[Federal Register Volume 62, Number 157 (Thursday, August 14, 1997)]
[Notices]
[Pages 43535-43538]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-21575]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 97N-0314]


Prescription Drug Products; Levothyroxine Sodium

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that 
orally administered drug products containing levothyroxine sodium are 
new drugs. There is new information showing significant stability and 
potency problems with orally administered levothyroxine sodium 
products. Also, these products fail to maintain potency through the 
expiration date, and tablets of the same dosage strength from the same 
manufacturer vary from lot to lot in the amount of active ingredient 
present. This lack of stability and consistent potency has the 
potential to cause serious health consequences to the public. 
Manufacturers who wish to continue to market orally administered 
levothyroxine sodium products must submit new drug applications 
(NDA's); manufacturers who contend that a particular drug product is 
not subject to the new drug requirements of the Federal Food, Drug, and 
Cosmetic Act (the act) should submit a citizen petition. FDA has 
determined that orally administered levothyroxine sodium products are 
medically necessary, and accordingly the agency is allowing current 
manufacturers 3 years to obtain approved NDA's.

EFFECTIVE DATE: August 14, 1997.

DATES: A citizen petition claiming that a particular drug product is 
not subject to the new drug requirements of the act should be submitted 
no later than October 14, 1997.

    After August 14, 2000, any orally administered drug product 
containing levothyroxine sodium, marketed on or before the date of this 
notice, that is introduced or delivered for introduction into 
interstate commerce without an approved application, unless found by 
FDA to be not subject to the new drug requirements of the act under a 
citizen petition submitted for that product, will be subject to 
regulatory action.

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. 97N-0314 and directed to the appropriate 
office named below:

    Applications under section 505 of the act (21 U.S.C. 355): 
Documents and Records Section (HFA-224), 5600 Fishers Lane, Rockville, 
MD 20857.
    Citizen petitions (see Sec. 10.30 (21 CFR 10.30)) contending that a 
particular drug product is not subject to the new drug requirements of 
the act: Dockets Management Branch (HFA-305), Food and Drug 
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.

    Requests for an opinion on the applicability of this notice to a 
specific product: Division of Prescription Drug Compliance and 
Surveillance (HFD-330), Center for Drug Evaluation and Research, Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT: Christine F. Rogers, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    Levothyroxine sodium is the sodium salt of the levo isomer of the 
thyroid hormone thyroxine (T4). Thyroid hormones affect 
protein, lipid, and carbohydrate metabolism; growth; and development. 
They stimulate the oxygen consumption of most cells of the body, 
resulting in increased energy expenditure and heat production, and 
possess a cardiostimulatory effect that may be the result of a direct 
action on the heart.
    Levothyroxine sodium was first introduced into the market before 
1962 without an approved NDA, apparently in the belief that it was not 
a new drug. Orally administered levothyroxine sodium is used as 
replacement therapy in conditions characterized by diminished or absent 
thyroid function such as cretinism, myxedema, nontoxic goiter, or 
hypothyroidism. The diminished or absent thyroid function may result 
from functional deficiency, primary atrophy, partial or complete 
absence of the thyroid gland, or the effects of surgery, radiation, or 
antithyroid agents. Levothyroxine sodium may also be used for 
replacement or supplemental therapy in patients with secondary 
(pituitary) or tertiary (hypothalamic) hypothyroidism.
    Hypothyroidism is a common condition. In the United States, 1 in 
every 4,000 to 5,000 babies is born hypothyroid. Hypothyroidism has a 
prevalence of 0.5 percent to 1.3 percent in adults. In people over 60, 
the prevalence of primary hypothyroidism

[[Page 43536]]

increases to 2.7 percent in men and 7.1 percent in women. Because 
congenital hypothyroidism may result in irreversible mental 
retardation, which can be avoided with early diagnosis and treatment, 
newborn screening for this disorder is mandatory in North America, 
Europe, and Japan.
    In addition to the treatment of hypothyroidism, levothyroxine 
sodium may be used to suppress the secretion of thyrotropin in the 
management of simple nonendemic goiter, chronic lymphocytic 
thyroiditis, and thyroid cancer. Levothyroxine sodium is also used with 
antithyroid agents in the treatment of thyrotoxicosis to prevent 
goitrogenesis and hypothyroidism.

II. Levothyroxine Sodium Products Must Be Consistent in Potency and 
Bioavailability

    Thyroid replacement therapy usually is a chronic, lifetime 
endeavor. The dosage must be established for each patient individually. 
Generally, the initial dose is small. The amount is increased gradually 
until clinical evaluation and laboratory tests indicate that an optimal 
response has been achieved. The dose required to maintain this response 
is then continued. The age and general physical condition of the 
patient and the severity and duration of hypothyroid symptoms determine 
the initial dosage and the rate at which the dosage may be increased to 
the eventual maintenance level. It is particularly important to 
increase the dose very gradually in patients with myxedema or 
cardiovascular disease to prevent precipitation of angina, myocardial 
infarction, or stroke.
    If a drug product of lesser potency or bioavailability is 
substituted in the regimen of a patient who has been controlled on one 
product, a suboptimal response and hypothyroidism could result. 
Conversely, substitution of a drug product of greater potency or 
bioavailability could result in toxic manifestations of hyperthyroidism 
such as cardiac pain, palpitations, or cardiac arrhythmias. In patients 
with coronary heart disease, even a small increase in the dose of 
levothyroxine sodium may be hazardous.
    Hyperthyroidism is a known risk factor for osteoporosis. Several 
studies suggest that subclinical hyperthyroidism in premenopausal women 
receiving levothyroxine sodium for replacement or suppressive therapy 
is associated with bone loss. To minimize the risk of osteoporosis, it 
is advisable that the dose be titrated to the lowest effective dose 
(Refs. 1 and 2).
    Because of the risks associated with overtreatment or 
undertreatment with levothyroxine sodium, it is critical that patients 
have available to them products that are consistent in potency and 
bioavailability. Recent information concerning stability problems 
(discussed in section V of this document) shows that this goal is not 
currently being met.

III. Adverse Drug Experiences

    Between 1987 and 1994, FDA received 58 adverse drug experience 
reports associated with the potency of orally administered 
levothyroxine sodium products. Forty-seven of the reports suggested 
that the products were subpotent, while nine suggested superpotency. 
Two of the reports concerned inconsistency in thyroid hormone blood 
levels. Four hospitalizations were included in the reports; two were 
attributed to product subpotency and two were attributed to product 
superpotency. More than half of the 58 reports were supported by 
thyroid function blood tests. Specific hypothyroid symptoms included: 
Severe depression, fatigue, weight gain, constipation, cold 
intolerance, edema, and difficulty concentrating. Specific hyperthyroid 
symptoms included: Atrial fibrillation, heart palpitations, and 
difficulty sleeping.
    Some of the problems reported were the result of switching brands. 
However, other adverse events occurred when patients received a refill 
of a product on which they had previously been stable, indicating a 
lack of consistency in stability, potency, and bioavailability between 
different lots of tablets from the same manufacturer.
    Because levothyroxine sodium products are prescription drugs 
marketed without approved NDA's, manufacturers are expressly required, 
under 21 CFR 310.305, to report adverse drug experiences that are 
unexpected and serious; they are not required, as are products with 
approved applications (see 21 CFR 314.80) periodically to report all 
adverse drug experiences, including expected or less serious events. 
Some adverse drug experiences related to inconsistencies in potency of 
orally administered levothyroxine sodium products may not be regarded 
as serious or unexpected and, as a result, may go unreported. Reports 
received by FDA, therefore, may not reflect the total number of adverse 
events associated with inconsistencies in product potency.

IV. Formulation Change

    Because orally administered levothyroxine sodium products are 
marketed without approved applications, manufacturers have not sought 
FDA approval each time they reformulate their products. In 1982, for 
example, one manufacturer reformulated its levothyroxine sodium product 
by removing two inactive ingredients and changing the physical form of 
coloring agents (Ref. 6). The reformulated product increased 
significantly in potency. One study found that the reformulated product 
contained 100 percent of stated content compared to 78 percent before 
the reformulation (Ref. 7). Another study estimated that the 
levothyroxine content of the old formulation was approximately 70 
percent of the stated value (Ref. 8).
    This increase in product potency resulted in serious clinical 
problems. On January 17, 1984, a physician reported to FDA: ``I have 
noticed a recent significant problem with the use of [this 
levothyroxine sodium product]. People who have been on it for years are 
suddenly becoming toxic on the same dose. Also, people starting on the 
medication become toxic on 0.1 mg [milligram] which is unheard of.'' On 
May 25, 1984, another physician reported that 15 to 20 percent of his 
patients using the product had become hyperthyroid although they had 
been completely controlled up until that time. Another doctor reported 
in May 1984 that three patients, previously well-controlled on the 
product, had developed thyroid toxicity. One of these patients 
experienced atrial fibrillation.
    There is evidence that manufacturers continue to make formulation 
changes to orally administered levothyroxine sodium products. As 
discussed in section V of this document, one manufacturer is 
reformulating in order to make its product stable at room temperature. 
In a 1990 study (Ref. 5), one manufacturer's levothyroxine sodium 
tablets selected from different batches showed variations in 
chromatographs suggesting that different excipients had been used.

V. Stability Problems

    FDA, in conjunction with the United States Pharmacopeial 
Convention, took the initiative in organizing a workshop in 1982 to set 
the standard for the use of a stability-indicating high-performance 
liquid chromatographic (HPLC) assay for the quality control of thyroid 
hormone drug products (Ref. 3). The former assay method was based on 
iodine content and was not stability- indicating. Using the HPLC 
method, there have been numerous reports indicating problems with the 
stability of orally administered levothyroxine sodium products in the 
past several years. Almost every manufacturer of

[[Page 43537]]

orally administered levothyroxine sodium products, including the market 
leader, has reported recalls that were the result of potency or 
stability problems.
    Since 1991, there have been no less than 10 firm-initiated recalls 
of levothyroxine sodium tablets involving 150 lots and more than 100 
million tablets. In all but one case, the recalls were initiated 
because tablets were found to be subpotent or potency could not be 
assured through the expiration date. The remaining recall was initiated 
for a product that was found to be superpotent. During this period, FDA 
also issued two warning letters to manufacturers citing stability 
problems with orally administered levothyroxine sodium products.
    At one firm, potency problems with levothyroxine sodium tablets 
resulted in destruction of products and repeated recalls. From 1990 to 
1992, the firm destroyed 46 lots of levothyroxine sodium tablets that 
failed to meet potency or content uniformity specifications during 
finished product testing. In August 1989, this firm recalled 21 lots 
due to subpotency. In 1991, the firm recalled 26 lots in February and 
15 lots in June because of subpotency.
    An FDA inspection report concerning another manufacturer of 
levothyroxine sodium showed that 14 percent of all lots manufactured 
from 1991 through 1993 were rejected and destroyed for failure to meet 
the assay specifications of 103 to 110 percent established by the firm.
    In March 1993, FDA sent a warning letter to a firm stating that its 
levothyroxine tablets were adulterated because the expiration date was 
not supported by adequate stability studies. Five lots of the firm's 
levothyroxine sodium tablets, labeled for storage within controlled 
room temperature range, had recently failed stability testing when 
stored at the higher end of the range. The warning letter also objected 
to the labeled storage conditions specifying a nonstandard storage 
range of 15 to 22  deg.C. FDA objected to this labeling because it did 
not conform to any storage conditions defined in United States 
Pharmacopeia (USP) XXII. In response, the firm changed the labeling 
instruction to store the product at 8 to 15  deg.C. The firm informed 
FDA that it would reformulate its levothyroxine sodium tablets to be 
stable at room temperature.
    The five failing lots named in FDA's warning letter were recalled 
in April 1994. Previously, in December 1993, a lot of levothyroxine 
sodium tablets was recalled by the same firm because potency was not 
assured through the expiration date. In November 1994, the renamed 
successor firm recalled one lot of levothyroxine sodium tablets due to 
superpotency.
    Another firm recalled six lots of levothyroxine sodium tablets in 
1993 because they fell below potency, or would have fallen below 
potency, before the expiration date. The USP specifies a potency range 
for levothyroxine sodium from 90 percent to 110 percent. Analysis of 
the recalled tablets showed potencies ranging from 74.7 percent to 90.4 
percent. Six months later, this firm recalled another lot of 
levothyroxine sodium tablets when it fell below labeled potency during 
routine stability testing. Content analysis found the potency of the 
failed lot to be 85.5 percent to 86.2 percent. Subsequently, an FDA 
inspection at the firm led to the issuance of a warning letter 
regarding the firm's levothyroxine sodium products. One of the 
deviations from good manufacturing practice regulations cited in that 
letter was failure to determine by appropriate stability testing the 
expiration date of some strengths of levothyroxine sodium. Another 
deviation concerned failure to establish adequate procedures for 
monitoring and control of temperature and humidity during the 
manufacturing process.
    In April 1994, one manufacturer recalled seven lots of 
levothyroxine sodium products because potency could not be assured 
through the expiration date. In February 1995, the same manufacturer 
initiated a major recall of levothyroxine sodium affecting 60 lots and 
50,436,000 tablets. The recall was initiated when the product was found 
to be below potency at 18-month stability testing.
    In December 1995, a manufacturer recalled 22 lots of levothyroxine 
sodium products because potency could not be assured through the 
expiration date.
    In addition to raising concerns about the consistent potency of 
orally administered levothyroxine sodium products, this pattern of 
stability problems suggests that the customary 2-year shelf life may 
not be appropriate for these products because they are prone to 
experience accelerated degradation in response to a variety of factors. 
Levothyroxine sodium is unstable in the presence of light, temperature, 
air, and humidity (Ref. 4). One study found that some excipients used 
with levothyroxine sodium act as catalysts to hasten its degradation 
(Ref. 5). In addition, the kinetics of levothyroxine sodium degradation 
is complex. Stability studies show that levothyroxine sodium exhibits a 
biphasic first order degradation profile, with an initial fast 
degradation rate followed by a slower rate (Ref. 4). The initial fast 
rate varies depending on temperature. To compensate for the initial 
accelerated degradation, some manufacturers use an overage of active 
ingredient in their formulation, which can lead to occasional instances 
of superpotency.

VI. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    (1) Paul, T. L. et al., ``Long-term L-Thyroxine Therapy Is 
Associated with Decreased Hip Bone Density in Pre-menopausal Women,'' 
Journal of the American Medical Association, 259:3137-3141, 1988.
    (2) Kung, A. W. C., and K. K. Pun, ``Bone Mineral Density in 
Premenopausal Women Receiving Long-term Physiological Doses of 
Levothyroxine,'' Journal of the American Medical Association, 265:2688-
2691, 1991.
    (3) Garnick, R. I. et al., ``Stability Indicating High-Pressure 
Liquid Chromatographic Method for Quality Control of Sodium 
Liothyronine and Sodium Levothyroxine in Tablet Formulations,'' in 
``Hormone Drugs,'' edited by J. L. Gueriguian, E. D. Bransome, and A. 
S. Outschoorn, United States Pharmacopeial Convention, pp. 504-516, 
Rockville, 1982.
    (4) Won, C. M., ``Kinetics of Degradation of Levothyroxine in 
Aqueous Solution and in Solid State,'' Pharmaceutical Research, 9:131-
137, 1992.
    (5) Das Gupta, V. et al., ``Effect of Excipients on the Stability 
of Levothyroxine Sodium Tablets,'' Journal of Clinical Pharmacy and 
Therapeutics, 15:331-336, 1990.
    (6) Hennessey, J. V., K. D. Burman, and L. Wartofsky, ``The 
Equivalency of Two L-Thyroxine Preparations,'' Annals of Internal 
Medicine, 102:770-773, 1985.
    (7) Stoffer, S. S., and W. E. Szpunar, ``Potency of Levothyroxine 
Products,'' Journal of the American Medical Association, 251:635-636, 
1984.
    (8) Fish, L. H. et al., ``Replacement Dose, Metabolism, and 
Bioavailability of Levothyroxine in the Treatment of Hypothyroidism; 
Role of Triiodothyronine in Pituitary Feedback in Humans,'' The New 
England Journal of Medicine, 316:764-770, 1987.

[[Page 43538]]

VII. Legal Status

    Levothyroxine sodium is used as replacement therapy when endogenous 
thyroid hormone production is deficient. The maintenance dosage must be 
determined on a patient-by-patient basis. Levothyroxine sodium products 
are marketed in multiple dosage strengths, that may vary by only 12 
micrograms, thus permitting careful titration of dose. Because of 
levothyroxine sodium's narrow therapeutic index, it is particularly 
important that the amount of available active drug be consistent for a 
given tablet strength.
    Variations in the amount of available active drug can affect both 
safety and effectiveness. Patients who receive superpotent tablets may 
experience angina, tachycardia, or arrhythmias. There is also evidence 
that overtreatment can cause osteoporosis. Subpotent tablets will not 
be effective in controlling hypothyroid symptoms or sequelae.
    The drug substance levothyroxine sodium is unstable in the presence 
of light, temperature, air, and humidity. Unless the manufacturing 
process can be carefully and consistently controlled, orally 
administered levothyroxine sodium products may not be fully potent 
through the labeled expiration date, or be of consistent potency from 
lot to lot.
    There is evidence from recalls, adverse drug experience reports, 
and inspection reports that even when a physician consistently 
prescribes the same brand of orally administered levothyroxine sodium, 
patients may receive products of variable potency at a given dose. Such 
variations in product potency present actual safety and effectiveness 
concerns.
    In conclusion, the active ingredient levothyroxine sodium is 
effective in treating hypothyroidism and is safe when carefully and 
consistently manufactured and stored, and prescribed in the correct 
amount to replace the deficiency of thyroid hormone in a particular 
patient. However, no currently marketed orally administered 
levothyroxine sodium product has been shown to demonstrate consistent 
potency and stability and, thus, no currently marketed orally 
administered levothyroxine sodium product is generally recognized as 
safe and effective. Accordingly, any orally administered drug product 
containing levothyroxine sodium is a new drug under section 201(p) of 
the act (21 U.S.C. 321(p)) and is subject to the requirements of 
section 505 of the act.
    Manufacturers who wish to continue to market orally administered 
levothyroxine sodium products must submit applications as required by 
section 505 of the act and part 314 (21 CFR part 314). FDA is prepared 
to accept NDA's for these products, including section 505(b)(2) 
applications. An applicant making a submission under section 505(b)(2) 
of the act may rely upon investigations described in section 
505(b)(1)(A) that were not conducted by or for the applicant and for 
which the applicant has not obtained a right of reference or use from 
the person by or for whom the investigations were conducted. For 
example, such an application may include literature supporting the 
safety and/or the effectiveness of levothyroxine sodium. A 
bioavailability study must be completed and submitted as part of an 
NDA, including a 505(b)(2) application, in order to evaluate the safety 
and efficacy of these products.
     If the manufacturer of an orally administered drug product 
containing levothyroxine sodium contends that the drug product is not 
subject to the new drug requirements of the act, this claim should be 
submitted in the form of a citizen petition under Sec. 10.30 and should 
be filed to Docket No. 97N-0314 no later than October 14, 1997. Sixty 
days is the time allowed for such submissions in similar proceedings. 
(See Sec. 314.200(c) and (e).) Under Sec. 10.30(e)(2), the agency will 
provide a response to each petitioner within 180 days of receipt of the 
petition. A citizen petition that contends that a particular drug 
product is not subject to the new drug requirements of the act should 
contain the quality and quantity of data and information set forth in 
Sec. 314.200(e). Note especially that a contention that a drug product 
is generally recognized as safe and effective within the meaning of 
section 201(p) of the act is to be supported by the same quantity and 
quality of scientific evidence that is required to obtain approval of 
an application for the product. (See Sec. 314.200(e)(1).)
    Levothyroxine sodium products are medically necessary because they 
are used to treat hypothyroidism and no alternative drug is relied upon 
by the medical community as an adequate substitute. Accordingly, FDA 
will permit orally administered levothyroxine sodium products to be 
marketed without approved NDA's until August 14, 2000, in order to give 
manufacturers time to conduct the required studies and to prepare and 
submit applications, and to allow time for review of and action on 
these applications. This provision for continuation of marketing, which 
applies only to levothyroxine sodium products marketed on or before the 
publication of this notice, is consistent with the order in Hoffmann-La 
Roche, Inc. v. Weinberger, 425 F. Supp. 890 (D.D.C. 1975), reprinted in 
the Federal Register of September 22, 1975 (40 FR 43531) and March 2, 
1976 (41 FR 9001).
    After August 14, 2000 any orally administered drug product 
containing levothyroxine sodium, marketed on or before the date of this 
notice, that is introduced or delivered for introduction into 
interstate commerce without an approved application will be subject to 
regulatory action, unless there has been a finding by FDA, under a 
citizen petition submitted for that product as described above, that 
the product is not subject to the new drug requirements of the act.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (secs. 502, 505 (21 U.S.C. 352, 355)) and under authority delegated 
to the Deputy Commissioner for Policy (21 CFR 5.20).

    Dated: August 7, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-21575 Filed 8-13-97; 8:45 am]
BILLING CODE 4160-01-F