Prinzide

DESCRIPTION

PRINZIDE® (Lisinopril-Hydrochlorothiazide) combines anangiotensin converting enzymeinhibitor, lisinopril, and adiuretic, hydrochlorothiazide.

Lisinopril, a syntheticpeptidederivative, is an oral long-actingangiotensinconverting enzyme inhibitor. It is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C₂₁H₃₁N₃O₅•2H₂O and its structural formula is:

Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C₇H₈ClN₃O₄S₂and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.73, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

PRINZIDE is available for oral use in two tablet combinations of lisinopril with hydrochlorothiazide: PRINZIDE 10-12.5, containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide and PRINZIDE 20-12.5, containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide.

Inactive ingredients are calcium phosphate, magnesium stearate, mannitol, and starch. PRINZIDE 10-12.5 also contains FD&C Blue #2 aluminum lake. PRINZIDE 20-12.5 also contains iron oxide.

INDICATIONS

PRINZIDE is indicated for the treatment of hypertension.

These fixed-dose combinations are not indicated for initial therapy (seeDOSAGE AND ADMINISTRATION).

In using PRINZIDE, consideration should be given to the fact that an angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that lisinopril does not have a similar risk. (See警告．)

In considering use of PRINZIDE, it should be noted that Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-Blacks. (See警告,Head and Neck Angioedema．)

DOSAGE AND ADMINISTRATION

Lisinopril is an effective treatment of hypertension in once-daily doses of 10-80 mg, while hydrochlorothiazide is effective in doses of 12.5-50 mg. In clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates generally increased with increasing dose of either component.

The side effects (see警告) of lisinopril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of lisinopril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

Dose Titration Guided by Clinical Effect

A patient whose blood pressure is not adequately controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to PRINZIDE 10-12.5 or PRINZIDE 20-12.5. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve similar or greater blood pressure control with less potassium loss if they are switched to PRINZIDE 10-12.5. Dosage higher than lisinopril 80 mg and hydrochlorothiazide 50 mg should not be used.

Replacement Therapy

The combination may be substituted for the titrated individual components.

Use in Renal Impairment

The usual regimens of therapy with PRINZIDE need not be adjusted as long as the patient's creatinine clearance is > 30 mL/min/1.73 m² (serum creatinine approximately ≤ 3 mg/dL or 265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so PRINZIDE is not recommended (see警告,Anaphylactoid reactions during membrane exposure).

HOW SUPPLIED

No. 8439 — Tablets PRINZIDE 10-12.5, are blue, hexagon-shaped tablets with code 145 on one side and plain on the other side. Each tablet contains 10 mg of lisinopril and 12.5 mg of hydrochlorothiazide.

They are supplied as follows:

NDC0006-0145-58 unit of use bottles of 100.

No. 8247 — Tablets PRINZIDE 20-12.5, are yellow, hexagon-shaped tablets with code MSD/140 on one side and scored on the other side. Each tablet contains 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide. They are supplied as follows:

NDC0006-0140-58 unit of use bottles of 100.

Storage

Store at controlled room temperature, 15-30°C (59-86°F). Protect from excessive light and humidity. Dispense in a well-closed container, if product package is subdivided.

Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Manufactured by: Merck Sharp & Dohme LTD., Cramlington, Northumberland, UK NE23 3JU. Revised: 05/2012

SIDE EFFECTS

PRINZIDE has been evaluated for safety in 930 patients, including 100 patients treated for 50 weeks or more.

In clinical trials with PRINZIDE no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with lisinopril or hydrochlorothiazide.

The most frequent clinical adverse experiences in controlled trials (including open label extensions) with any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5 percent), headache (5.2 percent), cough (3.9 percent), fatigue (3.7 percent) and orthostatic effects (3.2 percent), all of which were more common than in placebo-treated patients. Generally, adverse experiences were mild and transient in nature; but see警告regarding angioedema and excessive hypotension or syncope. Discontinuation of therapy due to adverse effects was required in 4.4 percent of patients, principally because of dizziness, cough, fatigue and muscle cramps.

不良经历发生在大于1percent of patients treated with lisinopril plus hydrochlorothiazide in controlled clinical trials are shown below.

	Percent of Patients in Controlled Studies
	Lisinopril-Hydrochlorothiazide (n=930) Incidence (discontinuation)	Placebo (n=207) Incidence
Dizziness	7.5 (0.8)	1.9
Headache	5.2 (0.3)	1.9
Cough	3.9 (0.6)	1.0
Fatigue	3.7 (0.4)	1.0
Orthostatic Effects	3.2 (0.1)	1.0
腹泻	2.5 (0.2)	2.4
Nausea	2.2 (0.1)	2.4
Upper Respiratory Infection	2.2 (0.0)	0.0
Muscle Cramps	2.0 (0.4)	0.5
Asthenia	1.8 (0.2)	1.0
Paresthesia	1.5 (0.1)	0.0
Hypotension	1.4 (0.3)	0.5
Vomiting	1.4 (0.1)	0.5
Dyspepsia	1.3 (0.0)	0.0
Rash	1.2 (0.1)	0.5
Impotence	1.2 (0.3)	0.0

Clinical adverse experiences occurring in 0.3 to 1.0 percent of patients in controlled trials included:Body as a Whole:Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection.Cardiovascular:Palpitation, orthostatic hypotension. Digestive: Gastrointestinal cramps, dry mouth, constipation, heartburn.Musculoskeletal:Back pain, shoulder pain, knee pain, back strain, myalgia, foot pain.Nervous/Psychiatric:Decreased libido, vertigo, depression, somnolence.Respiratory:Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis, pharyngeal discomfort.Skin:Flushing, pruritus, skin inflammation, diaphoresis.Special Senses:Blurred vision, tinnitus, otalgia.Urogenital:Urinary tract infection.

Angioedema

Angioedema has been reported in patients receiving PRINZIDE, with an incidence higher in Black than in non-Black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with PRINZIDE should be discontinued and appropriate therapy instituted immediately. In rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including lisinopril. (See警告．)

Hypotension

In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (1.4), orthostatic hypotension (0.5), other orthostatic effects (3.2). In addition syncope occurred in 0.8 percent of patients. (See警告．)

Cough

SeePRECAUTIONS,Cough．

Clinical Laboratory Test Findings

Serum Electrolytes:SeePRECAUTIONS．

Creatinine, Blood Urea Nitrogen:Minor reversible increases in blood urea nitrogen and serum creatinine 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 renal artery stenosis. (SeePRECAUTIONS．)

Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium:SeePRECAUTIONS．Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.5 g percent and 1.5 vol percent, 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 percent of patients discontinued therapy due to anemia.

Liver Function Tests:Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see警告,Hepatic Failure).

Other adverse reactions that have been reported with the individual components are listed below

Lisinopril

In clinical trials adverse reactions which occurred with lisinopril were also seen with PRINZIDE. In addition, and since lisinopril has been marketed, the following adverse reactions have been reported with lisinopril and should be considered potential adverse reactions for PRINZIDE:Body as a Whole:Anaphylactoid reactions (see警告,Anaphylactoid and Possibly Related Reactions), malaise, edema, facial edema, pain, pelvic pain, flank pain, chills;Cardiovascular:Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in highrisk patients (see警告,Hypotension), pulmonary embolism and infarction, worsening of heart failure, arrhythmias (including tachycardia, ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia, and premature ventricular contractions), angina pectoris, transient ischemic attacks, paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema, vasculitis;Digestive:Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see警告,Hepatic Failure), gastritis, anorexia, flatulence, increased salivation;Endocrine:Diabetes mellitus, syndrome of inappropriate antidiuretic hormone secretion (SIADH);Hematologic:Rare cases of neutropenia, thrombocytopenia, and bone marrow depression have been reported. Hemolytic anemia has been reported; a causal relationship to lisinopril cannot be excluded;Metabolic:Gout, weight loss, dehydration, fluid overload, weight gain;Musculoskeletal:Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain, lumbago;Nervous System/Psychiatric:共济失调、记忆障碍、震颤、失眠、stroke, nervousness, confusion, peripheral neuropathy (e.g., paresthesia, dysesthesia), spasm, hypersomnia, irritability;Respiratory:Malignant lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities;Skin:荨麻疹、脱发、带状疱疹、photosensitivity, skin lesions, skin infections, pemphigus, erythema. Other severe skin reactions (including toxic epidermal necrolysis, Stevens- Johnson syndrome and cutaneous pseudolymphoma) have been reported rarely; causal relationship has not been established;Special Senses:Visual loss, diplopia, photophobia, taste disturbances;Urogenital:Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal dysfunction (seePRECAUTIONSandDOSAGE AND ADMINISTRATION), pyelonephritis, dysuria, breast pain.

Miscellaneous

A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash, and other dermatological manifestations.

Fetal/Neonatal Morbidity and Mortality

See警告,Pregnancy,Lisinopril,Fetal/Neonatal Morbidity and Mortality．

Hydrochlorothiazide

Body as a Whole:Weakness;Digestive:Anorexia, gastric irritation, cramping, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis, constipation;Hematologic:Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia;Musculoskeletal:Muscle spasm;Nervous System/Psychiatric:Restlessness;Renal:Renal failure, renal dysfunction, interstitial nephritis (see警告);Skin:Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia;Special Senses:Xanthopsia;Hypersensitivity:Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

DRUG INTERACTIONS

Lisinopril

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. If it is necessary to continue the diuretic, initiate therapy with lisinopril at a dose of 5 mg daily, and provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour. (See警告andDOSAGE AND ADMINISTRATION．) When a diuretic is added to the therapy of a patient receiving lisinopril, an additional antihypertensive effect is usually observed. (SeeDOSAGE AND ADMINISTRATION．)

Non-steroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 (COX-2) Inhibitors

Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the antihypertensive effect of ACE inhibitors, including lisinopril. This interaction should be given consideration in patients taking NSAIDs or selective COX-2 inhibitors concomitantly with ACE inhibitors.

In some patients with compromised renal function (e.g., elderly patients or patients who are volumedepleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors, may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible.

These interactions should be considered in patients taking NSAIDS including selective COX-2 inhibitors concomitantly with diuretics and angiotensin II antagonists or ACE inhibitors. Therefore, monitor effects on blood pressure and renal function when administering the combination, especially in the elderly.

Dual Blockade of the Renin-angiotensin-aldosterone System:

Dual blockade of the renin-angiotensinaldosterone system is associated with increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure). Closely monitor blood pressure, renal function, and electrolytes in patients on PRINZIDE and angiotensin II receptor antagonists.

Other Agents

Lisinopril has been used concomitantly with nitrates and/or digoxin without evidence of clinically significant adverse interactions. No meaningful clinically important pharmacokinetic interactions occurred when lisinopril was used concomitantly with propranolol, digoxin, or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of lisinopril.

Agents Increasing Serum Potassium

Lisinopril attenuates potassium loss caused by thiazide-type diuretics. Use of lisinopril with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated, because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium.

Lithium

Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored frequently if lisinopril is administered concomitantly with lithium.

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 PRINZIDE.

Hydrochlorothiazide

When administered concurrently the following drugs may interact with thiazide diuretics.

Alcohol, barbiturates, or narcotics —potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin) —dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs —additive effect or potentiation.

Cholestyramine and colestipol resins —Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, ACTH —intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine) —possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) —possible increased responsiveness to the muscle relaxant.

Lithium —should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with PRINZIDE.

Non-steroidal Anti-inflammatory Drugs —In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassiumsparing and thiazide diuretics. Therefore, when PRINZIDE and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of PRINZIDE is obtained.

警告

General

Lisinopril

Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including PRINZIDE) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including lisinopril. This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. In such cases PRINZIDE should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery.Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided. (SeeADVERSE REACTIONS．)

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

Intestinal Angioedema

肠道血管性水肿病人一直在报道s treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid reactions during desensitization

Two patients undergoing desensitizing treatment with hymenopteravenomwhile receivingACE inhibitorssustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during membrane exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-densitylipoproteinapheresiswith dextran sulfate absorption.

Hypotension and Related Effects

Excessivehypotensionwas rarely seen in uncomplicatedhypertensivepatients but is a possible consequence of lisinopril use in salt/volume-depleted persons, such as those treated vigorously with diuretics or patients ondialysis．(SeePRECAUTIONS:DRUG INTERACTIONSandADVERSE REACTIONS．)

Syncopehas been reported in 0.8 percent of patients receiving PRINZIDE. In patients withhypertensionreceiving lisinopril alone, the incidence of syncope was 0.1 percent. The overall incidence of syncope may be reduced by proper titration of the individual components. (SeePRECAUTIONS:DRUG INTERACTIONS,ADVERSE REACTIONSandDOSAGE AND ADMINISTRATION．)

In patients with severecongestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated witholiguriaand/or progressiveazotemia, and rarely withacute renal failureand/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of lisinopril and/or diuretic is increased. Similar considerations apply to patients with ischemic heart orcerebrovasculardisease in whom an excessive fall in blood pressure could result in a myocardialinfarctionorcerebrovascular accident．

If hypotension occurs, the patient should be placed insupineposition and, if necessary, receive an intravenous infusion of normalsaline．A transienthypotensiveresponse is not acontraindicationto further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion.

Neutropenia/Agranulocytosis

Another angiotensin converting enzyme inhibitor, captopril, has been shown to causeagranulocytosisandbone marrowdepression, rarely in uncomplicated patients but more frequently in patients with renal impairment, especially if they also have acollagenvasculardisease. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases ofneutropeniaand bone marrow depression in which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.

Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestaticjaundiceorhepatitisand progresses to fulminant hepaticnecrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Hydrochlorothiazide

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressiveliver disease, since minor alterations of fluid andelectrolytebalance may precipitate hepatic coma.

Sensitivity reactions may occur in patients with or without a history ofallergyor bronchialasthma．

The possibility of exacerbation or activation of systemiclupuserythematosus has been reported.

Lithiumgenerally should not be given with thiazides (seePRECAUTIONS:DRUG INTERACTIONS,Lisinopriland Hydrochlorothiazide).

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transientmyopiaand acuteangle-closure glaucoma．Symptoms include acute onset of decreasedvisual acuityorocularpain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closureglaucomacan lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if theintraocular pressureremains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide orpenicillinallergy.

Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal andneonatalmorbidity and death. Resultingoligohydramnioscan be associated with fetal lunghypoplasiaand skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue PRINZIDE as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure toantihypertensiveuse in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative therapy to drugs affecting the reninangiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amnioticenvironment．If oligohydramnios is observed, discontinue PRINZIDE, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to PRINZIDE for hypotension, oliguria, andhyperkalemia(seePRECAUTIONS,Pediatric Use).

Lisinopril-Hydrochlorothiazide

Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril in combination with 10 mg/kg/day of hydrochlorothiazide. This dose of lisinopril is 5 times (in mice) and 10 times (in rats) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis (mg/m²); the dose of hydrochlorothiazide is 0.9 times (in mice) and 1.8 times (in rats) the MRHDD. Maternal or fetotoxic effects were not seen in mice with the combination. In rats decreased maternal weight gain and decreased fetal weight occurred down to 3/10 mg/kg/day (the lowest dose tested). Associated with the decreased fetal weight was a delay in fetalossification．The decreased fetal weight and delay in fetal ossification were not seen in saline-supplemented animals given 90/10 mg/kg/day.

Noteratogeniceffects of lisinopril were seen in studies of pregnant mice, rats, and rabbits. On a body surface area basis, the doses used were up 55 times, 33 times, and 0.15 times, respectively, the MRHDD.

Hydrochlorothiazide

Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. These doses are more than 150 times the MRHDD on a body surface area basis. Thiazides cross the placental barrier and appear incordblood. There is a risk of fetal or neonatal jaundice,thrombocytopeniaand possibly other adverse reactions that have occurred in adults.

PRECAUTIONS

General

Lisinopril

Aortic Stenosis/Hypertrophic Cardiomyopathy

As with allvasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosteronesystem, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including lisinopril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

In hypertensive patients withunilateralorbilateralrenal arterystenosis, increases inblood urea nitrogenand serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of lisinopril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in bloodureaand serum creatinine, usually minor and transient, especially when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of lisinopril and/or discontinuation of the diuretic may be required.

Evaluation of the hypertensive patient should always include assessment of renal function.(SeeDOSAGE AND ADMINISTRATION．)

Hyperkalemia

In clinical trials hyperkalemia (serumpotassiumgreater than 5.7 mEq/L) occurred in approximately 1.4 percent of hypertensive patients treated with lisinopril plus hydrochlorothiazide. 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 include renal insufficiency,diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. PRINZIDE should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium. (SeePRECAUTIONS:DRUG INTERACTIONS．)

Cough

Presumably due to the inhibition of the degradation ofendogenousbradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in thedifferential diagnosisof cough.

Surgery/Anesthesia

In patients undergoing major surgery or duringanesthesiawith agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory rennin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hydrochlorothiazide

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: namely,hyponatremia, hypochloremicalkalosis, andhypokalemia．Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receivingparenteralfluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness,lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps,muscularfatigue, hypotension, oliguria,tachycardia, andgastrointestinaldisturbances such as nausea and vomiting.

Hypokalemia may develop, especially with briskdiuresis, when severecirrhosisis present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiacarrhythmiaand may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increasedventricularirritability). Because lisinopril reduces the production of aldosterone, concomitant therapy with lisinopril attenuates the diuretic-induced potassium loss (seePRECAUTIONS:DRUG INTERACTIONS,Agents Increasing Serum Potassium).

Although any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is lifethreatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemiamay occur or frankgoutmay be precipitated in certain patients receiving thiazide therapy.

In diabetic patients dosage adjustments ofinsulinor oralhypoglycemicagents may be required.Hyperglycemiamay occur with thiazide diuretics. Thuslatentdiabetesmellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result inhypomagnesemia．

噻嗪类可能会减少尿钙排泄。Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calciummetabolism．Markedhypercalcemiamay be evidence of hiddenhyperparathyroidism．Thiazides should be discontinued before carrying out tests for parathyroid function. Increases incholesteroland triglyceride levels may be associated with thiazide diuretic therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lisinopril-Hydrochlorothiazide

Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen test using Salmonella typhimurium (Ames test) orEscherichia coliwith or without metabolic activation or in a forward mutation assay using Chinese hamster lung cells. Lisinopril-hydrochlorothiazide did not produce DNA single strand breaks in anin vitroalkaline elution rat hepatocyte assay. In addition, it did not produce increases in chromosomal aberrations in anin vitrotest in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.

Lisinopril

There was no evidence of a tumorigenic effect when lisinopril was administered orally for 105 weeks to male and female rats at doses up to 90 mg/kg/day or for 92 weeks to male and female mice at doses up to 135 mg/kg/day. These doses are 10 times and 7 times, respectively, the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.

Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in anin vitroalkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in anin vitrotest in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.

There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface area basis).

Hydrochlorothiazide

两年的喂养小鼠和大鼠conducte研究d under the auspices of the National Toxicology Program (NTP) uncovered no evidence of acarcinogenicpotential of hydrochlorothiazide in female mice at doses of up to approximately 600 mg/kg/day (53 times the MRHDD when compared on a body surface area basis) or in male and female rats at doses of up to approximately 100 mg/kg/day (18 times the MRHDD when compared on a body surface area basis). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxicin vitroin the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethaltraitgene. Positive test results were obtained only in thein vitroCHO Sister Chromatid Exchange (clastogenicity) and in the MouseLymphoma细胞(诱变)化验,使用浓度of hydrochlorothiazide from 43 to 1300 μg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior toconceptionand throughout gestation. In mice and rats these doses are 9 times and 0.7 times, respectively, the MRHDD when compared on a body surface area basis.

Nursing Mothers

It is not known whether lisinopril is secreted in human milk. However, milk of lactating rats contains radioactivity following administration of 14C lisinopril. In another study, lisinopril was present in rat milk at levels similar to plasma levels in the dams. Thiazides do appear in human milk. Because of the potential for serious reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a decision should be made whether to discontinue nursing or to discontinue PRINZIDE, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to PRINZIDE:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renalperfusion．Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Lisinopril, which crosses the placenta, has been removed from neonatalcirculationbyperitoneal dialysiswith some clinical benefit, and theoretically may be removed by exchangetransfusion, although there is no experience with the latter procedure.

Geriatric Use

Clinical studies of PRINZIDE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In a multiple-dose pharmacokinetic study in elderly versus young hypertensive patients using the lisinopril/hydrochlorothiazide combination, area under the plasma concentration time curve (AUC) increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function. (SeeDOSAGE AND ADMINISTRATION．)

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 ofemesisand/orgastriclavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Lisinopril

Following a single oral dose of 20 mg/kg, no lethality occurred in rats and death occurred in one of 20 mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Lisinopril can be removed byhemodialysis．(See警告,Anaphylactoid reactions during membrane exposure．)

Hydrochlorothiazide

Oral administration of a single oral dose of 10 mg/kg to mice and rats was not lethal. 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.

CONTRAINDICATIONS

PRINZIDE is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history ofangioedemarelated to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary oridiopathicangioedema. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

CLINICAL PHARMACOLOGY

Lisinopril-Hydrochlorothiazide

As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of lisinopril blocks the reninangiotensin-aldosterone axis and tends to reverse the potassium loss associated with the diuretic.

In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril and hydrochlorothiazide was approximately additive. The PRINZIDE 10-12.5 combination worked equally well in Black and Caucasian patients. The PRINZIDE 20-12.5 and PRINZIDE 20-25 (a previously – marketed strength) combinations appeared somewhat less effective in Black patients, but relatively few Black patients were studied. In most patients, the antihypertensive effect of PRINZIDE was sustained for at least 24 hours.

In a randomized, controlled comparison, the mean antihypertensive effects of PRINZIDE 20-12.5 and PRINZIDE 20-25 were similar, suggesting that many patients who respond adequately to the latter combination may be controlled with PRINZIDE 20-12.5. (SeeDOSAGE AND ADMINISTRATION．)

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.

Lisinopril

Mechanism of Action

Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by theadrenal cortex．抑制ACE结果在降低等离子体giotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was less than 0.1 mEq/L; however, approximately 15 percent of patients had increases greater than 0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L. In the same study, patients treated with lisinopril plus a thiazide diuretic showed essentially no change in serum potassium. (SeePRECAUTIONS．)

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.

While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low-renin hypertension. Although lisinopril was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to lisinopril monotherapy than non-Black patients.

Pharmacokinetics and Metabolism

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 appear to be bound to other serum proteins.

Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large intersubject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food in thegastrointestinal tract．

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

Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and area under the plasma concentration time curve (AUC) than younger patients. (SeeDOSAGE AND ADMINISTRATION．) Lisinopril can be removed by hemodialysis.

Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. However, milk of lactating rats contains radioactivity following administration of 14C lisinopril. By whole bodyautoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.

Pharmacodynamics

Administration of lisinopril to patients with hypertension results in a reduction of supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomaticpostural hypotensionis usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients. (See警告．)

In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.

In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy.

At recommended single daily doses, antihypertensive effects have been maintained for at least 24 hours after dosing, although the effect at 24 hours was substantially smaller than the effect six hours after dosing.

The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure; nor with a significant overshoot of pretreatment blood pressure.

In hemodynamic studies in patients withessentialhypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change incardiac outputand in heart rate. In a study in nine 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.

In patients with renovascular hypertension lisinopril has been shown to be well tolerated and effective in controlling blood pressure (seePRECAUTIONS).

Hydrochlorothiazide

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure.

Hydrochlorothiazide is a diuretic and antihypertensive. It affects thedistalrenal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts.Natriuresismay be accompanied by some loss of potassium andbicarbonate．

After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours.

氢氯噻嗪不是代谢,但琳inated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

PATIENT INFORMATION

Angioedema

Angioedema, includinglaryngeal水肿,可能发生ny time during treatment with angiotensin converting enzyme inhibitors, including lisinopril. 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 swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Symptomatic Hypotension

Patients should be cautioned to reportlightheadednessespecially 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.

Hyperkalemia

Patients should be told not to use salt substitutes containing potassium without consulting 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.

Pregnancy

Female patients of childbearing age should be told about the consequences of exposure to PRINZIDE during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.