Download FDA Approves Generic Levothyroxine Sodium: Joint Statement by Thyroid Associations and more Study Guides, Projects, Research Pharmacy in PDF only on Docsity!
Joint Statement on the U.S. Food and Drug
Administration's Decision Regarding Bioequivalence of
Levothyroxine Sodium
American Thyroid Association, The Endocrine Society, and American Association of Clinical Endocrinologists
On June 24, 2004, the U.S. Food and Drug Administration (FDA) rejected a citizen petition filed in August 2003 regarding bioequivalence of levothyroxine sodium products and approved first-time generic levothyroixine sodium for the treatment of hypothyroidism. The American Thyroid Association (ATA), The Endocrine Society (TES), and the American Association of Clinical Endocrinologists (AACE), representing more than 4,600 clinical endocrinologists, are concerned that the FDA has moved to approve generic levothyroxine preparations as equivalent to branded preparations without seeking the input of the expert clinicians treating thyroid disease.
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. We believe that this recent FDA action may pose unnecessary risks for the 13 million Americans currently taking levothyroxine products and, therefore, want to alert physicians about this change so that they are prepared to advise their thyroid patients.
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 that could occur from excessive or inadequate treatment with levothyroxine include: recurrence of symptoms, osteoporosis, atrial fibrillation, worsening of ischemic heart disease, preterm delivery in pregnancy, and hypercholesterolemia. 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 our societies for patients switching between branded levothyroxine products is to have repeat thyroid function testing 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 be aware of a change in preparation before adverse events occur.
What should physicians caring for patients on levothyroxine therapy do to reduce the chances of adverse effects of generic levothyroxine?
- Alert your patients that their levothyroxine preparation may be switched at the pharmacy.
- Encourage your patients to ask to remain on their current levothyroxine
preparation.
- 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.
Subsequently, Adverse Drug Experience Reports-some citing serious clinical consequences, brought to light problems with preparation potency (both under and oversuper), preparation 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 beenwas 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 those physicians caring for them. A confusing array of new LlevothyroxineNew 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:
- Patients did not know that their thyroxine preparation was changed
- Physicians did not know that a different thyroxine preparation was dispensed to their patients
- Pharmacists did not know about formulation changes and, therefore, could not properly counsel patients about their thyroid medication
- 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
- 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 nameof 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 reevaluated, retested by measuring serum TSH in six (6) weeks, and the drug retitratedreiterated as needed. Since small changes in levothyroxine administration can cause significant changes in TSH serum concentrations, precise and accurate TSH control is critical 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 your dose from one brand of thyroid medication to another, from your brand of thyroid medication to a generic
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 makes 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 to the contrary 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! (move paragraph up)
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 ingredients(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-
Levo-T (Alara NDA 021342) and Levothyroxine Sodium (Mylan ANDA 76187) tablets have been determined to be therapeutically equivalent to corresponding strengths of Synthroid (Abbott NDA 021402) tablets.
Levo-T (Alara NDA 021342), Unithroid (Jerome Stevens NDA 021210) and Levothyroxine Sodium (Mylan ANDA 076187) tablets have been determined to be therapeutically equivalent to corresponding strengths of Levoxyl (King/Jones Pharma NDA 021301) tablets.
Novothyrox (Genpharm NDA 021292) 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 021116) 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 021137) 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.
Trade Name Applicant Potency TE CodeAppl NoProduct No UNITHROID STEVENS J 0.025MGAB1 21210 001 LEVOTHYROXINE SODIUM MYLAN^ 0.025MGAB1^7618 LEVOXYL JONES PHARMA 0.025MGAB1 21301 001
SYNTHROID ABBOTT 0.025MGAB2 21402 001 LEVOTHYROXINE SODIUM
MYLAN 0.025MGAB2 76187 001
LEVO-T ALARA PHARM 0.025MGAB2 21342 001
LEVOXYL JONES PHARMA 0.025MGAB3 21301 001
LEVO-T ALARA PHARM 0.025MGAB3 21342 001
UNITHROID STEVENS J 0.025MGAB3 21210 001
LEVOTHYROXINE
SODIUM
MYLAN 0.025MGAB3 76187 001
NOVOTHYROX GENPHARM 0.025MGBX 21292 001
THYRO-TABS LLOYD 0.025MGBX 21116 001
LEVOLET VINTAGE PHARMS0.025MGBX 21137 001
BASEURL = http://www.fda.gov/cder/orange/supplement/cspreface.htm URL= http://fda.gov/cder/orange/supplement/cspreface.htm Modified=DOAC29F6DC74C401B
APPENDIX VIII
THYROXINE PRODUCT STATUS: JUNE 23, 2004
Synth- roid
Lev- oxyl
Levo- throid
Uni- throid
LT4-
Sandoz
LT4-
Mylan
Novo- thyrox
Lev- olet Synthroid (Abbott)
- BX BX BX AB2 AB2 BX BX
Levoxyl (Jones)
BX - BX AB3 AB3 AB3 BX BX
Levothroid (Forest: Formerly Lloyd Thyro-tabs)
BX BX - BX BX BX BX BX
Unithroid^1 (Stevens) BX AB1 BX - BX AB1 BX BX LT4-Sandoz (^) AB2 AB3 BX BX - (^) BX BX BX LT4-Mylan AB2 AB3 BX AB1 BX - BX - Novothyrox (Gen-pharm)BX BX BX BX BX BX - BX Levolet (Vintage) BX BX BX BX BX BX BX -
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 Levoxyl 3.
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
