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.

Oral

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 mg 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 3 to 5 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 section 4-4).

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 mg 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.

May be administered with food or milk

Warnings

•    Use with caution in severe renal disease. In patients with renal disease, Hydrochlorothiazide may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

•    Hydrochlorothiazide 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.

•    Hydrochlorothiazide 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 section 4-5).

•   Choroidal effusion, acute myopia and secondary angle-closure glaucoma:

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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 Hydrochlorothiazide .

•    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.

•    Hydrochlorothiazide have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

•   Hydrochlorothiazide may decrease urinary calcium excretion.

Hydrochlorothiazide 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. Hydrochlorothiazide 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.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product

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%, respectively.

•   Corticosteroids

Intensify electrolyte depletion, particularly hypokalemia.

•   Pressor amines (e.g., norepinephrine)

Possibly decrease 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.

 •  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

Hydrochlorothiazide should be discontinued before carrying out tests for parathyroid function (see Section 4-4).

Pregnancy Category B

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. Hydrochlorothiazide are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (see section 4-4). 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.

Hydrochlorothiazide 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.

MONOZIDE may impair the patient's reactions, especially at the beginning of treatment, e.g. when driving or using machines.

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 section 4-4), hyperglycemia, glycosuria, hyperuricemia.

•   Musculoskeletal: Muscle spasm.

•   Nervous System/Psychiatric:

Vertigo, paresthesias, dizziness, headache, restlessness.

•   Renal:

Renal failure, renal dysfunction, interstitial nephritis (see section 4-4).

•   Skin:

Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia.

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 cellcarcinoma (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 acumulative dose of ≥50,000mg the risk increase was approximately 1additional SCC case for every 6,700 patients per year.

•   Special Senses:

Transient blurred vision, xanthopsia.

•   Urogenital: Impotence.

Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

•     Eye disorders: choroidal effusion (frequency not known)

For bendroflumethiazide, cicletanine, clopamide, cyclopenthiazide, hydroflumethiazide, metipamide, metolazone, xipamide-containing products (choroidal effusion has not yet been reported but is considered a class effect): Cases of choroidal effusion with visual field defect have been reported after the use of thiazide and thiazide-like diuretics.

Saudi Arabia: To report any side effect(s): National Pharmacovigilance Center (NPC):  Fax: +966-11-205-7662, SFDA Call center: 19999, E-mail: npc.drug@sfda.gov.sa, Website: https://ade.sfda.gov.sa

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

1             List of excipients

Lactose

Maize Starch

Colloidal Anhydrous Silica

Magnesium Stearate

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.

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.

Three years

Lactose

Maize Starch

Colloidal Anhydrous Silica

Magnesium Stearate

Not applicable.Three years

Do not store above 30ºC

MONOZIDE 25 Tablets are packed in boxes of 30 and 1000 Tablets blistered in PVC/PE/ PVDC (90) /Aluminum foil blisters.

Any unused product or waste material should be disposed of accordance with local requirements.