|
|
|
Prescribing Information for Nature-Throid™ (Thyroid USP) Tablets
DESCRIPTION
Nature-Throid™ (Thyroid USP) Tablets, micro-coated, easy to
swallow with a reduced odor, for oral use are natural
preparations derived from porcine thyroid glands (T3
liothyronine is approximately four times as potent as T4
levothyroxine on a microgram for microgram basis). They
provide 38 mcg levothyroxine (T4) and 9 mcg liothyronine
(T3) for each 65 mg (1 Grain) of the labeled content of
thyroid.
INACTIVE INGREDIENTS
Colloidal Silicon Dioxide, Dicalcium Phosphate, Lactose
Monohydrate*, Magnesium Stearate, Microcrystalline
Cellulose, Croscarmellose Sodium, Stearic Acid, Opadry II
85F19316 Clear. *Present in traceable amount as part of
Thyroid USP (diluent) The structural formulas of
liothyronine (T3) and levothyroxine (T4) are as follows:
CLINICAL PHARMACOLOGY
The steps in the synthesis of the thyroid hormones are
controlled by thyrotropin (Thyroid Stimulating Hormone, TSH)
secreted by the anterior pituitary. This hormone’s secretion
is in turn controlled by a feedback mechanism affected by
the thyroid hormones themselves and by thyrotropin releasing
hormone (TRH), a tripeptide of hypothalamic origin.
Endogenous thyroid hormone secretion is suppressed when
exogenous thyroid hormones are administered to euthyroid
individuals in excess of the normal gland’s secretion. The
mechanisms by which thyroid hormones exert their physiologic
action are not well understood. These hormones enhance
oxygen consumption by most tissues of the body, increase the
basal metabolic rate, and the metabolism of carbohydrates,
lipids, and proteins. Thus, they exert a profound influence
on every organ system in the body and are of particular
importance in the development of the central nervous system.
The normal thyroid gland contains approximately 200 mcg of
levothyroxine (T4) per gram of gland, and 15 mcg of
liothyronine (T3) per gram. The ratio of these two hormones
in the circulation does not represent the ratio in the
thyroid gland, since about 80 percent of peripheral
liothyronine (T3) comes from monodeiodination of
levothyroxine (T4). Peripheral monodeiodination of
levothyroxine (T4) at the 5 position (inner ring) also
results in the formation of reverse liothyronine (T3), which
is calorigenically inactive. Liothyronine (T3) levels are
low in the fetus and newborn, in old age, in chronic caloric
deprivation, hepatic cirrhosis, renal failure, surgical
stress, and chronic illnesses representing what has been
called the “T3 thyronine syndrome”.
Pharmacokinetics
Animal studies have shown that levothyroxine (T4) is only
partially absorbed from the gastrointestinal tract. The
degree of absorption is dependent on the vehicle used for
its administration and by the character of the intestinal
contents, the intestinal flora, including plasma protein,
and soluble dietary factors, all of which bind thyroid,
thereby making it unavailable for diffusion. Only 41 percent
is absorbed when given in a gelatin capsule, as opposed to
74 percent absorption when given with an albumin carrier.
Depending on other factors, absorption has varied from 48 to
79 percent of the administered dose. Fasting increases
absorption. Malabsorption syndromes, as well as dietary
factors, (children’s soybean formula, concomitant use of
anionic exchange resins such as cholestyramine) cause
excessive fecal loss. Liothyronine (T3) is almost totally
absorbed, 95 percent in 4 hours. The hormones contained in
the natural preparations are absorbed in a manner similar to
the synthetic hormones.
More than 99 percent of circulating hormones are bound to
serum proteins, including thyroid-binding globulin (TBg),
thyroid-binding pre-albumin (TBPA), and albumin (TBa), whose
capacities and affinities vary for the hormones. The higher
affinity of levothyroxine (T4) for both TBg and TBPA, as
compared to liothyronine (T3), partially explains the higher
serum levels and longer half-life of the former hormone.
Both protein-bound hormones exist in reverse equilibrium
with minute amounts of free hormone, the latter accounting
for the metabolic activity. Deiodination of levothyroxine
(T4) occurs at a number of sites, including liver, kidney,
and other tissues. The conjugated hormone, in the form of
glucuronide or sulfate, is found in the bile and gut where
it may complete an enterohepatic circulation. Eighty-five
percent of levothyroxine (T4) metabolized daily is
deiodinated.
INDICATIONS AND USAGE
1. As replacement of supplemental therapy in patients with
hypothyroidism of any etiology, except transient
hypothyroidism during the recovery phase of subacute
thyroiditis. This category includes cretinism, myxedema, and
ordinary hypothyroidism in patients of any age (children,
adults, the elderly), or state (including pregnancy);
primary hypothyroidism resulting from functional deficiency,
primary atrophy, partial or total absence of thyroid gland,
or the effects of surgery, radiation, or drugs, with or
without the presence of goiter; and secondary (pituitary),
or tertiary (hypothalamic) hypothyroidism (See WARNINGS).
2. As pituitary TSH suppressants, in the treatment or
prevention of various types of euthyroid goiters, including
thyroid nodules, subacute, or chronic lymphocytic
thyroiditis (Hashimoto’s), multinodular goiter, and in the
management of thyroid cancer.
3. As diagnostic agents in suppression tests to
differentiate suspected mild hyperthyroidism or thyroid
gland anatomy.
CONTRAINDICATIONS
Thyroid hormone preparations are generally contraindicated
in patients with diagnosed, but as yet, uncorrected adrenal
cortical insufficiency, untreated thyrotoxicosis, and
apparent hypersensitivity to any of their active or
extraneous constituents. There is no well documented
evidence in the literature of true allergic or idiosyncratic
reactions to thyroid hormone.
WARNINGS
Drugs with thyroid hormone activity, alone or together with
other therapeutic agents, have been used for the treatment
of obesity. In euthyroid patients, doses within the range of
daily hormonal requirements are ineffective for weight
reduction. Larger doses may produce serious or even
life-threatening manifestations of toxicity, particularly
when given in association with sympathomimetic amines such
as those used for their anorectic effects.
The use of thyroid hormones in the therapy of obesity, alone
or combined with other drugs, is unjustified and has been
shown to be ineffective. Neither is their use justified for
the treatment of male or female infertility unless this
condition is accompanied by hypothyroidism.
PRECAUTIONS
General: Thyroid hormones should be used with great caution
in a number of circumstances where the integrity of the
cardiovascular system, particularly the coronary arteries,
is suspected. These include patients with angina pectoris or
the elderly, whom have a greater likelihood of occult
cardiac disease. With these patients, therapy should be
initiated with low doses, i.e. 16.25 - 32.5 mg. When, in
such patients, a euthyroid state can only be reached at the
expense of an aggravation of the cardiovascular disease,
thyroid hormone dosage should be reduced.
Thyroid hormone therapy in patients with concomitant
diabetes mellitus or diabetes insipidus or adrenal cortical
insufficiency aggravates the intensity of their symptoms.
Appropriate adjustments of the various therapeutic measures
directed at these concomitant endocrine diseases are
required. The therapy of myxedema coma requires simultaneous
administration of glucorticoids (See DOSAGE AND
ADMINISTRATION).
Hypothyroidism decreases and hyperthyroidism increases the
sensitivity to oral anticoagulants. Prothrombin time should
be closely monitored in thyroid treated patients on oral
anticoagulants and dosage of the latter agents should be
adjusted on the basis of frequent prothrombin time
determinations. In infants, excessive doses of thyroid
hormone preparations may produce craniosynostosis.
Information for the Patient: Patients on thyroid hormone
preparations and parents of children on thyroid therapy
should be informed that:
1. Replacement therapy is to be taken essentially for life,
with the exception of cases of transient hypothyroidism,
usually associated with thyroiditis, and in those patients
receiving a therapeutic trial of the drug.
2. They should immediately report, during the course of
therapy, any signs or symptoms of thyroid hormone toxicity,
e.g., chest pain, increased pulse rate, palpitations,
excessive sweating, heat intolerance, nervousness, or any
other unusual event.
3. In case of concomitant diabetes mellitus, the daily
dosage of antidiabetic medication may need readjustment as
thyroid hormone replacement is achieved. If thyroid
medication is stopped, a downward readjustment of the dosage
of insulin or oral hypoglycemic agent may be necessary to
avoid hypoglycemia. At all times, close monitoring of
urinary glucose levels is mandatory in such patients.
4. In case of concomitant oral anticoagulant therapy, the
prothrombin time should be measured frequently to determine
if the dosage of oral anticoagulants is to be readjusted.
5. Partial loss of hair may be experienced by children in
the first few months of thyroid therapy, but this is usually
a transient phenomenon and later recovery is usually the
rule.
Laboratory Tests: Treatment of patients with thyroid
hormones requires the periodic assessment of thyroid status
by means of appropriate laboratory tests, besides the full
clinical evaluation. The TSH suppression test can be used to
test the effectiveness of any thyroid preparation, bearing
in mind the relative insensitivity of the infant pituitary
to the negative feedback effect of thyroid hormones. SerumT4
levels can be used to test the effectiveness of all thyroid
medications except T3. When the total serum T4 is low but
TSH is normal, a test specific to assess unbound (free) T4
levels is warranted. Specific measurements of T4 and T3 by
competitive protein binding or radioimmunoassay are not
influenced by blood levels of organic or inorganic iodine.
Drug Interactions: Oral Anticoagulants-Thyroid
hormones appear to increase catabolism of vitamin K-
dependent clotting factors. If oral anticoagulants are also
being given, compensatory increases in clotting factor
synthesis are impaired. Patients stabilized on oral
anticoagulants that are found to require thyroid replacement
therapy should be watched very closely when thyroid is
started. If a patient is truly hypothyroid, it is likely
that a reduction in anticoagulant dosage will be required.
No special precautions appear to be necessary when oral
anticoagulant therapy is begun in a patient already
stabilized on maintenance thyroid replacement therapy.
Insulin or Oral Hypoglycemic-Initiating thyroid replacement
therapy may cause increases in insulin or oral hypoglycemic
requirements. The effects seen are poorly understood and
depend upon a variety of factors such as dose and type of
thyroid preparations and endocrine status of the patient.
Patients receiving insulin or oral hypoglycemic should be
closely watched during initiation of thyroid replacement
therapy.
Cholestyramine or Colestipol- Cholestyramine or Colestipol
binds both levothyroxine (T4) and liothyronine (T3) in the
intestine, thus impairing absorption of these thyroid
hormones. In vitro studies indicate that the binding is not
easily removed. Therefore, four to five hours should elapse
between administration of Cholestyramine or Colestipol and
thyroid hormones.
Estrogen, Oral Contraceptives- Estrogens tend to increase
serum thyroxinebinding globulin (TBg). In a patient with a
nonfunctioning thyroid gland who is receiving thyroid
replacement therapy, free levothyroxine (T4) may be
decreased when estrogens are started thus increasing thyroid
requirements. However, if the patient’s thyroid gland has
sufficient function, the decreased free levothyroxine (T4)
will result in a compensatory increase in levothyroxine (T4)
output by the thyroid. Therefore, patients without a
functioning thyroid gland who are on thyroid replacement
therapy, may need to increase their thyroid dose if
estrogens or estrogen-containing oral contraceptives are
given.
Drug/Laboratory Test Interactions: The following
drugs or moieties are known to interfere with laboratory
tests performed in patients on thyroid hormone therapy:
androgens, corticosteroids, estrogens, oral contraceptives
containing estrogens, iodine-containing preparations, and
the numerous preparations containing salicylates.
1. Changes in TBg concentration should be taken into
consideration in the interpretation of levothyroxine (T4)
and liothyronine (T3) values. In such cases, the unbound
(free) hormone should be measured. Pregnancy, estrogens, and
estrogen-containing oral contraceptives increase TBg
concentrations. TBg may also be increased during infectious
hepatitis. Decreases in TBg concentrations are observed in
nephrosis, acromegaly, and after androgen or corticosteroid
therapy. Familial hyper or
hypothyroxine-binding-globulinemias have been described. The
incidence of TBg deficiency approximates 1 in 9,000. The
binding of levothyroxine by TBPA is inhibited by salicylates.
2. Medicinal or dietary iodine interferes with all in vivo
tests of radio-iodine uptake, producing low uptakes which
may not be relative of a true decrease in hormone synthesis.
3. The persistence of clinical and laboratory evidence of
hypothyroidism in spite of adequate dosage replacement
indicates; either poor patient compliance, poor absorption,
excessive fecal loss, or inactivity of the preparation.
Intracellular resistance to thyroid hormone is quite rare.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: A
reportedly apparent association between prolonged thyroid
therapy and breast cancer
has not been confirmed and patients on thyroid for
established indications should not discontinue therapy. No
confirmatory long-term studies in animals have been
performed to evaluate carcinogenic potential, mutagenicity,
or impairment of fertility in either males or females.
Pregnancy-Category A: Thyroid hormones do not readily
cross the placental barrier. The clinical experience to date
does not indicate any adverse effect on fetuses when thyroid
hormones are administered to pregnant women. On the basis of
current knowledge, thyroid replacement therapy to
hypothyroid women should not be discontinued during
pregnancy.
Nursing Mothers: Minimal amounts of thyroid hormones
are excreted in human milk. Thyroid is not associated with
serious adverse reactions and does not have a known
tumorigenic potential. However, caution should be exercised
when thyroid is administered to a nursing woman.
Pediatric Use: Pregnant mothers provide little or no
thyroid hormone to the fetus. The incidence of congenital
hypothyroidism is relatively high (1:4,000) and the
hypothyroid fetus would not derive any benefit from the
small amounts of hormone crossing the placental barrier.
Routine determination of serumT4 and/or TSH is strongly
advised in neonates in view of the deleterious effects of
thyroid deficiency on growth and development. Treatment
should be initiated immediately upon diagnosis, and
maintained for life, unless transient hypothyroidism is
suspected; in which case, therapy may be interrupted for 2
to 8 weeks after the age of 3 years to reassess the
condition. Cessation of therapy is justified in patients who
have maintained a normal TSH during those 2 to 8 weeks.
Geriatric use: Clinical studies of Thyroid Tablets,
USP did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly
patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
ADVERSE REACTIONS
Adverse reactions other than those indicative of
hyperthyroidism because of therapeutic overdosage, either
initially or during the maintenance period, are rare (See
OVERDOSAGE).
OVERDOSAGE
Signs and Symptoms: Excessive doses of thyroid result in a
hypermetabolic state resembling in every respect the
condition of endogenous origin. The condition may be self
induced.
Treatment of Overdosage: Dosage should be reduced or
therapy temporarily discontinued signs and symptoms of
overdosage appear. Treatment may be reinstituted at a lower
dosage. In normal individuals, normal
hypothalamic-pituitary-thyroid axis function is restored in
6 to 8 weeks after thyroid suppression.
Treatment of acute massive thyroid hormone overdosage is
aimed at reducing gastrointestinal absorption of the drugs
and counteracting central and peripheral effects, mainly
those of increased sympathetic activity. Vomiting may be
induced initially if further gastrointestinal absorption can
reasonably be prevented and barring contraindications such
as coma, convulsions, or loss of the gagging reflex.
Treatment is symptomatic and supportive. Oxygen may be
administered and ventilation maintained. Cardiac glycosides
may be indicated if congestive heart failure develops.
Measures to control fever, hypoglycemia, or fluid loss
should be instituted if needed. Antiadrenergic agents,
particularly propranolol, have been used advantageously in
the treatment of increased sympathetic activity. Propranolol
may be administered intravenously at a dosage of 1 to 3 mg,
over a 10 minute period or orally, 80 to 160 mg/day,
initially, especially when no contraindications exist for
its use.
DOSAGE AND ADMINISTRATION
The dosage of thyroid hormones is determined by the
indication and must in every case be individualized
according to patient response and laboratory findings.
Thyroid hormones are given orally. In acute, emergency
conditions, injectable levothyroxine sodium (T4) may be
given intravenously when oral administration is not feasible
or desirable (as in the treatment of myxedema coma, or
during parenteral nutrition). Intramuscular administration
is not advisable because of reported poor absorption.
Hypothyroidism: Therapy is usually instituted using
low doses, with increments which depend on the
cardiovascular status of the patient. The usual starting
dose is 32.5 mg, with increment of 16.25 mg every 2 to 3
weeks. A lower starting dosage, 16.25 mg/day, is recommended
in patients with longstanding myxedema, particularly if
cardiovascular impairment is suspected, in which case
extreme caution is recommended. The appearance of angina is
an indication for reduction in dosage. Most patients require
65 - 130 mg/day. Failure to respond to doses of 195 mg
suggests lack of compliance or malabsorption. Maintenance
dosages 65 - 130 mg/day usually result in normal serum T4
and T3 levels. Adequate therapy usually results in normal
TSH and T4 levels after 2 or 3 weeks of therapy.
Readjustment of thyroid hormone dosage should be made within
the first four weeks of therapy, after proper clinical and
laboratory evaluations, including serum levels of T4, bound
and free, and TSH.
Liothyronine (T3) may be used in preference to levothyroxine
(T4) during radio-isotope scanning procedures, since
induction of hypothyroidism in those cases is more abrupt
and can be of shorter duration. It may also be preferred
when impairment of peripheral conversion of levothyroxine
(T4) and liothyronine (T3) is suspected.
Myxedema Coma: Myxedema coma is usually precipitated in the
hypothyroid patient of longstanding by intercurrent illness
or drugs such as sedatives and anesthetics and should be
considered a medical emergency. Therapy should be directed
at the correction of electrolyte disturbances and possible
infection, besides the administration of thyroid hormones.
Corticosteroids should be administered routinely.
Levothyroxine (T4) and Liothyronine (T3) may be administered
via a nasogastric tube, but the preferred route of
administration of both hormones is intravenous.
Levothyroxine sodium (T4) is given at a starting dose of 400
mcg (100 mcg/mL) given rapidly, and is usually well
tolerated, even in the elderly. This initial dose is
followed by daily supplements of 100 to 200 mcg given IV.
Normal T4 levels are achieved in 24 hours, followed in 3
days by threefold elevation of T3. Oral therapy with thyroid
hormone would be resumed as soon as the clinical situation
has been stabilized and the patient is able to take oral
medication.
Thyroid Cancer: Exogenous thyroid hormone may produce
regression of metastases from follicular and papillary
carcinoma of the thyroid and is used as ancillary therapy of
these conditions with radioactive iodine. TSH should be
suppressed to low or undetectable levels. Therefore, larger
amounts of thyroid hormone than those used for replacement
therapy are required. Medullary carcinoma of the thyroid is
usually unresponsive to this therapy.
Thyroid Suppression Therapy: Administration of
thyroid hormone in doses higher than those produced
physiologically by the gland results in suppression of the
production of endogenous hormone. This is the basis for the
thyroid suppression test and is used as an aid in the
diagnosis of patients with signs of mild hyperthyroidism, in
whom base line laboratory tests appear normal, or to
demonstrate thyroid gland autonomy in patients with Grave’s
ophthalmopathy. 1 uptake is determined before and after the
administration of the exogenous hormone. A fifty percent or
greater suppression of uptake indicates a normal thyroid
pituitary axis, and thus rules out thyroid gland autonomy.
For adults, the usual suppressive dose of levothyroxine (T4)
is 1.56 mg/kg of body weight per day given for 7 to 10 days.
These doses usually yield normal serum T4 and T3 levels and
lack of response to TSH. Thyroid hormones should be
administered cautiously to patients in whom there is strong
suspicion of thyroid gland autonomy, in view of the fact
that the exogenous hormone effects will be additive to the
endogenous source.
Pediatric Dosage: Pediatric dosage should follow the
recommendations summarized in Table 1. In infants with
congenital hypothyroidism, therapy with full doses should be
instituted as soon as the diagnosis has been made.
TABLE 1. Recommended Pediatric Dosage for Congenital
Hypothyroidism
Age Dose per day Daily dose per kg of body weight
0 - 6 months 16.25 - 32.5 mg 4.8-6.0 mg
6 - 12 months 32.5 - 48.75 mg 3.6-4.8 mg
1 - 5 years 48.75 - 65 mg 3.3-6.0 mg
6 - 12 years 65 - 97.5 mg 2.4-3.0 mg
Over 12 years Over 97.5 mg 1.2-1.8 mg
HOW SUPPLIED:
Nature-Throid™ (Thyroid USP) Tablets are supplied as
follows:
16.25 mg. (1/4 gr.) in bottles of 100 Count (NDC
64727-3298-1), 990 Count
Polybags (NDC 64727-3298-3), 1,000 Count (NDC 64727-3298-2),
1,008
Count Polybags (NDC 64727-3298-8)
32.5 mg (1/2 gr.) in bottles of 100 Count (NDC
64727-3299-1), 990 Count
Polybags (NDC 64727-3299-3), 1,000 Count (NDC 64727-3299-2),
1,008
Count Polybags (NDC 64727-3299-8)
65 mg (1 gr.) in bottles of 100 Count (NDC 64727-3300-1),
990 Count
Polybags (NDC 64727-3300-3), 1,000 Count (NDC 64727-3300-2),
1,008
Count Polybags (NDC 64727-3300-8)
130 mg (2 gr.) in bottles of 100 Count (NDC 64727-3308-1),
990 Count
Polybags (NDC 64727-3308-3), 1,000 Count (NDC 64727-3308-2),
1,008
Count Polybags (NDC 64727-3308-8)
195 mg (3 gr.) in bottles of 100 Count (NDC 64727-3312-1),
990 Count
Polybags (NDC 64727-3312-3), 1,000 Count (NDC 64727-3312-2),
1,008
Count Polybags(NDC 64727-3312-8)
STORAGE: Store at controlled room temperature; 15°-30°C
(59°-86°F)
Dispense in tight, light-resistant containers as defined in
the USP/NF
Rx Only. |
| |
|
|
