[Federal Register Volume 62, Number 157 (Thursday, August 14, 1997)]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-21575]
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.
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
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,
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.
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
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
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
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
orally administered levothyroxine sodium products, including the market
leader, has reported recalls that were the result of potency or
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
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
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
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
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-
(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,
(4) Won, C. M., ``Kinetics of Degradation of Levothyroxine in
Aqueous Solution and in Solid State,'' Pharmaceutical Research, 9:131-
(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,
(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.
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
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