HYDROCHLOROTHIAZIDE
-
hydrochlorothiazide tablet
International Labs, Inc.
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Hydrochlorothiazide Tablets USP - Package LabelsDESCRIPTION
DESCRIPTION
Hydrochlorothiazide is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. It is chemically designated as
6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and has the following structural formula:
Hydrochlorothiazide is a white, or practically white, crystalline powder which is slightly soluble in water, but freely soluble in sodium hydroxide
solution. Each tablet for oral administration contains 12.5 mg, 25 mg and 50 mg hydrochlorothiazide, USP. In addition, each tablet contains
the following inactive ingredients: corn starch, dibasic calcium phosphate, FDC yellow 6, lactose monohydrate, magnesium stearate,
pregelatinized starch, and sodium starch glycolate.
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure.
Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are
approximately equal in their diuretic efficacy.
Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by
some loss of potassium and bicarbonate.
After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Pharmacokinetics and Metabolism
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours,
the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within
24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
INDICATIONS & USAGE
INDICATIONS AND USAGE
Hydrochlorothiazide tablets are indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and
corticosteroid and estrogen therapy.
Hydrochlorothiazide tablets have also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute
glomerulonephritis, and chronic renal failure.
Hydrochlorothiazide tablets are indicated in the management of hypertension either as the sole therapeutic agent or to enhance the
effectiveness of other antihypertensive drugs in the more severe forms of hypertension.
Use in Pregnancy
Routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not
prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.
Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Thiazides
are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (see PRECAUTIONS,
Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the gravid uterus, is properly treated through
elevation of the lower extremities and use of support stockings. Use of diuretics to lower intravascular volume in this instance is illogical and
unnecessary. During normal pregnancy there is hypervolemia which is not harmful to the fetus or the mother in the absence of cardiovascular
disease. However, it may be associated with edema, rarely generalized edema. If such edema causes discomfort, increased recumbency will
often provide relief. Rarely this edema may cause extreme discomfort which is not relieved by rest. In these instances, a short course of diuretic
therapy may provide relief and be appropriate.
CONTRAINDICATIONS
CONTRAINDICATIONS
Anuria.
Hypersensitivity to this product or to other sulfonamide-derived drugs.
WARNINGS
WARNINGS
Use with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug
may develop in patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid
and electrolyte balance may precipitate hepatic coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Sensitivity reactions may occur in patients with or without a
history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with diuretics (see PRECAUTIONS, Drug Interactions).
PRECAUTIONS
PRECAUTIONS
General
All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic
alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively
or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth,
thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria,
tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present or after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may
also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may
be avoided or treated by use of potassium sparing diuretics or potassium supplements such as foods with a high potassium content. Although
any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver
disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in
edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when
the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide
diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence
of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be
discontinued before carrying out tests for parathyroid function. Increases in cholesterol and triglyceride levels may be associated with thiazide
diuretic therapy.
Laboratory Tests
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals.
Drug Interactions
When given concurrently the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics
Potentiation of orthostatic hypotension may occur.
Antidiabetic drugs - (oral agents and insulin)
Dosage adjustment of the antidiabetic drug may be required.
Other antihypertensive drugs
Additive effect or potentiation.
Cholestyramine and colestipol resins
Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol
resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.
Corticosteroids, ACTH
Intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine)
Possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) Possible increased responsiveness to the muscle relaxant.
Lithium
Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer
to the package insert for lithium preparations before use of such preparations with hydrochlorothiazide.
Non-steroidal Anti-inflammatory Drugs
In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive
effects of loop, potassium-sparing and thiazide diuretics. Therefore, when hydrochlorothiazide and non-steroidal anti-inflammatory agents
are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
Drug/Laboratory Test Interactions
Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS, General).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence
of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female
rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA
1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell
chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results
were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays,
using concentrations of hydrochlorothiazide from 43 to 1300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified
concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via
their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation.
Pregnancy
Teratogenic Effects – Pregnancy Category B
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis
at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects
Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly
other adverse reactions that have occurred in adults.
Nursing Mothers
Thiazides are excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made
whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.
Pediatric Use
There are no well-controlled clinical trials in pediatric patients. Information on dosing in this age group is supported by evidence from
empiric use in pediatric patients and published literature regarding the treatment of hypertension in such patients. (See DOSAGE AND
ADMINISTRATION, Infants and Children).
ADVERSE REACTIONS
ADVERSE REACTIONS
The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.
Body as a Whole
Weakness
Cardiovascular
Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs)
Digestive
Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea,
vomiting, sialadenitis, cramping, constipation, gastric irritation,
nausea,
anorexia
Hematologic
Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia
Hypersensitivity
Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous
vasculitis), respiratory distress including pneumonitis and pulmonary
edema, photosensitivity, fever, urticaria, rash, purpura
Metabolic
Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia
Musculoskeletal
Muscle spasm
Nervous System/Psychiatric
Vertigo, paresthesias, dizziness, headache, restlessness.
Renal
Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS)
Skin
Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia
Special Senses
Transient blurred vision, xanthopsia
Urogenital
Impotence
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
OVERDOSAGE
OVERDOSAGE
The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia)
and dehydration resulting from excessive diuresis. If digitalis has
also been administered, hypokalemia may accentuate cardiac arrhythmias.
In the event of overdosage, symptomatic and supportive measures should
be employed. Emesis should be induced or gastric lavage performed.
Correct dehydration, electrolyte imbalance, hepatic coma and
hypotension by established procedures. If required, give oxygen or
artificial
respiration for respiratory impairment. The degree to which
hydrochlorothiazide is removed by hemodialysis has not been
established. The oral
LD50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat.
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION
Therapy should be individualized according to patient response. Use the
smallest dosage necessary to achieve the required response.
Adults
For Edema
The usual adult dosage is 25 to 100 mg daily as a single or divided
dose. Many patients with edema respond to intermittent therapy, i.e.,
administration on alternate days or on three to five days each week.
With an intermittent schedule, excessive response and the resulting
undesirable electrolyte imbalance are less likely to occur.
For Control of Hypertension
The usual initial dose in adults is 25 mg daily given as a single dose.
The dose may be increased to 50 mg daily, given as a single or two
divided
doses. Doses above 50 mg are often associated with marked reductions in
serum potassium (see also PRECAUTIONS). Patients usually do not
require doses in excess of 50 mg of hydrochlorothiazide daily when used concomitantly with other antihypertensive agents.
Infants and Children
For Diuresis and For Control of Hypertension
The usual pediatric dosage is 0.5 to 1 mg per pound (1 to 2 mg/kg) per
day in single or two divided doses, not to exceed 37.5 mg per day in
infants up to 2 years of age or 100 mg per day in children 2 to 12
years of age. In infants less than 6 months of age, doses up to 1.5 mg
per
pound (3 mg/kg) per day in two divided doses may be required. (See PRECAUTIONS, Pediatric Use)
HOW SUPPLIED
HOW SUPPLIED
Hydrochlorothiazide tablets, USP are available as light orange colored, round, flat face, beveled edge, uncoated tablets.
25 mg
Each tablet contains 25 mg hydrochlorothiazide, USP and is debossed
with ‘I’ above the bisect and ‘26’ below the bisect on one side and
plain on the other side.
NDC 54458-941-10 Shellpaks® of 30 tablets
50 mg
Each tablet contains 50 mg hydrochlorothiazide, USP and is debossed
with ‘I’ above the bisect and ‘25’ below the bisect on one side and
plain on the other side.
NDC 54458-940-10 Shellpaks® of 30 tablets
PHARMACIST: Dispense in a well-closed container as defined in the USP. Use child-resistant closure (as required).
Store at 20°–25° C (68°–77° F). [See USP Controlled Room Temperature].
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Ipca Laboratories Limited
48, Kandivli Ind. Estate, Mumbai 400 067, India
Packaged by:
International Labs, Inc.
St. Petersburg, FL 33710
Distributed by:
Wal-Mart
Bentonville, AR 72716
Rev. 12/09 LI0022
HYDROCHLOROTHIAZIDE TABLETS, USP 25 mg
LB0139 - HYDROCHLOROTHIAZIDE TABLETS, USP 25 mg
HYDROCHLOROTHIAZIDE TABLETS, USP 50 mg
LB0141 - HYDROCHLOROTHIAZIDE TABLETS, USP 50 mg
| HYDROCHLOROTHIAZIDE
hydrochlorothiazide tablet |
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA040807 | 01/20/2010 | |
| HYDROCHLOROTHIAZIDE
hydrochlorothiazide tablet |
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA040807 | 02/12/2010 | |
| Labeler - International Labs, Inc. (023569924) |
| Registrant - International Labs, Inc. (023569924) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| International Labs, Inc. | 023569924 | manufacture, relabel, repack | |