Lisinopril and Hydrochlorothiazide

INDICATIONS AND USAGE Lisinopril and hydrochlorothiazide tablets USP 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 (eg., 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 USP, 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 the use of lisinopril and hydrochlorothiazide tablets USP, it should be noted that ACE inhibitors have been associated with a higher rate of angioedema in black than in nonblack patients. (See WARNINGS , Lisinopril ).

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 per day 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 may be associated with either or both dose-independent or dose-dependent side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics. To minimize dose-dependent 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 /HCTZ 10 /12.5 or lisinopril/HCTZ 20 /12.5, depending on current monotherapy dose. Further increases of either or both components should depend on clinical response with blood pressure measured at the interdosing interval to ensure that there is an adequate antihypertensive effect at that time. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. After addition of the diuretic it may be possible to reduce the dose of lisinopril. 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 without electrolyte disturbance if they are switched to Lisinopril/HCTZ 10 /12.5. 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 two to three days before beginning therapy with lisinopril to reduce the likelihood of hypotension (See WARNINGS ). If the patient's blood pressure is not controlled with lisinopril alone, diuretic therapy may be resumed. If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (See WARNINGS and PRECAUTIONS , Drug Interactions ). Concomitant administration of lisinopril and hydrochlorothiazide with potassium supplements, potassium salt substitutes or potassium-sparing diuretics may lead to increases of serum potassium (See PRECAUTIONS ). Replacement Therapy The combination may be substituted for the titrated individual components. Use in Renal Impairment Regimens of therapy with lisinopril/HCTZ need not take account of renal function as long as the patient's creatinine clearance is >30 mL/min/1.7m 2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so lisinopril/HCTZ is not recommended (see WARNINGS, Anaphylactoid Reactions During Membrane Exposure) .

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) 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. Lisinopril and hydrochlorothiazide 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 (eg., 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 hypertensive patients but is a…

CONTRAINDICATIONS Lisinopril and hydrochlorothiazide is contraindicated in patients who are hypersensitive to 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 is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer Lisinopril and Hydrochlorothiazide tablets USP within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS ). Do not co-administer aliskiren with lisinopril and hydrochlorothiazide in patients with diabetes (see PRECAUTIONS, Drug Interactions ).

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 risks 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 30mL/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 and other agents that affect the RAS. Do not co-administer aliskiren with lisinopril and hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with lisinopril and hydrochlorothiazide 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, including ACE inh…

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 adverse reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a decision should be made whether to discontinue nursing and/or discontinue lisinopril and hydrochlorothiazide, taking into account the importance of the drug to the mother.

ADVERSE REACTIONS Lisinopril and hydrochlorothiazide have been evaluated for safety in 930 patients, including 100 patients treated for 50 weeks or more. In clinical trials with lisinopril and hydrochlorothiazide 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 - 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 Clinical 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. 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 but were rarely of clinical importance unless another cause of anemia c…