Information for the Patient
Prinzide
Pharmacology
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 (6-60%) at all doses tested (5-80 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 5.6-14.8 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
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).
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.
Precautions
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 (see also Precautions, Hyperkalemia).
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.
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: Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
The antihypertensive effect of lisinopril may be diminished with concomitant non-steroidal anti-inflammatory drug use. In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors, the co-administration of ACE inhibitors or angiotensin II receptor antagonists may result in further deterioration of renal function.
Therefore, when PRINZIDE and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired antihypertensive effect is obtained.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including lisinopril.
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.
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 dialyzed 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.
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 stop taking the medication and 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.
Nursing Mothers: Patients should be advised not to breast-feed while taking PRINZIDE , as it is possible that PRINZIDE passes into breast milk.
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.
Supplied
Each blue, hexagon-shaped tablets, engraved 145 on one side and plain 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.
Each yellow, hexagon-shaped tablets, engraved MSD 140 on one side and scored 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.
The splitting of PRINZIDE tablets is not advised. Store at controlled room temperature (15 to 30°C). Protect from moisture.
Contraindications
In patients who are hypersensitive to any component of this product; have a history of angioneurotic edema relating to previous treatment with an angiotensin-converting enzyme inhibitor; and have hereditary or idiopathic angioedema.
Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Warnings
The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, PRINZIDE should be discontinued as soon as possible.
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, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.
Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.
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, limited experience with those procedures has not been associated with significant clinical benefit.
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.
Animal Data: Lisinopril was not teratogenic in mice treated on days 6-15 of gestation with up to 1000 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 1000 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 6-17 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 2-7 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 increased 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.
Adverse Effects
abdominal pain and indigestion, dry mouth, pancreatitis, vomiting.
mood alterations, mental confusion, paresthesia, vertigo.
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.
Rarely, hemolytic anemia has been reported.
Agranulocytosis and bone marrow depression, manifested as anemia, thrombocytopenia or leukopenia, have been caused by angiotensin-converting enzyme inhibitors, including lisinopril. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded (see Warnings, Neutropenia/Agranulocytosis).
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:
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).
In very rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors, including lisinopril.
Cases of pancreatitis have been reported.
Endocrine: Syndrome of inappropriate antidiuretic hormone secretion (SIADH).
No other adverse events have been reported with PRINZIDE which have not been reported with lisinopril or hydrochlorothiazide individually.
erythema multiforme, pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous pseudolymphoma.
bronchospasm, rhinitis, sinusitis.
alopecia, urticaria, pruritus, diaphoresis.
Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported.
Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients (see Warnings), tachycardia.
liver function abnormalities, hepatitis, jaundice (hepatocellular and/or cholestatic), hepatic failure.
Overdose
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
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. The splitting of PRINZIDE tablets is not advised.
Once the patient has been successfully titrated with the individual components as described below, either one PRINZIDE 10 mg/12.5 mg or, one or two 20 mg/12.5 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 <30 mL/min), a loop diuretic, rather than a thiazide diuretic, is preferred for use with lisinopril. Therefore, for patients with moderate or severe renal dysfunction the lisinopril-hydrochlorothiazide combination tablet is not recommended (see Precautions, Renal Impairment—Anaphylactoid Reactions during Membrane Exposure).
