Side Effects of Zestoretic (lisinopril and hydrochlorothiazide)

Does Zestoretic (lisinopril and hydrochlorothiazide) cause side effects?

Zestoretic (lisinopril and hydrochlorothiazide) is a combination of an ACE inhibitor and a "water pill" (diuretic) used to treat high blood pressure (hypertension). 

Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Lisinopril is an ACE inhibitor and works by relaxing blood vessels so that blood can flow more easily. Hydrochlorothiazide is a diuretic that causes you to make more urine, which helps the body get rid of extra salt and water. 

Zestoretic is used when one drug is not controlling your blood pressure. It may also be used to treat heart failure.

Common side effects of Zestoretic include

Serious side effects of Zestoretic include

Drug interactions of Zestoretic include aliskiren, lithium, drugs that may increase the level of potassium in the blood (such as ARBs including losartan/valsartan, birth control pills containing drospirenone). 

Check the labels on all medicines (such as cough-and-cold products, diet aids, or NSAIDs such as ibuprofen, naproxen) because they may contain ingredients that could increase blood pressure or worsen heart failure. 

Zestoretic is not recommended for use during pregnancy due to the risk for harm to a fetus. Consult your doctor for more details. 

It is unknown if lisinopril passes into breast milk. Hydrochlorothiazide passes into breast milk, but is unlikely to harm a nursing infant. Consult your doctor before breastfeeding.

What are the important side effects of Zestoretic (lisinopril and hydrochlorothiazide)?

Common side effects of Zestoretic include

Serious side effects of Zestoretic include

  • fainting,
  • high potassium blood levels,
  • signs of infection,
  • change in the amount of urine,
  • decrease in vision,
  • eye pain,
  • loss of too much body water (dehydration) and salt/minerals, and
  •  liver problems.

Zestoretic (lisinopril and hydrochlorothiazide) side effects list for healthcare professionals

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 prescribing information 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.

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.

Cough: See prescribing information.

Clinical Laboratory Test Findings

Serum Electrolytes

See prescribing information.

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.

Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides And Calcium

See prescribing information.

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, elevations of liver enzymes and/or serum bilirubin have occurred.

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 Zestoretic. 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 Zestoretic:

Body as a Whole: Anaphylactoid 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 high risk patients, 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), gastritis, anorexia, flatulence, increased salivation;

Endocrine: Diabetes mellitus, inappropriate antidiuretic hormone secretion;

Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia have been reported in which a causal relationship to lisinopril can not 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: Ataxia, memory impairment, tremor, insomnia, stroke, nervousness, confusion, peripheral neuropathy (e.g., paresthesia, dysesthesia), spasm, hypersomnia, irritability; mood alterations (including depressive symptoms); hallucinations;

Respiratory: Malignant lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, bronchospasm, asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities;

Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema, psoriasis, rare cases of other severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson Syndrome (causal relationship has not been established);

Special Senses: Visual loss, diplopia, photophobia, taste alteration, olfactory disturbance;

Urogenital: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal dysfunction, 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, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in combination with these symptoms.

Hydrochlorothiazide

Body as a Whole: Weakness;

Digestive: Anorexia, gastric irritation, cramping, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialoadenitis, constipation;

Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia;

Musculoskeletal: Muscle spasm;

Nervous System/Psychiatric: Restlessness;

Renal: Renal failure, renal dysfunction, interstitial nephritis;

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.

What drugs interact with Zestoretic (lisinopril and hydrochlorothiazide)?

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. When a diuretic is added to the therapy of a patient receiving lisinopril, an additional antihypertensive effect is usually observed.

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-albuminto-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, 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 discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored frequently if lisinopril is administered concomitantly with lithium.

mTOR (mammalian Target Of Rapamycin) Inhibitors

Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Neprilysin Inhibitors

Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema.

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%, 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 Zestoretic.

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, potassium-sparing and thiazide diuretics. Therefore, when Zestoretic and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of Zestoretic is obtained.

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 Zestoretic.

Summary

Zestoretic (lisinopril and hydrochlorothiazide) is a combination of an ACE inhibitor and a "water pill" (diuretic) used to treat high blood pressure (hypertension). Common side effects of Zestoretic include dizziness, lightheadedness, tiredness, headache, and dry cough. Zestoretic is not recommended for use during pregnancy due to the risk for harm to a fetus. It is unknown if lisinopril passes into breast milk.

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Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.