Lisinopril and Hydrochlorothiazide

INDICATIONS AND USAGE Lisinopril and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including lisinopril and hydrochlorothiazide. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND ADMINISTRATION ). In using lisinopril and hydrochlorothiazide tablets, 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 WARNINGS .) In considering use of lisinopril and hydrochlorothiazide tablets, it should be noted that Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-Black. (See WARNINGS, Head and Neck Angioedema .)

DOSAGE AND ADMINISTRATION Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10 mg to 80 mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5 mg to 50 mg per day. In clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10 mg to 80 mg and hydrochlorothiazide doses of 6.25 mg to 50 mg, the antihypertensive response rates generally increased with increasing dose of either component. The side effects (see WARNINGS ) 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 lisinopril and hydrochlorothiazide tablets 10-12.5 or lisinopril and hydrochlorothiazide tablets 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 lisinopril and hydrochlorothiazide tablets 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 lisinopril and hydrochlorothiazide tablets need not be adjusted as long as the patient's creatinine clearance is greater than 30 mL/min/1.73 m 2 (serum creatinine approximately less than or equal to 3 mg/dL or 265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so lisinopril and hydrochlorothiazide tablets are not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure ).

WARNINGS 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 lisinopril and hydrochlorothiazide tablets) 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 lisinopril and hydrochlorothiazide tablets 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 (See ADVERSE 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 also INDICATIONS AND USAGE and CONTRAINDICATIONS ). Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema (see PRECAUTIONS ). Intestinal Angioedema : Intestinal angioedema has been reported in patients 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 hymenoptera venom while receiving ACE inhibitors sustained 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: Sudden and potentially life-threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension and Related Effects Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of lisinopril use in salt/volume-depleted persons such a…

CONTRAINDICATIONS Lisinopril and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Lisinopril and hydrochlorothiazide tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer lisinopril and hydrochlorothiazide tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS ). Do not coadminister aliskiren with lisinopril and hydrochlorothiazide tablets in patients with diabetes.

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 WARNINGS , and DOSAGE AND ADMINISTRATION .) When a diuretic is added to the therapy of a patient receiving lisinopril, an additional antihypertensive effect is usually observed (See DOSAGE AND ADMINISTRATION .) Non-steroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 (COX-2) Inhibitors: In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including lisinopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving lisinopril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs. Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors (such as aliskiren) is associated with increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. The VA NEPHRON trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 ml/min), randomized them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of losartan and lisinopril did not obtain any additional benefit compared to monotherapy for the combined endpoint of decline in GFR, end state renal disease, or death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group. In general, avoid combined use of RAS inhibitors. Monitor blood pressure, renal function, and electrolytes in patients on lisinopril and hydrochlorothiazide tablets and other agents that affect the RAS. Do not coadminister aliskiren with lisinopril and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with PRINZIDE in patients with renal impairment (GFR <60 ml/min). 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, includ…

Nursing Mothers It is not known whether lisinopril is excreted in human milk. However, milk of lactating rats contains radioactivity following administration of 14 C 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 lisinopril and hydrochlorothiazide tablets, taking into account the importance of the drug to the mother.

ADVERSE REACTIONS Lisinopril and hydrochlorothiazide tablets have been evaluated for safety in 930 patients including 100 patients treated for 50 weeks or more. In clinical trials with lisinopril and hydrochlorothiazide tablets 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 tablets were: dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%) and orthostatic effects (3.2%) all of which were more common than in placebo-treated patients. Generally, adverse experiences were mild and transient in nature; but see WARNINGS regarding angioedema and excessive hypotension or syncope. Discontinuation of therapy due to adverse effects was required in 4.4% of patients principally because of dizziness, cough, fatigue and muscle cramps. Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus hydrochlorothiazide in controlled clinical trials are shown below. Percent of Patients in Controlled Studies Clinical adverse experiences occurring in 0.3% to 1.0% of patients in controlled trials included: 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 Diarrhea 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 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 WARNINGS ). Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (1.4 percent), orthostatic hypotension (0.5 percent), other orthostatic effects (3.2 percent). In addition syncope occurred in 0.8 percent of patients (See WARNINGS ). Cough: See PRECAUTIONS - Cough . Clinical Laboratory Test Findings Serum Electrolytes: (See PRECAUTIONS ). Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum creatinine were observed in patients with essential hypertension treated with lisinopril and hydrochlorothiazide tablets. More marked increases have also been reported and were more likely to occur in patients with renal artery stenosis (See PRECAUTIONS ). Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (See PRECAUTIONS ). Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mea…