 0.2 mg (men), it is an effective replacement of thyroid hormone in patients with thyroid disorders. Dosage adjustment is based on serum levels of thyroid stimulating hormone (TSH). Levothyroxine is designated as a drug with a narrow therapeutic index (NTI); slight increases or decreases in serum TSH levels can potentially result in adverse effects due to toxicity or lack of efficacy.6,7

The controversy
Both brand and generic formulations of levothyroxine have been available since the 1980s; however, key studies suggested that the products varied and could not be interchanged (table 1).1,8-10 The Food and Drug Administration (FDA) has designated specific generic levothyroxine products as therapeutically equivalent (AB-rated).11 A 2-period, cross-over study design is employed to assess levothyroxine bioequivalence. The dose used is 0.6 mg of levothyroxine, which is well above normal daily doses. The use of a higher dose is to prevent discrepancies due to endogenous thyroid hormone circulating in the body, as well as to ensure that high levels of levothyroxine are detected so that accuracy in testing is maintained. The FDA also performs dissolution tests; if the same amount of active ingredient is found in each tablet, then the amount of drug distributed in the body should be equivalent. However, controversy and issues still surround the bioequivalency testing for levothyroxine by the FDA, which are listed below.3,7

  1. Endogenous thyroid hormone may confound the levels of thyroxine detected after oral administration of levothyroxine.
  2. The designation of levothyroxine as an NTI may require specific study designs with strict confidence intervals (95% to 105%) compared to the confidence intervals of 80% to 125% for non-NTI drugs.
  3. Levothyroxine levels may not be the most appropriate measure, considering dosing is based on serum TSH levels and TSH levels change slowly over an 8-week period after a dose change.
  4. The use of a high dose (0.6 mg) does not mimic what is seen in clinical practice.
  5. There may be carryover effects due to the lack of a washout period between the brand and generic formulations.

Table 1. Key in vivo bioequivalency studies of levothyroxine.8-10

Author

Study design/

population

Interventions

Outcome measures

Results

Conclusion

Dong
1997 8

Single-blind, randomized, cross-over study of 22 women with hypothyroidism receiving levothyroxine 0.1 or 0.15 mg daily

Synthroid vs. Levoxyl vs. 2 generic formulations of levothyroxine (Geneva, Rugby laboratories)

Patients received 1 formulation of the study drug for 6-weeks before crossing over to another formulation.

Primary

  • AUC, Cmax, and time to Cmax of thyroxine, T3, and free thyroxine for all 4 products

Secondary

  • Therapeutic interchangeability (measured by 90% CI of 0.8 to 1.25)

No statistically significant differences found in AUC and Cmax for primary outcome for all 4 products (p>0.05).

Variability found in time to Cmax; after 2 hours, 73% (Synthroid), 52% (Levoxyl), 48% (Geneva), and 48% (Rugby) of patients reached peak concentrations of thyroxine (p>0.05).

AUC for all agents were in ±25% bioequivalence criterion for thyroxine, T3, and free thyroxine.

7 patients reported hyperthyroid effects; these adverse effects were not reported with 1 specific formulation and effects spontaneously resolved.

The 4 formulations studied are bioequivalent; however, the products are not identical and all patients may not benefit from interchangeability.

Hennessey
1985 9

Cross-over study of 34 patients with hypothyroidism receiving levothyroxine

Synthroid vs. Levothroid (mean daily dose 0.138 ± 0.04 mg [SD] for both groups)

Patients were assigned to receive the same dose of Synthroid or Levothroid for 6-weeks before crossing over to the other formulation.

Primary

  • Bioavailability measured by total and free thyroxine, T3, and T3 resin

Secondary

  • Serum thyrotrophin levels measured before and after thyrotrophin-releasing hormone

Mean free thyroxine level was significantly higher in patients who received Levothroid prior to Synthroid (p<0.05); no statistically significant difference was observed when the drugs were given in the reverse order.

Lower levels of serum thyrotrophin levels were observed with Synthroid at 15 and 30 minutes post thyrotrophin-releasing hormone (p<0.05).

Equal daily doses of Synthroid and Levothroid are similar, but not bioequivalent.

Stoffer
1980 10

Cross-over study of 3 patients with hypothyroidism receiving levothyroxine

Brand name product vs. 2 generic formulations (manufacturers not stated)

Patients received a dose of 0.2 mg daily for 6-weeks before crossing over to another formulation.

Primary

  • Bioavailability measured by free thyroxine index

Secondary

  • Thyroxine content of ten 0.2 mg tablets of each formulation

Two of the 3 patients had a free thyroxine index greater than the upper limit of normal with 1 of the generic products (p value not reported).

The thyroxine content of ten 0.2 mg generic tables was statistically significantly different when compared with the brand name product (p<0.001).

The expected potency of the brand name product was 78%.

All formulations of levothyroxine are not equivalent; generic products should not be substituted for brand name products.

Abbreviations: AUC=area under the curve; Cmax=maximum concentration; T3=triiodothyronine; SD=standard deviation

Federal bioequivalency
The Approved Drug Products with Therapeutic Equivalence, commonly known as the Orange Book, is a searchable, public, database that lists the FDA-approved drugs/drug products available in the United States.>12 The Orange Book comprises 4 sections, 1 of which lists the evaluations of therapeutic equivalence. In this section, the terminology and therapeutic coding system is explained in detail. The FDA defines pharmaceutical equivalents as products that contain the same active ingredient, dosage form, dosage strength, and route of administration; these products may differ in shape, color, and excipients.12,13 On the other hand, therapeutic equivalents are products that are pharmaceutically equivalent and must also have the same clinical safety and efficacy profile when administered to patients in equal doses. Therefore, 2 products that may be pharmaceutically equivalent may not be therapeutically equivalent, or interchangeable. When the FDA performs bioequivalency studies, the brand name product is referred to as the referenced listed drug, and based on the results of the studies, therapeutic equivalence ratings are assigned.

The therapeutic equivalence coding system contains a 2-letter code and was designed to allow practitioners to quickly determine if a particular product is therapeutically equivalent.12,13 The first letter of the code is either an “A” (therapeutically equivalent) or “B” (not therapeutically equivalent). The second letter correlates to a specific dosage form (i.e., AT for topical products). The designated term AB is used for oral dosage formulations in which “actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.”12 Multisource products that have the same active ingredient, dosage form, strength, and route of administration, may have more than 1 referenced listed drug for comparison.12,13 When this occurs, a number is added to the end of the standard 2-letter code (i.e., AB1, AB2, etc.). In these situations, only products with corresponding letters and numbers are therapeutically equivalent, thus, interchangeable. Levothyroxine is 1 of the drugs with 3-component therapeutic equivalency codes.11,13 The AB1 agents are therapeutically equivalent to AB1 agents, while AB2 agents are therapeutically equivalent to AB2 agents, and so on. AB1 agents are not considered therapeutically equivalent to AB2 agents. Table 2 lists the brand and generic products and their corresponding code.

Table 2. Therapeutic equivalence codes for all strengths of levothyroxine sodium tablets.2,11,13

Product name

Manufacturer

Therapeutic equivalence code(s)

Synthroid

Abbott

AB1, AB2

Levo-T

Alara Pharm

AB2, AB3

Levothyroxine sodium

Genpharm

AB2, AB3

Levoxyl

King Pharms

AB1, AB3

Levothroid

Lloyd

AB4

Levothyroxine

Mylan

AB1, AB2, AB3, AB4

Unithroid

Stevens J

AB1, AB2, AB3

State specific bioequivalency
Therapeutic substitutions of generic for brand name products vary by state.14 The majority of states follow the therapeutic equivalency codes listed in the Orange Book; however, others allow substitution provided state-specific substitution is met. Table 3 lists the states that follow the Orange book, and table 4 summarizes state generic substitution laws. Generally, all pharmacists should use professional judgment when deciding whether or not to substitute a brand name drug with a generic product.

Table 3. States that use the Orange Book to guide generic substitutions.14
Arizona Illinois Maryland New Jersey Texas
Arkansas Indiana Massachusetts Ohio Utah
Delaware Kansas Mississippi Oklahoma Texas
District of Columbia Kentucky Nebraska Pennsylvania Utah
Hawaii Louisiana Nevada South Dakota West Virginia
Idaho Maine New Hampshire Tennessee Wisconsin
        Wyoming

Table 4. States with specific requirements for generic substitution.14

State

Requirements

Alabama

  • Pharmacists may sell a pharmaceutically equivalent product containing the same active ingredient(s), dosage form, and strength

Alaska

  • Pharmacists may not dispense products that, in the pharmacist’s opinion, is not an equivalent drug product

California

  • Pharmacists may select another drug product with the same active chemical ingredient of the same strength, quantity, dosage form, and generic name

Colorado

  • Pharmacists may substitute a therapeutically equivalent drug product if the substituted drug product is the same generic drug type

Connecticut

  • Pharmacists may substitute a generic product with the same strength, quantity, dose, and dosage form

Florida

  • It is the responsibility of each community pharmacy to establish a formulary of generic and brand name drug products which, if selected as the drug product of choice, would not pose a threat to the health and safety of patients receiving prescription medication
  • The Florida Board of Pharmacy maintains a negative generic drug formulary

Georgia

  • Pharmacists may substitute a drug with the same generic name, strength, quantity, dose, and dosage form as the prescribed brand name drug product

Iowa

  • Pharmacists may use professional judgment in the economic interest of the patient by selecting a drug product with the same generic name and demonstrated bioavailability as the 1 prescribed for the patient

Michigan

  • Pharmacists may substitute with a generically equivalent product identical in dose, dosage form, and content of active ingredient

Minnesota

  • Pharmacists may substitute a generically equivalent drug that, in the pharmacist’s professional judgment, is safely interchangeable with the prescribed drug

Missouri

  • The Missouri Board of pharmacy maintains a negative generic drug formulary

Montana

  • Pharmacists may substitute a drug with the same generic name, strength, quantity, dose, and dosage form as the prescribed brand name drug product

North Carolina

  • The North Carolina Board of Pharmacy maintains a list of narrow therapeutic index drugs that are not to be substituted

North Dakota

  • Pharmacists may use professional judgment in the economic interest of the patient by selecting a drug product with the same generic name and demonstrated therapeutic equivalency as the 1 prescribed for the patient

Oregon

  • Therapeutically equivalent means drugs that are approved by the FDA for interstate distribution and the FDA has determined that the drugs will provide essentially the same efficacy and toxicity when administered to an individual in the same dosage regimen

Rhode Island

  • Pharmacists may substitute drugs containing the same active chemical ingredients of the same strength, quantity, and dosage form as the 1 prescribed for the patient

South Carolina

  • Pharmacists may substitute a drug product of the same dosage form and strength which, in his/her professional opinion, is a therapeutically equivalent drug product
  • The South Carolina Board of Pharmacy does not allow the substitution of narrow therapeutic index drugs; Premarin or Synthroid; critical drugs in the following categories: anticoagulation, anticonvulsants, anti-asthmatics, insulin, and cardiac glycosides

Vermont

  • Pharmacists shall select the lowest priced drug (brand or generic) from the formulary

Washington

  • Pharmacists shall not dispense any product that in his/her professional opinion does not meet adequate standards
Information is current as of August 2006; table adapted from reference 14

Recommendations
The American Association of Clinical Endocrinologists (AACE), The American Thyroid Association (ATA), and The Endocrine Society (TES) are in disagreement with the FDA regarding the therapeutic interchangeability of generic levothyroxine formulations for branded products.15,16 These organizations consider the methods used by the FDA for determining levothyroxine bioequivalence as inadequate and inaccurate. The AACE, ATA, and TES offer the following best practice guidelines for physicians caring for patients taking levothyroxine:

  1. Patients should be maintained on 1 brand of levothyroxine product.
  2. Serum TSH levels should be checked 6-weeks after switching a patient from 1 brand to another brand, from brand to generic, or from 1 generic product to another.
  3. Physicians should alert patients that their formulation of levothyroxine may be switched by the pharmacy.
  4. Patients should be encouraged to remain on the same formulation of levothyroxine and should not switch without consulting their physician.

The FDA continues to address concerns about the variability in levothyroxine products. In October 2007, the FDA issued letters to all manufacturers with new drug applications (NDA) and abbreviated new drug applications (ANDA) stating that levothyroxine products approved in humans will have to meet a more rigid potency specification of 95% to 105% throughout their label shelf-lives.17 The FDA will also work with the United States Pharmacopeia (USP) to revise the potency specifications. To date, no additional information has been published on this subject.

Role of the pharmacist
Pharmacists should always follow their State Board of Pharmacy laws regarding generic substitutions; however, individual pharmacists must play an active role with regards to levothyroxine substitution. Patient records should always be checked when re-filling a prescription for a levothyroxine product. If the patient received the brand name in the past, then the brand name drug should be dispensed. Pharmacists can prevent inadvertent substitution by stocking the same generic manufacturer’s product in the pharmacy. Additionally, all patients should be counseled if switching from 1 brand to another brand, from brand to generic, or from 1 generic product to another. Patients should be informed that generic formulations may look different from the brand name drug, but the active ingredient is still the same. They should be advised to monitor for hypo- and hyperthyroid adverse effects. Finally, pharmacists should instruct patients to make their physicians aware of the drug change.

References

  1. Wartofsky L. Levothyroxine: therapeutic use and regulatory issues related to bioequivalence. >Expert Opin Pharmacother. 2002;3(6):727-732.
  2. Scott GN. Levothyroxine substitution. 190811. Pharmacist’s Letter Online. Therapeutic Research Center. Stockton, CA. http://www.pharmacistsletter.com/. Accessed August 18, 2008.
  3. Anon. Generic levothyroxine. Med Letter Drugs. 2004;46(1192):77-78.
  4. Drug Topics. Top 200 generic drugs by units in 2007. http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/072008/491181/article.pdf. Accessed August 22, 2008.
  5. Drug Topics. Top 200 brand drugs by units in 2007. http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/072008/491207/article.pdf. Accessed August 22, 2008.
  6. Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med. 1993;119(6):492-502.
  7. Bolton S. Bioequivalence studies for levothyroxine. The AAPS Journal. 2005;7(1):E47-E53.
  8. Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA. 1997;277(5):1205-1213.
  9. Hennessey JV, Burman KD, Wartofsky L. The equivalency of two L-thyroxine preparations. Ann Intern Med. 1985;102(6):770-773.
  10. Stoffer SS, Szpunaz WE. Potency of brand name and generic levothyroxine products. JAMA. 1980;244(15):1704-1705.
  11. Food and Drug Administration Orange Book. Levothyroxine query. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=076752&TABLE1=OB_Rx. Accessed August 18, 2008.
  12. Food and Drug Administration Center for Drug Evaluation and Research. Approved drug products with therapeutic equivalency evaluations (preface). 28th ed. http://www.fda.gov/cder/ob/preface/ecpreface.htm. Accessed August 18, 2008.
  13. Manolakis PG. Prescription drug product substitution decision support. J Am Pharm Assoc. 2007;47(3):328-347.
  14. Anon. State regulations on generic substitution (modified July 3, 2007). 220901. Pharmacist’s Letter Online. Therapeutic Research Center. Stockton, CA. http://www.pharmacistsletter.com/. Accessed August 18, 2008.
  15. American Association of Clinical Endocrinologists. AACE/ATA/TES joint statement re: FDA approval of generic levothyroxine preparations as equivalent to branded preparations. June 24, 2004. http://www.aace.com/pub/positionstatements/levothyroxine.php. Accessed August 20, 2008.
  16. American Association of Clinical Endocrinologists. AACE, TES, and ATA joint position statement on the use and interchangeability of thyroxine products. http://www.aace.com/pub/pdf/guidelines/AACE-TES-ATA-ThyroxineProducts.pdf. Accessed August 20, 2008.
  17. Food and Drug Administration. Levothyroxine Sodium Product Information (October 3, 2007). http://www.fda.gov/cder/drug/infopage/levothyroxine/default.htm. Accessed August 22, 2008.