Prinzide (Lisinopril and Hydrochlorothiazide)

PRINZIDE®

MSD

Lisinopril – Hydrochlorothiazide

Angiotensin Converting Enzyme Inhibitor – Diuretic

Action And Clinical Pharmacology: Prinzide combines the action of an angiotensin converting enzyme inhibitor, lisinopril, and a diuretic, hydrochlorothiazide.

Lisinopril: Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of 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 lisinopril plus a thiazide diuretic, there was essentially no change in serum potassium (see Precautions).

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

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

When lisinopril is given together with thiazide-type diuretics, its blood pressure lowering effect is approximately additive.

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

Pharmacodynamics: Administration of lisinopril to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure. In most patients studied, after oral administration of an individual dose of lisinopril, the onset of antihypertensive activity is seen 1 hour with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing. On occasion, achievement of optimal blood pressure reduction may require 2 to 4 weeks of therapy.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in 9 hypertensive patients, following administration of lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

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: Lisinopril: Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not bind to plasma proteins other than ACE.

Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the extent of absorption of lisinopril is approximately 25%, with large inter-subject variability (6 to 60%) at all doses tested (5 to 80 mg).

Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract.

Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.

In a study in elderly healthy subjects (65 years and above), a single dose of lisinopril 20 mg produced higher serum concentrations than those seen in young healthy adults given a similar dose. In another study, single daily doses of lisinopril 5 mg were given for 7 consecutive days to young and elderly healthy volunteers. Maximum serum concentrations of lisinopril on Day 7 were higher in the elderly volunteers than in the young.

The elimination of lisinopril in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With renal function £30 mL/min, peak and trough lisinopril levels increase, time to peak concentration increases and time to steady state may be prolonged (see Dosage).

Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.

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.

Lisinopril-Hydrochlorothiazide: Concomitant administration of lisinopril 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.

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

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

Lisinopril 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.

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

Patients should be titrated on the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of Prinzide may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use 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 Prinzide should be discontinued as soon as possible (see Warnings, Pregnancy, and Information for the Patient).

Contra-Indications: Patients who are hypersensitive to any component of this product and 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 Prinzide. This may occur at any time during treatment. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema occurs, Prinzide 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, 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 lisinopril, 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, Prinzide 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 lisinopril 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 lisinopril 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 lisinopril 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/or serum bilirubin have occurred during therapy with lisinopril 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 Prinzide 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 Prinzide should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Prinzide 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, Prinzide should be discontinued as soon as possible.

In rare cases (probably less than once in every thousand pregnancies) 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, then Prinzide should be discontinued unless it is considered lifesaving for the mother. A non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending on 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.

Lisinopril 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: Lisinopril was not teratogenic in mice treated on days 6 to 15 of gestation with up to 1 000 mg/kg/day (625 times the maximum recommended human dose). There was an increase in fetal resorptions at doses down to 100 mg/kg; at doses of 1 000 mg/kg, this was prevented by saline supplementation. There was no fetotoxicity or teratogenicity in rats treated with up to 300 mg/kg/day (188 times the maximum recommended dose) of lisinopril at days 6 to 17 of gestation. In rats receiving lisinopril from day 15 of gestation through day 21 postpartum, there was an increased incidence in pup deaths on days 2 to 7 postpartum and a lower average body weight of pups on day 21 postpartum. The increase in pup deaths and decrease in pup weight did not occur with maternal saline supplementation.

Lisinopril, at doses up to 1 mg/kg/day, was not teratogenic when given throughout the organogenic period in saline supplemented rabbits. Saline supplementation (physiologic saline in place of tap water) was used to eliminate maternotoxic effects and enable evaluation of the teratogenic potential at the highest possible dosage level. The rabbit has been shown to be extremely sensitive to angiotensin converting enzyme inhibitors (captopril and enalapril) with maternal and fetotoxic effects apparent at or below the recommended therapeutic dosage levels in man.

Fetotoxicity was demonstrated in rabbits by an increase incidence of fetal resorptions at an oral dose of lisinopril of 1 mg/kg/day and by an increased incidence of incomplete ossification at the lowest dose tested (0.1 mg/kg/day). A single i.v. dose of 15 mg/kg of lisinopril administered to pregnant rabbits on gestation days 16, 21 or 26 resulted in 88% to 100% fetal death.

By whole body autoradiography, radioactivity was found in the placenta following administration of labeled lisinopril to pregnant rats, but none was found in the fetuses.

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 Prinzide should include appropriate assessment of renal function.

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

Hyperkalemia: In clinical trials hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1.4% of hypertensive patients. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes (see Drug Interactions).

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, triglyceride and glucose levels may be associated with thiazide diuretic therapy.

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril 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 responsivenes to tubocurarine.

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

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

Lactation: Milk of lactating rats contains radioactivity following administration of 4 lisinopril.

It is not known whether lisinopril is secreted in human milk; however, thiazides do appear in human milk. If the use of Prinzide is deemed essential, the patient should stop nursing.

Geriatrics: In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of lisinopril. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution.

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

Anaphylactoid Reactions during Hymenoptera Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, 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.

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 lisinopril. The possibility of hypotensive effects with lisinopril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with lisinopril (see Warnings and Dosage).

Agents Increasing Serum Potassium: Since lisinopril 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 with 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 Prinzide 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. Beta-adrenergic blocking drugs add some further antihypertensive effect to lisinopril.

Indomethacin: Indomethacin may diminish the antihypertensive efficacy of concomitantly administered lisinopril.

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 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 Prinzide 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 Prinzide. 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 Prinzide 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 Prinzide 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 930 patients, including 100 patients treated for 50 weeks or more, the most severe clinical adverse reactions were syncope (0.8%) and hypotension (1.9%). The most frequent clinical adverse reactions were: dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%) and orthostatic effects (3.2%).

Discontinuation of treatment due to adverse reactions occurred in 4.4% of patients, mainly because of dizziness, cough, fatigue or muscle cramps.

Adverse reactions that have occurred in clinical trials or in marketing experience are those which have been previously reported with lisinopril and hydrochlorothiazide when used separately for the treatment of hypertension.

Laboratory Test Findings: Hypokalemia, Hyperkalemia: See Precautions.

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (3.8%) and serum creatinine (4.2%) were observed in patients with essential hypertension treated with Prinzide. More marked increases have also been reported and were more likely to occur in patients with bilateral renal artery stenosis (see Precautions).

Increases in blood urea nitrogen and serum creatinine, usually reversible upon discontinuation of therapy, were observed in 1.1 and 1.6% of patients respectively with essential hypertension treated with lisinopril alone.

Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: See Precautions.

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.5 g % and 1.5 vol %, respectively) occurred frequently in hypertensive patients treated with Prinzide but were rarely of clinical importance unless another cause of anemia coexisted. In clinical trials, 0.4% of patients discontinued therapy due to anemia.

Other (Causal Relationship Unknown): Rarely, elevations of liver enzymes and/or serum bilirubin have occurred.

Adverse Reactions Reported in Uncontrolled Trials and/or Marketing Experience: Prinivil: Cardiovascular: Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients (see Warnings), tachycardia.

Dermatologic: allopecia, urticaria, diaphoresis, pemphigus, Stevens-Johnson syndrome.

Gastrointestinal: abdominal pain, dry mouth, pancreatitis.

Hematologic: hemolytic anemia.

Hepatic: liver function abnormalities, hepatitis, jaundice (hepatocellular and/or cholestatic).

Nervous System: mood alterations, mental confusion.

Respiratory: bronchospasm.

Special Senses: taste disorder.

Urogenital: uremia, oliguria/anuria, renal dysfunction, acute renal failure, impotence.

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may also occur.

Prinzide (Marketing Experience Only): Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see Warnings).

Cases of pancreatitis have been reported.

No other adverse events have been reported with Prinzide which have not been reported with lisinopril or hydrochlorothiazide individually.

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

Lisinopril: The most likely feature of overdosage would be hypotension, for which the usual treatment would be i.v. infusion of normal saline solution. Lisinopril may be removed from general circulation by hemodialysis.

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 Prinzide should be determined by the titration of the individual components.

Once the patient has been successfully titrated with the individual components as described below, either 1 Prinzide 10/12.5 mg or, 1 or 2 20/12.5 mg or 20/25 mg tablets once daily may be substituted if the titrated doses are the same as those in 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 antihypertensive agents.

For lisinopril monotherapy the recommended initial dose in patients not on diuretics is 10 mg of lisinopril once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range of lisinopril is 10 to 40 mg administered in a single daily dose. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. The maximum dose used in long-term controlled clinical trials was 80 mg/day. If blood pressure is not controlled with lisinopril alone, a low dose of a diuretic may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.

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

If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril alone should be administered and the patient remain under medical supervision for at least 2 hours, and until blood pressure has stabilized for at least an additional hour (see Warnings and Precautions, Drug Interactions).

Dosage Adjustment in Renal Impairment: In patients with creatinine clearance greater than 30 mL/min. the usual dose titration of the individual components is required.

For patients with creatinine clearance between 10 and 30 mL/min, the starting dose of lisinopril is 2.5 to 5 mg/day. The dosage may then be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

When concomitant diuretic therapy is required in patients with moderate to severe renal impairment (creatinine clearance

Availability And Storage: 10 mg/12.5 mg: Each blue, hexagon-shaped, bi-convex tablet, coded MSD 145 on one side and PRINZIDE on the other, contains: lisinopril 10 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, indigotine on aluminum substrate, magnesium stearate and mannitol. Bottles of 100 and blister packages of 30.

20 mg/12.5 mg: Each yellow, round, fluted-edge tablet, coded MSD 140 on one side and PRINZIDE on the other, contains: lisinopril 20 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, iron oxide, magnesium stearate and mannitol. Bottles of 100.

20 mg/25 mg: Each orange, round, fluted-edge tablet, coded MSD 142 on one side and PRINZIDE on the other, contains: lisinopril 20 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, iron oxide, magnesium stearate and mannitol. Bottles of 100.

Store at controlled room temperature (15 to 30°C). Protect from moisture. (Shown in Product Recognition Section)

PRINZIDE® MSD Lisinopril – Hydrochlorothiazide Angiotensin Converting Enzyme Inhibitor – Diuretic 

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