HYDROCHLOROTHIAZIDE (Page 2 of 3)

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 cholestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, 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
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

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, leucopenia, 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.

Postmarketing Experience
Non-melanoma Skin Cancer

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088 OR LEADING PHARMA, LLC AT 1-844-740-7500.

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 LD 50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat.

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