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WARNING This fixed-combination drug is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension is not static but must be reevaluated as conditions in each patient warrant. |
Hydralazine HCI and hydrochlorothiazide is an antihypertensive-diuretic combination available as capsules for oral administration. Hydralazine HCI and hydrochlorothiazide capsules of 25 mg /25 mg contain 25 mg of hydralazine hydrochloride USP and 25 mg of hydrochlorothiazide USP; capsules of 50 mg /50 mg contain 50 mg of hydralazine hydrochloride USP and 50 mg of hydrochlorothiazide USP; and capsules of 100 mg /50 mg contain 100 mg of hydralazine hydrochloride USP and 50 mg of hydrochlorothiazide USP.
Each tablet also contains the following inactive ingredients: Corn starch, crospovidone, gelatin, lactose monohydrate, pharmaceutical glaze, sodium starch glycolate, stearic acid, talc, and titanium dioxide. In addition, the 25 mg/25 mg capsule contains ammonium hydroxide, ethylene glycol monoethyl ether, propylene glycol and synthetic black iron oxide; the 50 mg/50 mg capsule contains FD&C Blue #1, FD&C Red #40, FD&C Yellow #6, synthetic red iron oxide and pharmaceutical shellac; and the 100 mg/50 mg capsule contains D&C Red #28, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, propylene glycol and synthetic black iron oxide. Hydralazine hydrochloride is 1 hydrazinophthalazine monohydrochloride.
Hydralazine hydrochloride USP is a white to off-white, odorless crystalline powder. It is soluble in water, slightly soluble in alcohol, and very slightly soluble in ether. It melts at about 275° C with decomposition, and has a molecular weight of 196.64. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H -1,2.4-benzothiadiazine-7-sulfonamide 1 ,1 -dioxide. Chemical structure is as follows:
Hydrochlorothiazide USP is a white, or practically white, practically odorless crystalline powder. It is freely soluble in sodium hydroxide solution, in butylamine, and in dimethylformamide; sparingly soluble in methanol: slightly soluble in water: and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.75. Chemical structure is as follows:
Hypertension (see boxed WARNING).
Dosage should be determined by individual titration (see boxed WARNING).
The usual dosage is one hydralazine HCl and hydrochlorothiazide capsule twice daily, the strength depending upon individual requirement following titration. For maintenance, the dosage should be adjusted to the lowest effective level.
When necessary, other antihypertensive agents such as sympathetic inhibitors may be added gradually in reduced dosages, and the effects should be watched carefully.
Hydralazine HCI and hydrochlorothiazide are supplied as two piece hard gelatin capsules, in three dosage strengths:
25 mg hydralazine hydrochloride and 25 mg hydrochlorothiazide capsules are white and imprinted "Par 143", and are available in bottles of 100 (NDC #49884-1 43-01) 500 (NDC #49884-1 43-05) and 1000 (NDC X49884-1 43-10).
50 mg hydralazine hydrochloride and 50 mg hydrochlorothiazide capsules are white/black and imprinted "Par 144", and are available in bottles of 100 (NDC X49884-144-01), 500 (NDC X49884-144-05) and 1000 (NDC #49884-144-10).
100 mg hydralazine hydrochloride and 50 mg hydrochlorothiazide capsules are powder blue/light blue and imprinted "Par 145", and are available in bottles of 100 (NDC #49884-1 45-01), 500 (NDC #49884-145-05) and 1000 (NDC #49884-145-10).
Store at controlled room temperature 15°-30° C (59°-86° F).
Dispense in a tight, light-resistant container as defined in the USP.
CAUTION: Federal law prohibits dispensing without prescription.
Adverse reactions are usually reversible upon reduction of dosage or discontinuation of hydralazine HCI and hydrochlorothiazide. Whenever adverse reactions are moderate or severe, it may be necessary to discontinue the drug.
Hydralazine
The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency.
Common
Headache, anorexia, nausea, vomiting, diarrhea, palpitations, tachycardia, angina pectoris.
Less Frequent
Digestive: Constipation, paralytic ileus. Cardiovascular: Hypotension, paradoxical pressor response, and edema. Respiratory: Dyspnea. Neurologic: Peripheral neuritis, evidenced by paresthesia, numbness, and tingling; dizziness; tremors; muscle cramps; psychotic reactions characterized by depression, disorientation, or anxiety. Genitourinary: Difficulty in urination. Hematologic: Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, purpura, lymphadenopathy, splenomegaly. Hypersensitive Reactions: Rash, urticaria, pruritus, fever, chills, arthralgia, eosinophilia, and rarely, hepatitis. Other: Nasal congestion, flushing, lacrimation, and conjunctivitis.Hydrochlorothiazide
The following adverse reactions have been observed but there has not been enough systematic collection of data to support an estimate of their frequency. Consequently the reactions are categorized by organ systems and are listed in decreasing order of severity and not frequency.
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia. Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics). Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. Musculoskeletal: Muscle spasm. Hematologic: Aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Metabolic: Hyperglycemia, glycosuria, and hyperuricemia. Hypersensitive Reactions: Necrotizing angitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity.Hydralazine
MAO inhibitors should be used with caution in patients receiving hydralazine.
When other potent parenteral antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide injections and hydralazine are used concomitantly.
Hydrochlorothiazide
Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Hypokalemia may develop during concomitant use of steroids or ACTH.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use.
Thiazides may increase the responsiveness to tubocurarine.
Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity.
There have been rare reports in the literature of hemolytic anemia occurring with the concomitant use of hydrochlorothiazide and methyldopa.
Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics.
Drug/Laboratory Test Interactions
Thiazides may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. Hydralazine HCI and hydrochlorothiazide should be discontinued before tests for parathyroid function are made (See General, Hydrochlorothiazide, Calcium excretion).
This fixed-combination drug is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension is not static but must be reevaluated as conditions in each patient warrant.
Included as part of the WARNINGS section.
Acute Toxicity
Oral LD50' s in rats (mg/kg): hydralazine, 173 and 187; hydrochlorothiazide, 2750.
Signs and Symptoms
Hydralazine: Signs and symptoms of overdosage include hypotension, tachycardia, headache, and generalized skin flushing. Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia and profound shock.
Hydrochlorothiazide: The most prominent feature of poisoning is acute loss of fluid and electrolytes.
Cardiovascular: Tachycardia, hypotension, and shock.
Neuromuscular: Weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue, impairment of consciousness.
Digestive: Nausea, vomiting, thirst.
Renal: Polyuria, oliguria or anuria (due to hemoconcentration).
Laboratory Findings: Hypokalemia, hyponatremia, hypochloremia, alkalosis; increased BUN (especially in patients with renal insufficiency).
Combined Poisoning: Signs and symptoms may be aggravated or modified by concomitant intake of antihypertensive medication, barbiturates, curare, digitalis (hypokalemia), corticosteroids, narcotics, or alcohol.
Treatment
There is no specific antidote.
The gastric contents should be evacuated, taking adequate precautions against aspiration and for protection of the airway. An activated charcoal slurry may be instilled if conditions permit. Dialysis may not be effective for elimination of hydralazine HCI and hydrochlorothiazide because of its plasma protein binding (see CLINICAL PHARMACOLOGY).
These manipulations may have to be omitted or carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock.
Support of the cardiovascular system is of primary importance in suspected hydralazine overdosage. Shock should be treated with plasma expanders. The patient's legs should be kept raised and lost fluid and electrolytes (potassium, sodium) should be replaced. If possible, vasopressors should not be given, but if a vasopressor is required, care should be taken not to precipitate or aggravate cardiac arrhythmia. Tachycardia responds to beta blockers. Digitalization may be necessary, and renal function should be monitored and supported as required.
Hydralazine
Hypersensitivity to hydralazine: coronary artery disease; mitral valvular rheumatic heart disease.
Hydrochlorothiazide
Anuria: hypersensitivity to this or other sulfonamide-derived drugs.
Hydralazine
Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state. The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output.
The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Hydralazine also maintains or increases renal and cerebral blood flow.
Hydrochlorothiazide
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium. The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.
Pharmacokinetics
Hydralazine: Hydralazine is rapidly absorbed after oral administration, and peak plasma levels are reached at l-2 hours. Plasma levels decline with a half-life of 3-7 hours. Binding to human plasma protein is 87%. Plasma levels of hydralazine vary widely among individuals. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine.
Administration of hydralazine with food results in higher levels of the drug in plasma.
Hydrochlorothiazide: Onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. The action persists for approximately 6-12 hours. Hydrochlorothiazide is rapidly absorbed, as indicated by peak concentrations l-2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the concentration in whole blood is 1.6-l .8 times higher than in plasma. Thiazides are eliminated rapidly by the kidney. After oral administration of 25 to 100 mg doses, 72-97% of the dose is excreted in the urine, indicating dose-independent absorption. Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life of 10-l 7 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9-30.0 Uhr; volume of distribution is 3.6-7.8 L/kg.
Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are considerably different in these patients.
Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed.
