Prescription Drug Products; Levothyroxine Sodium

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