As of January 26, 2008, A Florida State administrative judge ordered that levothyroxine sodium be taken off of the negative formulary list which had previously protected brand name thyroid hormone prescriptions. Now pharmacists have the ability to substitute generic levothyroxine sodium at their professional discretion without the consent of the physician or patient. To ensure that a name brand prescription or refill order is honored the prescriber must now specifically write “Medically Necessary” on written prescriptions, or similarly make this statement for verbal or electronic prescriptions. This is the practice already in place in much of the United States. Without this additional instruction the prescription may be substituted with one of four available generics.

The brand names removed from the negative formulary include: Levothroid, Levoxyl, Synthroid, and Unithroid. Click here to view the complete order.

Since 2004, the FDA has sanctioned the use of generic levothyroxine preparations as equivalent to specific branded preparations. Since that time the American Thyroid Association (ATA), along with the American Association of Clinical Endocrinologists (AACE), and The Endocrine Society (TES) have endorsed a joint statement expressing concern about the flawed methodology used to determine bioequivalence, and the potential harm it could bring to patients.

See related articles on Bioequivalence of Levothyroxine

Physician survey reveals significant adverse events in patients

On Oct. 4, 2006, the Food and Drug Administration (FDA) heard data presented by James Hennessey, MD, representing the American Thyroid Association (ATA), at a joint meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Advisory Committee for Pharmaceutical Science.  Data collection was spearheaded by the ATA in an effort to quantify the harmful impact of the FDA 1994 ruling that all levothyroxine (L-T4) preparations are therapeutically equivalent. Dr. Hennessey is professor of medicine at Brown University, Providence, R.I. and a member of the ATA public health committee.

The data shows that changes in levothyroxine preparation in a small fraction of patients were associated with significant adverse events. The information was collected via survey by members of the ATA, the American Association of Clinical Endocrinologists (AACE), and The Endocrine Society.  

“In 1997, the FDA changed the process for approving levothyroxine preparations after receiving 58 adverse drug event reports over a seven-year period on the potency of levothyroxine products,” said Dr. Hennessey. “In contrast, in 2006, in a period of a few weeks, we have through our survey, received 210 reports of suspected adverse events resulting from both super- and sub-potency. The majority of these reports were associated with a switching of levothyroxine preparations.  Somehow, we’ve yet to get the FDA’s full attention to this matter.”

Of the 1,421 physicians who responded to the survey, 210 levothyroxine prescribers suspected an adverse event and completed additional information. Of these responders, 160 provided information indicating that switching of levothyroxine preparations had occurred. Eighty-eight percent reported that their patients were switched without their knowledge. Of these patients who were switched, 31% experienced a significant adverse event, such as an urgent clinic visit, emergency room visit, hospitalization, and missed work.

Specific examples provided by physicians include:

• Failure to achieve target TSH levels in a thyroid cancer patient, an important goal to prevent tumor recurrence, due to the sub-potency of a substituted thyroxine preparation;
• Reoccurrence of heart disease symptoms, which abated after switching back to the original name brand preparation;
• Previously stable hypothyroidism becoming unstable on a new preparation; and
• Development of atrial fibrillation in a thyroid cancer patient due to the super-potency of a substituted preparation.

“The three endocrine societies have been voicing their concerns to the FDA for more than two years,” says Gregory Brent, MD, the ATA’s secretary & chief operating officer and professor of medicine and physiology, David Geffen School of Medicine at UCLA. “The primary concern, reiterated during the public comment period at this meeting, is that the method used by the FDA to compare the different levothyroxine products — and which has identified them as equivalent — is not sensitive enough to detect important differences in levothyroxine preparations.”

“While the meeting was a step in the right direction, we hope that our ongoing collaboration with the ATA will effectively address our concerns about the FDA’s current approach to assessing bioequivalence,” said AACE Representative Jeffrey Garber, MD, treasurer of AACE and chief of endocrinology at Harvard Vanguard Medical Associates, Boston.  

The societies also contend that that the FDA policy generates additional cost and inconvenience because patients are encouraged to return for additional blood tests and clinical assessment to determine the need for potential dose adjustments after being switched to a different levothyroxine preparation. Moreover, the thyroid experts pointed out that the FDA is not using the TSH test to assess and adjust levothyroxine dose in patients.

“For several years now, The Endocrine Society, ATA, and AACE have maintained that the FDA is insufficiently protecting millions of Americans who take levothyroxine by continuing to follow outdated standards,” said Leonard Wartofsky, MD, MPH, president of The Endocrine Society, past-president and past-secretary of the ATA, and chairman of the department of medicine at the Washington Hospital Center in Washington, D.C.

“This problem is multifaceted and relates to the FDA’s: (1) reliance on pharmacokinetic parameters to determine bioequivalence of different preparations; (2) failure to incorporate a pharmacodynamic parameter of levothyroxine action, i.e., serum TSH, in comparing products; (3) inadequate enforcement of “do not substitute” guidance to pharmacists; and (4) failure to acknowledge that levothyroxine, as a narrow therapeutic index medication, will be associated with adverse clinical outcomes, due to existing variations in marketed branded and generic preparations when products are “switched,” said Dr. Wartofsky. “We endocrinologists are not advocating one brand over another, but rather that the FDA employs and enforces modern bioequivalence standards. Until different products can be truly proven to be bioequivalent, patients must remain on the same consistent brand of product.”

In 1997, the FDA revised the drug approval process for levothyroxine after receiving 58 adverse drug event reports over a period of seven years. As part of this change in the approval process, the FDA issued standards for thyroxine bioequivalence, deeming that levothyroxine preparations that meet these standards have the same clinical effect and safety profile as the reference product to which they are compared. This then allows pharmacists to switch to generic versions of levothyroxine for another — not necessarily with the knowledge of the patient or the physician. Of concern is that levothyroxine is a drug known to have a narrow toxic-to-therapeutic ratio, with the potential for significant clinical consequences of even minor excessive or inadequate dosing.

#  #  #

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August 3, 2005

Steven Galson, M.D.
Director, Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, HFD-240
Rockville, MD 20857

Dear Dr. Galson:
We are writing on behalf of the American Thyroid Association, The Endocrine Society, and the American Association of Clinical Endocrinologists to express our deep concern and dismay that FDA has recently instructed some—and perhaps all thyroxine manufacturers—to delete the warning that patients have retitration of their thyroxine dose when they are switched between brands.

At our recent joint workshop, FDA itself acknowledged that not all thyroxine brands have been determined to be interchangeable. FDA further pledged to cooperate in heightening public awareness of this fact. As you are aware, our societies—representing this country’s clinical experts in thyroid disease management—also still have serious concerns about the lax bioequivalence standard that has been employed to approve certain thyroxine products as therapeutically equivalent.

In light of these facts, we find FDA’s action to remove the warning regarding dose retitration after switching brands to be inconsistent and irresponsible. It appears to neglect the welfare of 13 million Americans who depend on precise dosing of their thyroxine, which is widely recognized to be a narrow therapeutic index drug.

Consequently, we ask that you defer this action until there has been an opportunity to explain the agency’s reasoning and consider our serious concerns. We will be calling you soon to set up a meeting to discuss this important issue, and to explore the other items that we discussed pursuing at our joint workshop.

Yours truly,

Paul W. Ladenson, MD President American Thyroid Association	Leonard Wartofsky, MD President-Elect The Endocrine Society	Carlos R. Hamilton, Jr., MD, FACE Immediate Past President American Assn. of Clinical Endocrinologists

cc: Lester M. Crawford, DVM, PhD, Commissioner

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June 30, 2005

Steven Galson, M.D.
Director, Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, HFD-240
Rockville, MD 20857

Dear Dr. Galson:

We are writing on behalf of our societies–the American Thyroid Association (ATA), The Endocrine Society (TES), and American Association of Clinical Endocrinologists (AACE)–to follow-up on the May 23, 2005 Thyroxine Equivalence Workshop that FDA co-sponsored with us.

First, we would like to thank you for following through on Dr. Woodcock’s commitment to hold this meeting. Despite the long delay in convening the meeting, we appreciated the opportunity to voice our serious concerns about FDA standards for determining the equivalence of thyroxine formulations and present data in support of those concerns.

Although you did not participate in the meeting after your welcome message, we assume that Dr. Orloff and his colleagues briefed you on the serious and unanimous concerns that were expressed by our three societies, representing approximately 8,000 clinical experts in thyroidology in the United States, and by organizations representing the 13 million Americans who take levothyroxine products for thyroid disorders. Those concerns are:

1. Current FDA bioequivalence standards are too lax and overlook modest, but clinically important dosage differences in this narrow therapeutic index drug.
2. Current FDA standards for thyroxine therapeutic equivalence do not employ the pharmacodynamic measure that is used by clinicians around the world every day to determine if patients are optimally treated: TSH measurement.
3. Patients, pharmacists and physicians are unaware and confused by the complex set of relationships among approved thyroxine products, which are frequently being substituted for one another with little regard for which formulations have, in fact, been defined as equivalent by even today’s lax standard.
4. A properly designed and executed clinical trial, including TSH measurement and appropriate control observations, needs to be performed to settle this issue.

We heard from FDA a willingness to talk further with us about points 3 and 4 above. Our societies are currently considering our next steps and will be in touch with you again later this summer to discuss what steps you are willing to take to improve the safety and efficacy of thyroxine products.

Respectively yours,

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Download Agenda (PDF File, 27KB)

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[Federal Register: April 20, 2005 (Volume 70, Number 75)]
[Notices]
———————————————————————–
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2005N-0137]

Levothyroxine Sodium Therapeutic Equivalence; Public Meeting
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public meeting; request for comments.
———————————————————————–

SUMMARY: The Food and Drug Administration (FDA) is announcing a public meeting on the therapeutic equivalence of levothyroxine sodium drug products. This will be a workshop involving FDA staff and representatives of three medical societies: The American Thyroid Association (ATA), the Endocrine Society, and the American Association of Clinical Endocrinologists (AACE). The purpose of the public meeting is to discuss FDA’s regulatory standards and methodological approaches for determining therapeutic equivalence between levothyroxine sodium drug products. The agency is seeking comments and input from interested constituencies, including patient advocacy and education groups, and pharmaceutical sponsors.

DATES: The public meeting will be held on May 23, 2005, from 8:30 a.m. to 5 p.m. Submit written or electronic comments by July 23, 2005.

ADDRESSES: The public meeting will be held at the National Transportation Safety Board Boardroom and Conference Center, 429 L’Enfant Plaza, SW., Washington, DC 20594, 202-314-6421. The center can be reached by Metro using the L’Enfant Plaza station on the green, yellow, blue, and orange lines. For directions, see http://ntsb.gov/events/newlocation.htm. (FDA has verified the Web site address, but FDA is not responsible for any changes to the Web site after this document publishes in the Federal Register.)

Submit written comments to the Division of Dockets Management (HFA- 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Rose Cunningham, Center for Drug Evaluation and Research (HFD-006), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20852, 301-443-5595, e-mail: cunninghamr@cder.fda.gov.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of August 14, 1997 (62 FR 43535), FDA declared that oral drug products containing levothyroxine sodium were considered new drugs and subject to regulation as such. The document called for new drug applications (NDAs) for levothyroxine sodium products from sponsors wishing to market such products in the United States after August 14, 2000. This deadline was eventually extended to August 14, 2001.

The NDAs submitted for levothyroxine sodium products included literature references supporting the safety and effectiveness of levothyroxine sodium for the proposed indications and full manufacturing information supporting the purity, potency, and stability of the products. Manufacturers were required to target 100 percent of the labeled levothyroxine sodium content at release. (Some manufacturers had historically added a “stability overage” to give their products a longer shelf-life.) In addition, bioavailability and in vitro dissolution studies were required to establish that the products were readily and consistently absorbed across the range of dosage strengths proposed to be marketed. To assist manufacturers, in December 2000, FDA published a guidance on the conduct of in vivo pharmacokinetic and bioavailability studies and in vitro dissolution tests on these products.

FDA has approved seven NDAs for levothyroxine sodium products. None were originally rated as interchangeable with any other. Since their approval, FDA has approved supplemental NDAs from some sponsors demonstrating the therapeutic equivalence (interchangeability) of their products to other approved levothyroxine sodium products. The agency has also approved one levothyroxine sodium product under an abbreviated new drug application (ANDA).

ATA, the Endocrine Society, and AACE have questioned FDA’s regulatory and scientific standards for determination of therapeutic equivalence of levothyroxine sodium products, particularly FDA’s bioequivalence methodology.

II. Scope of the Public Meeting

The public meeting is intended to review FDA’s regulatory and scientific approach to levothyroxine sodium products, including manufacturing standards, in vitro dissolution studies, and bioavailability/bioequivalence methods.

The public meeting will also review clinical, scientific, and methodological issues relevant to the possible use of serum thyrotropin concentration as a pharmacodynamic measure of levothyroxine sodium bioequivalence.

The public meeting will include representatives from FDA and from the three medical societies. A series of brief presentations will frame the issues under consideration, followed by panel discussions involving speakers and moderators, with questions and comments from the audience. Other interested constituencies (e.g., patient advocacy and education groups, pharmaceutical sponsors, general public) will have an opportunity to provide input during the question and comment periods.

III. Registration, Agenda, and Presentations

No registration is required to attend the meeting. Seating will be on a first-come, first-served basis. If you need special accommodations due to a disability, please contact (see FOR FURTHER INFORMATION CONTACT).

The agenda for public meeting will be available on FDA’s Center for Drug Evaluation and Research Web site at http://www.fda.gov/cder/meeting/levothyroxine.htm and at the meeting. After the meeting, the agenda, presentations, and transcript will be placed on file in the Division of Dockets Management under the docket number found in the heading of this document and on CDER’s Web site identified previously.

IV. Comments

Interested persons may submit to the Division of Dockets Management (see ADDRESSES) written or electronic comments on the topics discussed in this document. Submit two copies of mailed comments, except that individuals may submit one paper copy. Comments are to be identified with the docket number found in brackets in the heading of this document. Received comments are available for public examination in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

V. Transcripts

Copies of the transcript may be requested in writing from the Freedom of Information Office (HFI-35), Food and Drug Administration, 5600 Fishers Lane, rm. 12A-16, Rockville, MD 20857, approximately 20 working days after the meeting at a cost of 10 cents per page or on compact disc at a cost of $14.25 each. You may also examine the transcript at the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

Dated: April 14, 2005.
Jeffery Shuren, Assistant Commissioner for Policy.
[FR Doc. 05-7883 Filed 4-19-05; 8:45 am]

BILLING CODE 4160-01-S

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December 8, 2004

AACE, TES, and ATA
Joint Position Statement on the Use and Interchangeability of Thyroxine Products

Recently, the FDA approved the use of additional thyroxine products. A press release and notice to the American Association of Clinical Endocrinologists (AACE), The Endocrine Society (TES), and American Thyroid Association (ATA) members followed.

AACE, TES, and ATA are issuing this joint statement to address the introduction of several generic levothyroxine products to the market that the FDA has deemed to be equivalent to some currently branded preparations.

1. We are concerned about the FDA’s method for determining bioequivalence.
   The FDA had recently acknowledged concerns about its methods for determining bioequivalence. In fact, it made a commitment to address the concerns of AACE, TES, and ATA by agreeing to hold a workshop in order to do so.
2. The FDA has failed to satisfactorily address questions relating to the bioequivalence of thyroxine preparations.
   Despite a written commitment to address the concerns of AACE, TES, and ATA as organizations that represent those most knowledgeable about caring for patients with thyroid disorders and thyroid hormone metabolism, the FDA proceeded to grant generic status to additional levothyroxine preparations.
3. Physicians and patients should be educated about our concerns.
   Practicing physicians and patients should be well informed of AACE, TES, and ATA’s scientifically based concerns about the FDA’s methodology for establishing generic status. These concerns are the basis for our recommendation not to substitute thyroxine preparations for one another– FDA generic equivalence notwithstanding.
4. Physicians should become familiar with the historical background and glossary of terms related to the use of thyroxine preparations.
   This will enhance the ability of physicians to educate patients and other health care professionals about the use of thyroxine preparations.

Background¹ :

Thyroid hormone was first used in 1891 by injecting sheep thyroid extract into a patient with myxedema. Kendall discovered thyroxine in 1914 and Harrington established its structure in 1926, and went on to synthesize it. Nevertheless, desiccated thyroid, made from animal thyroid glands, remained the mainstay of therapy until the 1970’s. A high yield synthetic technique was developed in 1949. However, it was not until 1962 that levothyroxine came to market after the realization that sodium L-thyroxine form was much better absorbed than the free acid thyroxine. The FDA did not require a New Drug Application (NDA) for levothyroxine, based on the belief that it was not a new drug.

Subsequently, Adverse Drug Experience Reports, citing serious clinical consequences, brought to light problems with preparation potency (both under and over), stability, and consistency in lot-to-lot bioavailability. In some instances, reformulations with different excipients (including color agents and fillers that were generally thought to be inert) proved to be responsible for some within brand variations.

By 1997, the FDA concluded that no marketed levothyroxine preparation had been shown to have consistent potency and stability and therefore could not be recognized by the FDA as “safe and effective.” In light of this, the FDA ruled that an NDA would be required in order to market a levothyroxine product after August 14, 2000, and that pre-existing products that were “non-NDA approved” could only be distributed until August 14, 2001.

The FDA has been cognizant of the “narrow toxic to therapeutic ratio with significant clinical consequences of excessive or inadequate treatment” which may have an impact on the heart, bone, and pregnancy status. This is reflected in the shelf life potency requirements that prevent thyroxine preparations from losing more than 20% potency under standard storage conditions. It has continued to use pharmacokinetic methods to establish therapeutic equivalence that are potentially flawed for endogenously-produced substances, and, by its own recent admission, should be subjected to formal review. These methods employ Area Under the Curve [AUC] and maximum concentration [Cmax] determinations in normal subjects with normal thyroid function. These indices of bioavailabilty are used to establish bioequivalence and, in turn, conclude therapeutic equivalence. Uncorrected, these methods fail to account for the subjects’ own endogenous contribution to thyroxine levels (baseline contribution). In addition, TSH levels, the widely accepted best single laboratory tool for establishing thyroid status, are not part of the FDA’s determinations of equivalence.

“Uncorrected,” the FDA’s methodology may lead to the conclusion that preparations that differ by as much as 33% are equivalent. “Correcting” for baseline values may reduce the difference detected to less than 25% but greater than 12.5% ². Even though the FDA has asserted that its current methodology makes it unlikely that generics that differ by 9, 12, or 15% from a branded product will be approved, the sensitivity of their current methodology for detecting differences less than 25% has not been directly demonstrated. Moreover, the FDA recently approved Levothyroxine Sodium-Sandoz as a bioequivalent alternative to Synthroid, even though baseline corrected AUC data between 0 and 48 hours demonstrated that on average the Sandoz product had 12.5% greater bioavailability than Synthroid. It is widely appreciated that in many, if not most, clinical situations, a 33% or 25% difference in thyroxine dose may have a substantial clinical impact. What is perhaps less well appreciated is that differences less than 25% may not only have a significant impact on serum TSH levels, but in certain clinical settings, such as the elderly with cardiac disease or pregnancy, the impact may be clinically highly significant. In fact, this is the basis for manufacturing multiple thyroxine doses. For example, the difference between 137 mcg of thyroxine and 150 mcg is only 9%.

Not only did the FDA’s new ruling have an impact on pharmaceutical companies making levothyroxine preparations, it also had an unintentional impact on patients taking thyroxine preparations as well as physicians caring for them. A confusing array of new levothyroxine preparations came to market. To date, these have included: preparations made by companies that previously did not make thyroxine, reformulation of existing products, and replacement of one company’s product with an FDA-approved product made by another company. Most recently, the FDA has granted approval of three preparations as equivalent to longstanding branded products, despite the concerns referred to above. As a result, the following has frequently happened:

1. Patients did not know that their thyroxine preparation was changed.
2. Physicians did not know that a different thyroxine preparation was dispensed to their patients.
3. Pharmacists did not know about formulation changes and, therefore, could not properly counsel patients about their thyroid medication.
4. Physicians were deluged with patients’ concerns about the quality of their thyroxine preparations. This was particularly prevalent in 2001 when patients were led to believe that their thyroxine preparations (not yet FDA approved) may be unreliable and potentially hazardous to their health.
5. Physicians and other health care personnel have spent an extraordinary amount of time counseling patients about the use of thyroxine products, and money testing for therapeutic equivalence by employing TSH and other thyroid hormone levels, thereby adding a substantial burden to our health care system.

Conclusion:

Best Physician Practices:

Patients should be maintained on the same brand name levothyroxine product. If the brand of levothyroxine medication is changed, either from one brand to another brand, from a brand to a generic product, or from a generic product to another generic product, patients should be retested by measuring serum TSH in six (6) weeks, and the drug reiterated as needed. Since small changes in levothyroxine administration can cause significant changes in TSH serum concentrations, precise and accurate TSH control is necessary to avoid potential adverse iatrogenic effects.

Best Patient Practices:

Use the same brand of thyroid medication throughout your treatment. Thyroid disease often requires lifelong therapy and is best managed with consistent and precise treatment with the same brand of thyroid hormone. Your doctor may change your dose of thyroid hormone, but the brand of your thyroid hormone medication should always stay the same.

When you go to the pharmacy, do not change the brand of your thyroid medication without checking with your doctor. You should not change from one brand of thyroid medication to another, from your brand of thyroid medication to a generic product, or from one generic product to another without first checking with your doctor. Repeat blood tests and visits to your doctor may be required, and your dose may need to be readjusted if your thyroid medication is changed, or if you switch to a generic product.

Thyroid disease often requires lifelong therapy and is best managed with consistent and precise treatment. Do not change the brand of your thyroid medication without checking with your doctor. If the pharmacist suggests changing brands or recommends a generic product, you should also check with your doctor. Your insurance company or state aid program may not pay for the cost of a brand name drug or charge a higher co-payment if you want a specific brand name drug. Repeat blood tests and visits to your doctor may be required, and your dose may need to be readjusted if your thyroid medication is changed to a different brand, a generic product, or a different generic product.

References

¹ Hennessey JV. Levothyroxine a New Drug? Since When? How Could That Be? Thyroid. 2003; 13,279-282.

² Blakesley V, Awni W, Locke C, Ludden T, Granneman GR, Braverman LE. Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable? Thyroid. 2004;14:191-200.

APPENDIX I

Glossary:

Generic Drugs: A generic drug is a copy that is the same as a brand-name drug in dosage, safety, strength, how it is taken, performance, and intended use (Source: FDA (cite the URL of the FDA web site). Note: a generic drug, bearing the chemical name of the drug, can only serve as a substitute for the brand(s) to which it was designated to be equivalent. In the case of thyroxine preparations, it requires an AB rating (see below). Until recently (as of 2002), Mylan Pharmaceuticals made the only approved generic levothyroxine, which could only be used as a substitute for Unithroid, a brand of levothyroxine made by Stevens. Recently, the FDA approved a previously NDA approved levothyroxine preparation made by ALARA (Levo-T) and to be distributed by Sandoz that can be substituted for Synthroid made by Abbott Pharmaceuticals as well as Levoxyl made by Jones Pharmaceuticals. It also ruled that the levothyroxine preparation made by Mylan Pharmaceuticals could be substituted for Synthroid and Levoxyl and that Unithroid could be substituted for Levoxyl.

Therapeutic Equivalents (TE): Drugs that are pharmaceutical equivalents (identical amounts of the same active drug ingredient, same dosage, same route of administration) and bioequivalent (see below). Drugs can be considered therapeutic equivalents even if they have different release mechanisms. Therapeutic equivalents can be substituted for one another with the expectation that there will be similar clinical effects and that follow-up testing would not be required.

Bioavailability and Bioequivalence: Bioavailability refers to the rate and extent to which the active ingredient or therapeutic ingredient is absorbed from a drug product and becomes available “at the site of drug action.” Two drugs are considered bioequivalent if they have an “equivalent rate and extent of absorption from these formulations,” or, in other words, appear to have comparable bioavailability. The FDA’s language (see web site) indicates that the formulations do not have to undergo comparison “at the site of drug action,” which would be reflected in a pharmacodynamic parameter, such as serum TSH measurements in the case of levothyroxine. Bioequivalence, in turn, establishes therapeutic equivalence and, therefore, interchangeability. Hence, a generic drug that is demonstrated to be bioequivalent by pharmacokinetic methods along the lines outlined above to the pioneer (innovator) drug, may be marketed as a generic version of that product.

AB: This is one of a number of “Therapeutic Equivalent Evaluation Codes” used by the FDA to denote therapeutic equivalence to other pharmaceutically equivalent drug products, when “actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.”

Generic levothyroxine preparations have AB codes. Branded levothyroxine preparations that have generic equivalents have AB codes.

The terminology “AB to” or “AB rated to” thereby indicates that two products are considered interchangeable by FDA standards and will be substituted unless the physician designates that they are not (e.g., “NO SUBSTITUTION”) to be exchanged.

Note: Drug I may be AB to Drug II and Drug II AB to Drug III. However, this does not mean that Drug I and III are AB to each other. This is because Drug II and Drug III may not have been compared with one another, rather than proven not to be equivalent. This point is illustrated by the following example: Drug I on average is more bioavailable than II but close enough for FDA approval to be considered equivalent. Drug III is less bioavailable than II but close enough to be considered equivalent. However, when Drugs I and III are compared directly to one another, they do not correspond sufficiently to be considered equivalent by the FDA.

AB-#: When more than one drug is listed under the same FDA “reference” (i.e. levothyroxine), and the drugs are not bioequivalent, the FDA employs three character designations: AB1, AB2, AB3, AB4… (See Appendix III from FDA Orange Book description of this designation and Appendix IV for Levothyroxine Sodium update) in order to classify products with identical active ingredients, dosage form, and route of administration. Since Levoxyl, for example, was not AB to Synthroid, we correctly anticipated that the FDA’s recent approval of additional generic products would lead to the implementation of three character designations for levothyroxine products.

We believe that multiple character designations make matters even more complex for pharmacists, physicians, and patients. As a result, not only will it continue to be virtually impossible to remain on the same generic product (which is one of our fundamental concerns about generic products), but it will also become increasingly difficult for patients to remain on the same branded product.

BX: This is one of a number of Therapeutic Equivalent Evaluation Codes used by the FDA to denote that a pharmaceutically equivalent drug product is not therapeutically equivalent, because actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence. The BX code is the designation used by the FDA when the data reviewed by the FDA are “insufficient to determine therapeutic equivalence.” Currently, branded levothyroxine preparations that do not have generic equivalents, and, therefore, cannot be interchanged with a pharmaceutically equivalent drug product, common pharmacy practices notwithstanding, have a BX code.

APPENDIX II

Current List and Status of Thyroxine Preparations:

Before June 23, 2004, only Unithroid (Stevens) and Levothyroxine (Mylan) were AB rated. Synthroid (Abbott), Levo-T (Alara), Novothyrox (Genpharm), Levoxyl (Jones [related to Monarch and King]), Thyro-Tabs (which has become the new Levothroid preparation made by Lloyd but owned by Forest), and Levolet (Vintage) were all BX rated.

Since June 23, 2004, the FDA deemed Levo-T (ALARA), to be distributed as levothyroxine (Sandoz), to be equivalent to Synthroid and Levoxyl. The makers of Levoxyl are currently contesting this. In addition, levothyroxine (Mylan) was deemed equivalent to Synthroid and Levoxyl, while Unithroid was designated bioequivalent to Levoxyl. The FDA Orange Book should reflect this by changing Levo-T, Synthroid, and Levoxyl from BX to AB and adding the levothyroxine preparation (Sandoz) to its AB listings. Levothyroxine (Mylan) previously was AB to Unithroid, as noted above.

Of especial interest is the fact that the bioequivalence of the designated generic preparations levothyroxine (Mylan) and levothyroxine (Sandoz) have not been compared to one another, and would therefore be considered BX to one another even though each one is designated AB3 to Levoxyl and AB2 to Synthroid.

APPENDIX III

(From the FDA Web site www.fda.gov/cder/ob/docs)

AB, AB1, AB2, AB3… Products meeting necessary bioequivalence requirements

Multisource drug products listed under the same heading (i.e., identical active ingredient(s), dosage form, and route(s) of administration) and having the same strength (see Therapeutic Equivalence-Related Terms, Pharmaceutical Equivalents) generally will be coded AB if a study is submitted demonstrating bioequivalence.

In certain instances, a number is added to the end of the AB code to make a three-character code (i.e., AB1, AB2, AB3, etc.). Three-character codes are assigned only in situations when more than one reference listed drug of the same strength has been designated under the same heading. Two or more reference listed drugs are generally selected only when there are at least two potential reference drug products which are not bioequivalent to each other. If a study is submitted that demonstrates bioequivalence to a specific listed drug product, the generic product will be given the same three-character code as the reference listed drug it was compared against. For example, Adalat® CC (Miles) and Procardia XL® (Pfizer), extended-release tablets, are listed under the active ingredient nifedipine. These drug products, listed under the same heading, are not bioequivalent to each other. Generic drug products deemed by FDA to be bioequivalent to Adalat® CC and Procardia XL® have been approved. Adalat® CC and Procardia XL® have been assigned ratings of AB1 and AB2, respectively. The generic drug products bioequivalent to Adalat® CC would be assigned a rating of AB1 and those bioequivalent to Procardia XL® would be assigned a rating of AB2. (The assignment of an AB1 or AB2 rating to a specific product does not imply product preference.) Even though drug products of distributors and/or repackagers are not included in the List, they are considered therapeutically equivalent to the application holder’s drug product, if the application holder’s drug product is rated either with an AB or three-character code or is single source in the List. Drugs coded as AB under a heading are considered therapeutically equivalent only to other drugs coded as AB under that heading. Drugs coded with a three-character code under a heading are considered therapeutically equivalent only to other drugs coded with the same three-character code under that heading.

APPENDIX IV

APPROVED DRUG PRODUCTS with THERAPEUTIC EQUIVALENCE EVALUATIONS
24th EDITION
Cumulative Supplement 6

Prepared By
Office of Pharmaceutical Science
Office of Generic Drugs
Center for Drug Evaluation and Research, FDA
June 2004

1.4 LEVOTHYROXINE SODIUM

Because there are multiple reference listed drugs of levothyroxine sodium tablets and some reference listed drugs’ sponsors have conducted studies to establish their drugs’ therapeutic equivalence to other reference listed drugs, FDA has determined that its usual practice of assigning two or three character TE codes may be potentially confusing and inadequate for these drug products. Accordingly, FDA provides the following explanation and chart of therapeutic equivalence evaluations for levothyroxine sodium drug products.

Levothyroxine Sodium (Mylan ANDA 76187) tablets have been determined to be therapeutically equivalent to corresponding strengths of Unithroid (Jerome Stevens NDA 21210) tablets.

Levo-T (Alara NDA 21342) and Levothyroxine Sodium (Mylan ANDA 76187) tablets have been determined to be therapeutically equivalent to corresponding strengths of Synthroid (Abbott NDA 21402) tablets.

Levo-T (Alara NDA 21342), Unithroid (Jerome Stevens NDA 21210) and Levothyroxine Sodium (Mylan ANDA 76187) tablets have been determined to be therapeutically equivalent to corresponding strengths of Levoxyl (King/Jones Pharma NDA 21301) tablets.

Novothyrox (Genpharm NDA 21292) requires further investigation and review to establish therapeutic equivalence to corresponding strengths of any other levothyroxine sodium drug products and is rated BX.

Thyro-Tabs (Lloyd NDA 21116) requires further investigation and review to establish therapeutic equivalence to corresponding strengths of any other levothyroxine sodium drug products and is rated BX.

Levolet (Vintage NDA 21137) requires further investigation and review to establish therapeutic equivalence to corresponding strengths of any other levothyroxine sodium drug products and is rated BX.

The chart outlines TE codes for all 0.025mg products with other products being similar. Therapeutic equivalence has been established between products that have the same AB+ number TE code. More than one TE code may apply to some products. One common TE code indicates therapeutic equivalence between products.

BASE URL = http://www.fda.gov/cder/orange/supplement/cspreface.htm
URL = http://www.accessdata.fda.gov/scripts/cder/ob/eclink.cfm
Modified = DOAC29F6DC74C401B0

APPENDIX V

THYROXINE PRODUCT STATUS: JUNE 23, 2004

AB1: Product rating using Unithroid as “reference drug,”2 considered interchangeable with Unithroid. Generic product LT4-Mylan listed may be exchanged with Unithroid.

AB2: Product rating using Synthroid as “reference drug,” considered interchangeable with Synthroid. Generic products LT4-Mylan and LT4-Sandoz may be exchanged with Synthroid3.

AB3: Product rating using Levoxyl as “reference drug,” considered interchangeable with Levoxyl. Generic products LT4-Mylan and LT4-Sandoz may be exchanged with Levoxyl3.

Drugs within a TE rating will likely be interchanged within the same three character products unless prescriber specifies “No Substitution,” “Brand Name Necessary,” “Dispense as Written,” etc.

BX: Not Interchangeable

NOTE¹: Lannett is distributing Unithroid (made by Stevens) as a generic product “LT4-Lannett,” which the FDA has designated as TE to Levoxyl. This has been omitted from the table, because FDA postings did not cite its three-character designation(s) by the time this document was completed.

NOTE² When applicable, row titles list “reference drugs” with table columns designating the drug that is being compared to the “reference drug.” Examples:

Row 2: Unithroid is “AB3 to Levoxyl”
Row 4: Levoxyl is “AB1 to Unithroid

For completeness we created rows for the “Generic products” (LT4-Sandoz, LT4-Mylan). These are not “reference drugs.” Therefore, the respective three character designations listed in their rows are “referenced” to the products appearing in the columns. Examples:

Row 5: LT4-Sandoz is “AB2 to Synthroid”
Row 6: LT4-Mylan is “AB3 to Levoxyl”

NOTE³: LT4-Sandoz and LT4-Mylan are both AB2 to Synthroid and AB3 to Levoxyl. However, LT4-Mylan and LT4-Sandoz are not interchangeable (BX) because they have not been evaluated in regard to one another. See Appendix I for explanation.

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Generic bioequivalence data confirms medical societies’ concern about recently approved generic levothyroxine preparations

August 11, 2004

(FALLS CHURCH, VA)—Two organizations representing more than 5,400 clinical endocrinologists today warned patients taking thyroid medication, prescribing physicians, and pharmacists dispensing these drugs that clinically important differences do, in fact, exist between one recently approved generic levothyroxine preparation and the most widely prescribed brand of levothyroxine. The members of these organizations, the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE), specialize in treatment of hormonal disorders.

Levothyroxine is taken by more than 13 million Americans to treat an underactive thyroid, thyroid gland enlargement, nodules, or cancer. In June, the Food and Drug Administration (FDA) ruled that several generic levothyroxine preparations had the same clinical effect and safety profile as certain branded products. As a result, pharmacists may substitute a patient’s current levothyroxine preparation for another, sometimes without their physician’s approval.

According to bioequivalence data used to acquire FDA approval, one recently approved generic levothyroxine preparation (Sandoz Levothyroxine Sodium) is significantly more potent than the most widely used brand of levothyroxine (Synthroid®). Information from bioequivalence studies submitted to the FDA show that the new generic may be as much as one-eighth more potent (+12.5%) than the widely prescribed branded product.

Furthermore, levothyroxine is a drug known to have a narrow toxic-to-therapeutic ratio with significant clinical consequences of even minor excessive or inadequate dosing. Potential adverse events include symptoms, osteoporosis, atrial fibrillation, worsening of heart disease, preterm delivery in pregnancy, impaired fetal brain development, and high cholesterol.

“Unfortunately, this information confirms our concern that current FDA standards defining the equivalence of levothyroxine products are too lax,” said Carlos Hamilton, MD, AACE President. “Switching between two products could compromise the effectiveness of treatment and even result in serious side effects.”

The ATA and AACE have repeatedly expressed their concerns about the FDA’s recent decision to approve generic substitutes for levothyroxine products and its implications for the millions of Americans who depend on this drug. The societies have also made public their disappointment that the FDA made their decision before considering the input offered by clinical endocrinologists, the recognized experts who care for thyroid patients.

Both the FDA and the societies recommend that patients switching between levothyroxine products have repeat thyroid blood testing to be certain that the treatment dose remains effective and safe. “Under a policy of allowing generic levothyroxine substitution,” said Gregory Brent, MD, ATA Secretary, “more frequent thyroid function testing will be necessary. Regrettably, some patients and doctors will not even be aware of a change in preparation before adverse events occur.”

The ATA and AACE advise physicians caring for patients on levothyroxine therapy to —

1. Alert patients that their levothyroxine preparation may be switched at the pharmacy,
2. Encourage patients to remain on their current levothyroxine preparation when possible,
3. Ensure that patients understand if they receive a new levothyroxine preparation that they will need to repeat a thyroid-stimulating hormone (TSH) blood test four to six weeks later to determine if they need further dose adjustment.

The societies also strongly urge pharmacists, pharmacies, and health plans to respect the wishes of patients and physicians who choose to continue the same levothyroxine preparation. They caution those who dispense and pay for levothyroxine products that there can be serious health consequences if patients and their doctors are not fully informed about the potential risks of substitution and the requirement for retesting if they choose to switch to another levothyroxine preparation.

The ATA’s previous statements related to this matter can be found on the ATA’s web site 

Founded in 1923, the ATA is a professional society of 900 U.S. and international physicians and scientists who specialize in the research and treatment of thyroid diseases. The Association is dedicated to promoting scientific and public understanding of the biology of the thyroid gland and its disorders, so as to improve methods for their prevention, diagnosis, and management. The ATA fosters excellence in research, patient care, and education of patients, the public, and the medical and scientific communities while guiding public policy about the prevention and management of thyroid diseases.

AACE is a professional medical organization with over 4,900 members in the United States and 70 other countries. Founded in 1991, AACE is dedicated to the optimal care of patients with endocrine problems. AACE initiatives inform the public about endocrine disorders. AACE also conducts continuing education programs for clinical endocrinologists, physicians whose advanced, specialized training enables them to be experts in the care of endocrine disease, such as diabetes, thyroid disorders, growth hormone deficiency, osteoporosis, cholesterol disorders, hypertension and obesity.

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FDA approval of generic levothyroxine preparations as equivalent to branded products is major concern of thyroid experts

June 28, 2004

(FALLS CHURCH, VA)—Three organizations whose members specialize in the treatment of endocrine disorders recently voiced concern and dismay at the Food and Drug Administration’s (FDA) decision to approve generic substitutes for levothyroxine products, which are used to treat hypothyroidism, or an underactive thyroid, without input from clinical endocrinologists, the recognized experts who care for thyroid patients.

These generic drugs are now judged to have the same clinical effect and safety profile as the branded product, allowing a pharmacist to substitute one drug for the other without physician approval. In a June 24, 2004, statement, the American Thyroid Association (ATA), The Endocrine Society (TES), and the American Association of Clinical Endocrinologists (AACE) outlined their concerns for the health of the millions of Americans using levothyroxine products while alerting physicians about this change to prepare them to advise their thyroid patients.

The organizations explain that the FDA had previously indicated that it would seek input from clinical endocrinologists and would carefully consider standards of thyroxine bioequivalence and testing before making such a decision.

“Our organizations established a dialogue with the FDA over the past year about this matter and other issues of assessing levothyroxine therapy,” says Gregory Brent, MD, ATA Secretary, “only to have the FDA make this decision without our input. The goal of the more than 4,600 clinical endocrinologist members of our groups continues to be the development of a responsible and scientifically informed approach to levothyroxine therapeutic substitution for the 13 million Americans who take these products,” adds Dr. Brent. “The FDA’s recent actions will result in patients being switched among a number of levothyroxine preparations, often without their or their doctors’ knowledge, with the possibility of an increase in adverse events.”

Levothyroxine is a drug recognized to have a narrow toxic to therapeutic ratio with significant clinical consequences of excessive or inadequate treatment, says the statement. Some of the potential adverse events include the recurrence of symptoms, osteoporosis, atrial fibrillation, worsening of ischemic heart disease, preterm delivery in pregnancy, and high cholesterol.

The statement goes on to warn that those especially susceptible to incorrect titration of levothyroxine products include the elderly, pregnant women and their developing fetuses, and those with thyroid cancer.

The current recommendation by the FDA and these organizations is that patients switching between branded levothyroxine products have repeat thyroid function testing, which will allow for dose retitration if the therapeutic target is not being achieved with the new preparation. “Under a policy of allowing generic levothyroxine substitution,” the statement concludes, “more frequent thyroid function testing will be necessary.” Furthermore, the statement cautions, the patient and doctor may not be aware of a change in preparation before adverse events occur.

As a result of the FDA decision, the ATA, TES, and AACE advise physicians caring for patients on levothyroxine therapy to —
1. Alert their patients that their levothyroxine preparation may be switched at the pharmacy,
2. Encourage their patients to ask to remain on their current levothyroxine preparation, and
3. Make sure their patients understand that if they receive a new levothyroxine preparation that they will need to be retested with a serum TSH to determine if they need dose retitration.

The statement can be found on the ATA’s web site

Founded in 1923, the ATA is a professional society of 900 U.S. and international physicians and scientists who specialize in the research and treatment of thyroid diseases. The Association is dedicated to promoting scientific and public understanding of the biology of the thyroid gland and its disorders, so as to improve methods for their revention, diagnosis, and management. The ATA fosters excellence in research, patient care, and education of patients, the public, and the medical and scientific communities while guiding public policy about the prevention and management of thyroid diseases.

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June 24, 2004

The American Thyroid Association (ATA), The Endocrine Society (TES), and the American Association of Clinical Endocrinologists (AACE), representing 4,600 clinical endocrinologists, are deeply disappointed that the FDA has moved to approve generic levothyroxine preparations as equivalent to branded preparations. Levothyroxine is a drug recognized to have a narrow toxic to therapeutic ratio with significant clinical consequences of excessive or inadequate treatment. Some of the potential adverse events include; recurrence of symptoms, osteoporosis, atrial fibrillation, worsening of ischemic heart disease, preterm delivery in pregnancy, and hypercholesterolemia. There are 12 tablet strengths of levothyroxine available that vary by as little as 9% in drug content, reflecting the close titration that is required for optimal patient management. Thirteen million Americans are on levothyroxine products and those especially susceptible to incorrect titration include the elderly, pregnant women and their developing fetuses, and those with thyroid cancer.

The current recommendation by the FDA and our societies is that patients switching between branded levothyroxine products have repeat thyroid function testing. This is to allow for dose retitration if the therapeutic target is not being achieved with the new preparation. Under a policy of allowing generic levothyroxine substitution, more frequent thyroid function testing will be necessary. Furthermore, the patient and doctor may not even be aware of a change in preparation before adverse events occur.

Serious questions have repeatedly been raised about the methodology used by the FDA to determine bioequivalence. The ATA, TES, and AACE have worked with the FDA for over one year to promote a workshop to carefully consider standards of thyroxine bioequivalence and testing. We were assured in a September 15, 2003 meeting with Dr. Janet Woodcock, and by her successor Dr. Steven Galson in a November 5, 2003 letter, that the FDA was “..committed to plan and hold a workshop…to address all of the relevant issues raised at our meeting: [levothyroxine] bioequivalence testing, baseline correction, optimal test subjects, and acceptable confidence limits; and TSH as a pharmacodynamic measure”. Furthermore, the FDA stated, “We acknowledge the concerns raised at the meeting and in your letter regarding the thyroxine dose precision and limitations in current bioequivalence standard”. Despite these assurances and submission of a draft workshop agenda by us on December 30, 2003, the FDA has made this decision without input from clinical endocrinologists, the recognized experts in this area and those who care for thyroid patients.

What should physicians caring for patients on levothyroxine therapy do as a result of this decision?

1. Alert your patients that their levothyroxine preparation may be switched at the pharmacy.
2. Encourage your patients to ask to remain on their current levothyroxine preparation.
3. Make sure your patients understand that if they receive a new levothyroxine preparation, they will need to be retested with a serum TSH to determine if they need dose retitration.

See related articles on Bioequivalence of Levothyroxine