Zestoretic

INDICATIONS AND USAGE ZESTORETIC is 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 ZESTORETIC, 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 ZESTORETIC, 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 ZESTORETIC 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 ).

CONTRAINDICATIONS ZESTORETIC 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. ZESTORETIC is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer ZESTORETIC within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS ). Do not co-administer aliskiren with ZESTORETIC in patients with diabetes (see PRECAUTIONS, Drug Interactions ).

ADVERSE REACTIONS ZESTORETIC has been evaluated for safety in 930 patients including 100 patients treated for 50 weeks or more. In clinical trials with ZESTORETIC 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) 1.9 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 ZESTORETIC. 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 ZESTORETIC but were rarely of clinical importance unless another cause of anemia coexisted. In clinical trials, 0.4% of patients discontinued therapy due to anemia. Liver Function Tests: Rarely, el …

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 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 ZESTORETIC and other agents that affect the RAS. Do not co-administer aliskiren with ZESTORETIC in patients with diabetes. Avoid use of aliskiren with ZESTORETIC 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 inhibitors. Lithium toxicity was usually reversible upon discontinuatio …

DESCRIPTION ZESTORETIC ® (Lisinopril and Hydrochlorothiazide) combines an angiotensin converting enzyme inhibitor, lisinopril, and a diuretic, hydrochlorothiazide. Lisinopril, USP a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor. It is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C 21 H 31 N 3 O 5 . 2H 2 O and its structural formula is: Lisinopril, USP is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol. Hydrochlorothiazide, USP is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: Hydrochlorothiazide, USP is a white, or practically white, crystalline powder with a molecular weight of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. ZESTORETIC is available for oral use in three tablet combinations of lisinopril, USP with hydrochlorothiazide, USP: ZESTORETIC 10-12.5 containing 10 mg lisinopril, USP and 12.5 mg hydrochlorothiazide, USP; ZESTORETIC 20-12.5 containing 20 mg lisinopril, USP and 12.5 mg hydrochlorothiazide, USP; and, ZESTORETIC 20-25 containing 20 mg lisinopril, USP and 25 mg hydrochlorothiazide, USP. Inactive Ingredients: 10-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, corn starch, yellow ferric oxide. 20-12.5 Tablets - calcium phosphate, magnesium stearate, mannitol, corn starch. 20-25 Tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, corn starch, yellow ferric oxide.

OVERDOSAGE No specific information is available on the treatment of overdosage with ZESTORETIC. Treatment is symptomatic and supportive. Therapy with ZESTORETIC should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures. Lisinopril Following a single oral dose of 20 g/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 by hemodialysis (see WARNINGS , Anaphylactoid Reaction During Membrane Exposure ). Hydrochlorothiazide Oral administration of a single oral dose of 10 g/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.

HOW SUPPLIED ZESTORETIC 10-12.5 Tablets: Peach, round, biconvex, uncoated tablets identified with "141" debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 90 tablets (NDC 52427-435-90). ZESTORETIC 20-12.5 Tablets: White, round, biconvex, uncoated tablets identified with "142" debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 90 tablets (NDC 52427-436-90). ZESTORETIC 20-25 Tablets: Peach, round, biconvex, uncoated tablets identified with “145” debossed on one side and "ZESTORETIC" on the other side are supplied in bottles of 90 tablets (NDC 52427-437-90). Storage Store at controlled room temperature, 20°C to 25°C (68°F to 77°F) [see USP]. Protect from excessive light and humidity.