Lisinopril and Hydrochlorothiazide 20 mg; 12.5 mg Tablet, 500-count — NDC 51407-565-05 (Billing 51407-0565-05)

WARNINGS 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 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 nonblack patients. In such cases Lisinopril and Hydrochlorothiazide Tablets should be promptly discontinued and the 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 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.

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 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: Thiazide-containing combination products are not recommended in patients with severe renal dysfunction. Sudden and potentially life-threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g., AN69 ® *) 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 hy… [Excerpted — this section continues on DailyMed.]

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 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 Lisinopril and Hydrochlorothiazide (n=930) Incidence (discontinuation) Placebo (n=207) Incidence Dizziness 7.5 (0.8)

1.9Headache 5.2 (0.3)

1.9Cough 3.9 (0.6)

1.0Fatigue 3.7 (0.4)

1.0Orthostatic Effects 3.2 (0.1)

1.0Diarrhea 2.5 (0.2)

2.4Nausea 2.2 (0.1)

2.4Upper Respiratory Infection 2.2 (0.0)

0.0Muscle Cramps 2.0 (0.4)

0.5Asthenia 1.8 (0.2)

1.0Paresthesia 1.5 (0.1)

0.0Hypotension 1.4 (0.3)

0.5Vomiting 1.4 (0.1)

0.5Dyspepsia 1.3 (0.0)

0.0Rash 1.2 (0.1)

0.5Impotence 1.2 (0.3)

0.0Clinical adverse experiences occurring in 0.3% to 1.0% of patients in controlled trials and rarer, serious, possibly drug-related events reported in marketing experience are listed below: 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, cutaneous pseudolymphoma. Special Senses: Blurred vision, tinnitus, otalgia. Urogenital: Urinary tract infection.

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see WARNINGS ). In rare cases, intestinal angioedema has been reported in post marketing experience. 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% 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 (mean decreases of approximately 0.5 g% and 1.5 vol%, respectively) occurred frequently in hypertensive patients treated with Lisinopril and Hydrochlorothiazide Tablets but were rarely of clinical importance unless another c… [Excerpted — this section continues on DailyMed.]

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 Inhibitors (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 aliskiren is associated with increased risk of hypotension, 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 mL/min 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, closely monitor blood pressure, renal function, and electrolytes in patients on Lisinopril and Hydrochlorothiazide Tablets and other agents that affect the RAS.

Do not co-administer aliskiren with Lisinopril and Hydrochlorothiazide Tablets in patients with diabetes. Avoid use of aliskiren with Lisinopril and Hydrochlorothiazide Tablets 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 eliminatio… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Lisinopril Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, 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-aldosterone system, 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 with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and 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 blood urea and 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 ( see DOSAGE AND ADMINISTRATION ). Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater 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.

Lisinopril and Hydrochlorothiazide Tablets should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium (see PRECAUTIONS, Drug Interactions ). Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, almost always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. 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, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. 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, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged… [Excerpted — this section continues on DailyMed.]