Vaseretic (Enalapril Maleate and Hydrochlorothiazide)

VASERETIC®

Frosst

Enalapril Maleate – Hydrochlorothiazide

Angiotensin Converting Enzyme Inhibitor – Diuretic

Action And Clinical Pharmacology: Vaseretic combines the action of an angiotensin converting enzyme inhibitor, enalapril maleate, and that of a diuretic, hydrochlorothiazide.

Enalapril Maleate: Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. After absorption, enalapril, a pro-drug, is hydrolyzed to enalaprilat, its active metabolite, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback to renin release) and decreased aldosterone secretion. Although the latter decrease is small, it results in a small increase in serum potassium. In patients treated with enalapril and a thiazide diuretic there was essentially no change in serum potassium (see Precautions).

ACE is identical to kininase II. Thus, enalapril may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of enalapril is unknown.

While the mechanism through which enalapril lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, enalapril also lowers blood pressure in patients with low-renin hypertension.

Administration of enalapril to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure. In most patients studied, after oral administration of an individual dose of enalapril, the onset of antihypertensive activity is seen at 1 hour with peak reduction of blood pressure achieved by 4 to 6 hours. At recommended doses, the antihypertensive effect has been shown to be maintained for at least 24 hours. In some patients the effect may diminish towards the end of the dosing interval (see Dosage). On occasion, achievement of optimal blood pressure reduction may require several weeks of therapy.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril, there was an increase in renal blood flow; glomerular filtration rate was usually unchanged.

The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black than in nonblack patients.

Hydrochlorothiazide: Hydrochlorothiazide is a diuretic and antihypertensive which interferes with the renal tubular mechanism of electrolyte reabsorption. It increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. While this compound is predominantly a saluretic agent, in vitro studies have shown that it has a carbonic anhydrase inhibitory action which seems to be relatively specific for the renal tubular mechanism. It does not appear to be concentrated in erythrocytes or the brain in sufficient amounts to influence the activity of carbonic anhydrase in those tissues.

Hydrochlorothiazide is useful in the treatment of hypertension. It may be used alone or as an adjunct to other antihypertensive drugs. Hydrochlorothiazide does not affect normal blood pressure. The mechanism of its antihypertensive action is not known. Lowering of the sodium content of arteriolar smooth muscle cells and diminished response to norepinephrine have been postulated.

Onset of the diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours.

Pharmacokinetics: Enalapril Maleate: Following oral administration, enalapril is rapidly absorbed with peak serum concentrations of enalapril occurring within 1 hour. Based on urinary recovery the extent of absorption of enalapril from enalapril maleate is approximately 60%.

Following absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor (which itself is poorly absorbed). Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril maleate. Excretion of enalapril maleate is primarily renal. Approximately 94% of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The absorption of enalapril is not influenced by the presence of food in the gastrointestinal tract.

Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. The plasma half-life is 5.6 to 14.8 hours when the plasma levels can be followed for at least 24 hours. At least 61% 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.

Enalapril Maleate – Hydrochlorothiazide: Concomitant administration of enalapril and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.

Pharmacodynamics: Enalapril Maleate: The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min (0.50 mL/s) or less. With renal function £30 mL/min (£0.50 mL/s), peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency (see Dosage). Enalaprilat is dialyzable at the rate of 62 mL/min (1.03 mL/s).

Studies in dogs indicate that enalapril crosses the blood brain barrier poorly, if at all; enalaprilat does not enter the brain.

Indications And Clinical Uses: In the treatment of essential hypertension in patients for whom this combination therapy is appropriate.

In using Vaseretic consideration should be given to the risk of angioedema (see Warnings).

Enalapril should normally be used in those patients in whom treatment with diuretic or beta blocker was found ineffective or has been associated with unacceptable adverse effects.

Vaseretic is not indicated for initial therapy. Patients in whom enalapril and diuretic are initiated simultaneously can develop symptomatic hypotension (see Precautions, Drug Interactions).

Patients should be titrated on individual drugs. If the fixed combination represents the dose and dosing frequency determined by this titration, the use of Vaseretic may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary it is advisable to use the individual drugs.

Pregnancy: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected Vaseretic should be discontinued as soon as possible (see Warnings: in Pregnancy, and Information for the Patient).

Contra-Indications: Patients who are hypersensitive to any component of this product and in patients with a history of angioneurotic edema relating to previous treatment with an angiotensin converting enzyme inhibitor. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Manufacturers’ Warnings In Clinical States: Angioedema: Angioedema has been reported in patients treated with Vaseretic. Angioedema associated with laryngeal edema and/or shock may be fatal. This may occur at any time during treatment. If angioedema occurs, Vaseretic should be promptly discontinued and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Where swelling is confined to the face, lips and mouth the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy such as s.c. epinephrine (0.5 mL 1:1 000) should be administered promptly when indicated.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in nonblack patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).

Hypotension: Symptomatic hypotension has occurred after administration of enalapril, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting. Therefore, Vaseretic should not be used to start therapy or when a dose change is needed. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see Adverse Effects). Because of the potential fall in blood pressure in these patients, therapy with enalapril should be started under very close medical supervision, usually in a hospital. Such patients should be followed closely for the first 2 weeks of treatment and whenever the dose of enalapril and/or hydrochlorothiazide is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death.

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an i.v. infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion.

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by angiotensin converting enzyme inhibitors. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to enalapril cannot be excluded. Current experience with the drug shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and renal disease.

Azotemia: Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued.

Patients with Impaired Liver Function: Hepatitis, jaundice (hepatocellular and/or cholestatic), elevations of liver enzymes and/serum bilirubin have occurred during therapy with enalapril in patients with or without pre-existing liver abnormalities (see Adverse Effects). In most cases the changes were reversed on discontinuation of the drug.

Should the patient receiving Vaseretic experience any unexplained symptoms (see Information for the Patient), particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of Vaseretic should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Enalapril should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

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.

Hypersensitivity Reactions: Sensitivity reactions to hydrochlorothiazide 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 in patients treated with hydrochlorothiazide.

Pregnancy: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, Vaseretic should be discontinued as soon as possible.

In rare cases (probably less than once in every thousand) in which no alternative to ACE inhibitor therapy will be found, the mothers should be apprised of the potential hazards to their fetuses. Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, Vaseretic should be discontinued unless it is considered life-saving for the mother. A nonstress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, experience with those procedures has been limited.

Enalapril has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit and may, theoretically, be removed by exchange transfusion, although there is no experience with the latter procedure.

Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

Animal Data: Maternal and fetal toxicity occurred in some rabbits given enalapril at doses of 1 mg/kg/day or more. Saline supplementation prevented the maternal and fetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day (50 times the maximum human dose). Enalapril was not teratogenic in rabbits.

There was no fetotoxicity or teratogenicity in rats treated with enalapril at doses up to 200 mg/kg/day (333 times the maximum human dose). Fetotoxicity expressed as a decrease in average fetal weight, occurred in rats given 1 200 mg/kg/day of enalapril, but did not occur when these animals were supplemented with saline. The drug crosses the placental barrier in rats and hamsters.

Precautions: Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of Vaseretic should include appropriate assessment of renal function.

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are inefffective at creatinine clearance values of 30 mL/min or below (i.e., moderate or severe renal insufficiency).

Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately 1% of hypertensive patients in clinical trials with enalapril alone. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28% of hypertensive patients. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (see Drug Interactions, Agents Increasing Serum Potassium).

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Metabolism: Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Thiazides have been shown to increase 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.

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril blocks angiotensin II formation, secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Thiazides may increase the responsiveness to tubocurarine.

Cough: A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of enalapril has been reported.

Such possibility should be considered as part of the differential diagnosis of the cough.

Lactation: Both enalapril and thiazides appear in human milk. In general, nursing hould be interrupted if Vaseretic is given to a nursing mother.

Children: Vaseretic has not been studied in children and, therefore, use in this age group is not recommended.

Anaphylactoid Reactions during Membrane Exposure: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g.: polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid Reactions during Desensitization: There have been isolated reports of patients experiencing life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bee, wasp) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions during LDL Apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Drug Interactions: Hypotension: Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril (see Warnings and Dosage).

Agents Increasing Serum Potassium: Since enalapril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution.

Agents Causing Renin Release: The antihypertensive effect of Vaseretic is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

Agents Affecting Sympathetic Activity: Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. b-adrenergic blocking drugs add some further antihypertensive effect to enalapril.

Lithium: Lithium generally should not be given with diuretics or ACE inhibitors. Diuretic agents and ACE inhibitors reduce the renal clearance of lithium and add a high risk of lithium toxicity.

d-tubocurarine: Thiazide drugs may increase the responsiveness to tubocurarine.

Insulin: Insulin requirements in diabetic patients treated with thiazide diuretics, may be increased. Diabetes mellitus which has been latent may become manifest during thiazide administration.

Alcohol, Barbiturates or Narcotics: In the presence of thiazide diuretics, potentiation of orthostatic hypotension may occur.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia may occur when given concomitantly with thiazide diuretics.

Pressor Amines (e.g., norepinephrine): In the presence of thiazide diuretics, possible decreased response to pressor amines may be seen but not sufficient to preclude their use.

Nonsteroidal Anti-inflammatory Drugs: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Vaseretic and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Information for the Patient: Angioedema: Angioedema, including laryngeal edema, may occur during treatment with Vaseretic. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.

Impaired Liver Function: Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include viral-like symptoms in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Pregnancy: Patients should be advised to report promptly to their physician if they become pregnant, since the use of Vaseretic during pregnancy can cause injury and even death of the developing fetus.

Note: As with many other drugs, certain advice to patients being treated with Vaseretic is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Adverse Reactions: In clinical trials involving 1 580 hypertensive patients, including over 300 patients treated for 1 year or more, the most severe adverse reactions were: angioedema (0.3%), syncope (1.3%) and renal failure (0.1%).

The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6%), headache (5.5%), fatigue (3.9%) and cough (3.5%).

Adverse experiences that have occurred, have been those that were previously reported with enalapril maleate or hydrochlorothiazide when used separately for the treatment of hypertension.

Laboratory Test Findings: Hyperkalemia: (see Precautions).

Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.6% of patients with essential hypertension treated with Vaseretic.

In patients treated with enalapril alone, increases in serum creatinine and BUN were reported in about 20% of patients with renovascular hypertension and in about 0.2% of patients with essential hypertension.

Hemoglobin and Hematocrit: Decreases in hemoglobin and hematocrit (mean approximately 0.34 g% and 1 vol% respectively) occurred frequently in hypertensive patients treated with enalapril but were rarely of clinical importance. In clinical trials, less than 0.1% of patients discontinued therapy due to anemia.

Others: Elevations of liver enzymes and/or serum bilirubin have occurred (see Warnings).

Adverse Reactions Reported in Uncontrolled Trials and/or Marketing Experience: Vasotec: The following occurred in an incidence of 0.5 to 1.0%: insomnia, impotence, renal dysfunction, renal failure and oliguria.

The following occurred at an incidence of

  • Cardiovascular: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Warnings). Cardiac arrest, pulmonary embolism, rhythm disturbances, angina pectoris;
  • Dermatologic: pemphigus, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrosis, urticaria, photosensitivity, alopecia;
  • Gastrointestinal: anorexia, ileus, pancreatitis, dyspepsia, constipation, stomatitis;
  • Hematologic: hemolytic anemia, neutropenia, thrombocytopenia, bone marrow depression;
  • Hepatic: liver function abnormalities, hepatitis (hepatocellular and/or cholestatic, hepatic failure, jaundice;
  • Nervous System/Psychiatric: vertigo, depression, confusion, ataxia;
  • Respiratory: bronchospasm/asthma, rhinorrhea, pulmonary infiltrates;
  • Other: flushing, tinnitus, hearing impairment, glossitis, blurred vision.

A symptom complex has been reported which may include fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur. These symptoms have disappeared after discontinuation of therapy.

Laboratory Test Findings: hyponatremia.

Vaseretic (Marketing Experience Only): arthralgia, asthenia, constipation, decreased libido, dry mouth, dyspepsia, flatulence, gout, hypotension, tachycardia, tinnitus, vertigo.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No specific information is available on the treatment of overdosage with Vaseretic. Treatment is symptomatic and supportive. Therapy with Vaseretic should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Enalaprilat may be removed from the general circulation by hemodialysis.

Enalapril Maleate: The most prominent feature of overdosage reported to date is marked hypotension, beginning some 6 hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Serum enalaprilat levels 100 times and 200 times higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril maleate, respectively.

Hydrochlorothiazide: 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.

Dosage And Administration: Dosage must be individualized. The fixed combination is not for initial therapy. The dose of Vaseretic should be determined by the titration of the individual components.

Once the patient has been successfully titrated with the individual components as described below, Vaseretic (1 or 2 tablets daily) may be substituted if the titrated doses and dosing schedule can be achieved by the fixed combination (see Indications and Warnings).

Patients usually do not require doses in excess of 50 mg of hydrochlorothiazide daily, particularly when combined with hypertensive agents. Therefore, since each tablet of Vaseretic includes 25 mg of hydrochlorothiazide, the daily dosage of Vaseretic should not exceed 2 tablets. If further blood pressure control is indicated, additional doses of enalapril or other nondiuretic, antihypertensive agents should be considered.

For enalapril monotherapy the recommended initial dose in patients not on diuretics is 5 mg of enalapril once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range of enalapril is 10 to 40 mg/day administered in a single dose or 2 divided doses. In some patients treated once daily, the antihypertensive effects may diminish toward the end of the dosing interval. In such patients an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with enalapril alone, a diuretic may be added. In the elderly the starting dose of enalapril should be 2.5 mg since some elderly patients may be more responsive to enalapril than younger patients.

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of enalapril. The diuretic should, if possible, be discontinued for 2 to 3 days before beginning therapy with enalapril to reduce the likelihood of hypotension (see Warnings). If the patient’s blood pressure is not controlled with enalapril alone, diuretic therapy may be resumed.

If the diuretic cannot be discontinued, an initial dose of 2.5 mg of enalapril should be used to determine whether excessive hypotension occurs.

In patients with mild to moderate renal impairment (creatinine clearance >30 mL/min.), the usual dose titration of the individual components is required. The recommended initial dose of enalapril maleate, when used alone in patients with mild renal impairment, is 5 mg. In patients with moderate renal impairment, the initial dose of enalapril, when used alone, is 2.5 mg.

When concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic, rather than a thiazide diuretic is preferred for use with enalapril. Therefore, for patients with severe renal dysfunction, Vaseretic is not recommended (see Precautions – Anaphylactoid Reactions during Membrane Exposure).

Availability And Storage: Each red, squared capsule-shaped, compressed tablet, engraved 720 on one side and VASERETIC on the other, contains: enalapril maleate 10 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, red ferric oxide and sodium bicarbonate. Blister packages of 30. Store at controlled room temperature (15 to 30°C). Keep container tightly closed. Protect from moisture.

VASERETIC® Frosst Enalapril Maleate – Hydrochlorothiazide Angiotensin Converting Enzyme Inhibitor – Diuretic

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