Lisinopril Side Effects

Brand Names: Prinivil, Zestril

Please note - some side effects for Lisinopril may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Lisinopril - for the consumer

Lisinopril

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Lisinopril:

Cough; diarrhea; dizziness; headache; tiredness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the hands, eyes, mouth, face, lips, or tongue; hoarseness); chest pain; dark urine; decreased urination; difficulty swallowing; infection (eg, fever, chills, persistent sore throat); irregular or slow heartbeat; stomach pain (with or without nausea or vomiting); symptoms of low blood pressure (eg, fainting, severe dizziness, lightheadedness); yellowing of the skin or eyes.

Lisinopril/Hydrochlorothiazide

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Lisinopril/Hydrochlorothiazide:

Dizziness; headache; lightheadedness; nausea; persistent nonproductive cough; tiredness; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain or discomfort; confusion; dark urine; fainting; fast, slow, or irregular heartbeat; increased thirst; joint pain, stiffness, or swelling; muscle cramps or weakness; numbness or tingling of hands or feet; persistent and unusual stomach pain; persistent sore throat or fever; red, swollen, or blistered skin; severe dizziness or lightheadedness; shortness of breath; sudden unusual weight loss or gain; trouble swallowing; unusual bruising or bleeding; unusual or severe weakness or tiredness; vision changes; yellowing of the skin or eyes.

For the professional

Lisinopril

Lisinopril has been found to be generally well tolerated in controlled clinical trials involving 1969 patients with hypertension or heart failure. For the most part, adverse experiences were mild and transient.

Hypertension

In clinical trials in patients with hypertension treated with Lisinopril, discontinuation of therapy due to clinical adverse experiences occurred in 5.7% of patients. The overall frequency of adverse experiences could not be related to total daily dosage within the recommended therapeutic dosage range. For adverse experiences occurring in greater than 1% of patients with hypertension treated with Lisinopril or Lisinopril plus hydrochlorothiazide in controlled clinical trials, and more frequently with Lisinopril and/or Lisinopril plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below:

Chest pain and back pain were also seen, but were more common on placebo than Lisinopril.

Heart Failure

In patients with heart failure treated with Lisinopril for up to four years, discontinuation of therapy due to clinical adverse experiences occurred in 11% of patients. In controlled studies in patients with heart failure, therapy was discontinued in 8.1% of patients treated with Lisinopril for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks.

The following table lists those adverse experiences which occurred in greater than 1% of patients with heart failure treated with Lisinopril or placebo for up to 12 weeks in controlled clinical trials, and more frequently on Lisinopril than placebo.

Also observed at > 1% with Lisinopril but more frequent or as frequent on placebo than Lisinopril in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough and pruritus.

Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia, depression, chest sound abnormalities, and pulmonary edema were also seen in controlled clinical trials, but were more common on placebo than Lisinopril.

In the two-dose ATLAS trial in heart failure patients, withdrawals due to adverse events were not different between the low and high groups, either in total number of discontinuation (17 to 18%) or in rare specific events (< 1%). The following adverse events, mostly related to ACE inhibition, were reported more commonly in the high dose group:

Acute Myocardial Infarction

In the GISSI–3 trial, in patients treated with Lisinopril for six week following acute myocardial infarction, discontinuation of therapy occurred in 17.6% of patients.

Patients treated with Lisinopril had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking Lisinopril.

In the GISSI–3 trial, hypotension (9.7%), renal dysfunction (2%), cough (0.5%), post-infarction angina (0.3%), skin rash and generalized edema (0.01%), and angioedema (0.01%) resulted in withdrawal of treatment. In elderly patients treated with Lisinopril, discontinuation due to renal dysfunction was 4.2%.

Other clinical adverse experiences occurring in 0.3% to 1% of patients with hypertension or heart failure treated with Lisinopril in controlled trials and rarer, serious, possibly drug-related events reported in uncontrolled studies or marketing experience are listed below, and within each category, are in order of decreasing severity:

Anaphylactoid reactions, syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial edema, virus infection, fever, chills, malaise

Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients; pulmonary embolism and infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia and premature ventricular contractions), palpitations, transient ischemic attacks, paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema, vasculitis

Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry mouth

Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia

Diabetes mellitus

Weight loss, dehydration, fluid overload, gout, weight gain

Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported in post-marketing experience.

Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain, shoulder pain, arm pain, lumbago

Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability, and nervousness

Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, bronchospasm, asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, bronchitis, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea

Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema, flushing, diaphoresis, cutaneous pseudolymphoma. Other severe skin reactions have been reported rarely, including toxic epidermal necrolysis and Stevens-Johnson syndrome; causal relationship has not been established.

Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances

Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal dysfunction, pyelonephritis, dysuria, urinary tract infection, breast pain

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.

Angioedema has been reported in patients receiving Lisinopril (0.1%) 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 Lisinopril should be discontinued and appropriate therapy instituted immediately.

In rare cases, intestinal angioedema has been reported in postmarketing experience.

In hypertensive patients, hypotension occurred in 1.2% and syncope occurred in 0.1% of patients with an incidence higher in Black than in non-Black patients. Hypotension or syncope was a cause of discontinuation of therapy in 0.5% of hypertensive patients. In patients with heart failure, hypotension occurred in 5.3% and syncope occurred in 1.8% of patients. These adverse experiences were possibly dose-related and caused discontinuation of therapy in 1.8% of these patients in the symptomatic trials. In patients treated with Lisinopril for six weeks after acute myocardial infarction, hypotension (systolic blood pressure ≤ 100 mmHg) resulted in discontinuation of therapy in 9.7% of the patients.

See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

See PRECAUTIONS, Cough.

No relevant differences between the adverse experience profile for pediatric patients and that previously reported for adult patients were identified.

Clinical Laboratory Findings

Hyperkalemia, hyponatremia

Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 2% of patients with essential hypertension treated with Lisinopril alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis. Reversible minor increases in blood urea nitrogen and serum creatinine were observed in approximately 11.6% of patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.

Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.4 g% and 1.3 vol%, respectively) occurred frequently in patients treated with Lisinopril but were rarely of clinical importance in patients without some other cause of anemia. In clinical trials, less than 0.1% of patients discontinued therapy due to anemia. Hemolytic anemia has been reported; a causal relationship to Lisinopril cannot be excluded.

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

In hypertensive patients, 2% discontinued therapy due to laboratory adverse experiences, principally elevations in blood urea nitrogen (0.6%), serum creatinine (0.5%) and serum potassium (0.4%).

In the heart failure trials, 3.4% of patients discontinued therapy due to laboratory adverse experiences; 1.8% due to elevations in blood urea nitrogen and/or creatinine and 0.6% due to elevations in serum potassium.

In the myocardial infarction trial, 2% of patients receiving Lisinopril discontinued therapy due to renal dysfunction (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration); less than 1% of patients discontinued therapy due to other laboratory adverse experiences: 0.1% with hyperkalemia and less than 0.1% with hepatic enzyme alterations.

By body system

Cardiovascular side effects

Hypotension is most likely in patients who are sodium and intravascular volume depleted. In large studies, patients have reported "heart pounding" and chest pain, although the relationship to lisinopril is questionable.

A possible relationship between lisinopril use and a case of penile angioedema has been published. After six days of lisinopril therapy, a 74-year-old patient complained of penile "swelling". Lisinopril was suspected as the cause of the angioedema and was discontinued. The localized angioedema resolved within a few days following discontinuation.

Cardiovascular side effects have included hypotension (0.6% to 1.0% of patients) and angioneurotic edema (0.2% of patients). Angina pectoris, orthostatic hypotension, and palpitations are each reported in approximately 1% of patients. Patients with heart failure are more likely to experience hypotension. In one study the incidence of hypotension-related undesirable side effects was only 0.6% compared to 4% in patients with CHF.

Renal side effects

Renal side effects have included new (usually mild) or worsened renal insufficiency which has rarely developed during ACE inhibitor therapy. Patients with renal artery stenosis should not receive lisinopril or any other ACE inhibitor. Proteinuria has also been reported.

Patients with renal artery stenosis maintain glomerular filtration by efferent arteriolar vasoconstriction, which is blocked by lisinopril.

Although lisinopril may be associated with a rise in serum creatinine and BUN, GFR has been shown to remain unchanged or improve in most patients.

Nervous system side effects

Nervous system side effects have included dizziness in up to 13% and headache in up to 6% of patients. Paresthesias are reported in 1% of patients.

Respiratory side effects

Respiratory side effects have included a reversible dry cough in up to 3% of patients. Cough has appeared as common in women as men, but in some reviews women have reported cough more often than men. Other respiratory system side effects are limited to stridor secondary to hypersensitivity to lisinopril.

A retrospective study has revealed a significantly higher incidence of discontinuation of angiotensin converting enzyme inhibitor therapy due to cough among black patients compared with non-black patients (9.6% vs. 2.4%).

Several agents have been studied for treating cough with ACE inhibitors. No long term trials exist to allow a definitive treatment option. Cromolyn has the most data showing some benefit. Other agents studied include baclofen, theophylline, sulindac, and benzonatate.

Metabolic side effects

A rise in serum potassium is due to a mild reduction in serum aldosterone concentrations.

Metabolic side effects are unusual and have included a moderate, often clinically insignificant rise in serum potassium. Lisinopril and other ACE inhibitors appear to have a beneficial effect on plasma insulin levels. Cases of hypoglycemia have been reported in diabetic patients receiving ACE inhibitors when concurrently treated with oral antidiabetic agents or insulin.

Gastrointestinal side effects

Gastrointestinal side effects have included diarrhea (4%), nausea (3%), and vomiting (1%). Taste disturbances and constipation are reported in less than 1% of patients. Acute pancreatitis has been associated with lisinopril.

Hypersensitivity side effects

In at least two cases of lisinopril-associated angioedema of the face and neck, the affected patients did not have a history of reactive airways disease. Patients with intestinal angioedema generally present with abdominal pain (with or without nausea or vomiting) and in some cases there was no prior history of facial angioedema, and C-1 esterase levels were normal. These symptoms resolve after stopping the ACE inhibitor.

Hypersensitivity reactions to lisinopril, as with some other angiotensin converting enzyme (ACE) inhibitors, may be life-threatening. Angioedema occurs in approximately 0.2% of patients. Angioedema of the face, extremities, lips, tongue, glottis and/or pharynx have been reported rarely in patients receiving ACE inhibitors. Obstructive laryngeal and glossal angioedema due to lisinopril is a rare, but potentially fatal reaction. In addition, intestinal angioedema has been reported in patients treated with ACE inhibitors. It is recommended that any patient with dyspnea, dysphagia, or significant facial angioedema stop therapy immediately and avoid ACE inhibitor therapy in general.

Dermatologic side effects

Dermatologic side effects are rare. Reversible rash, alopecia, erythema, and pruritus are reported in 1% or less of patients. In addition, cutaneous pseudolymphoma has been reported.

Hematologic side effects

A 64-year-old woman with aortic insufficiency, coronary artery disease, and atrial fibrillation developed fever and anorexia associated with pancytopenia within seven days after starting furosemide, digoxin, warfarin, and lisinopril. She died despite intensive supportive measures. Autopsy revealed bone marrow aplasia and changes consistent with hepatorenal failure. There was no evidence of infection or autoantibody disease. At least one other (reversible) case has been reported.

Hematologic side effects, including neutropenia and fatal aplastic anemia, have rarely been associated with lisinopril or other ACE inhibitors. A case of Henoch-Schonlein purpura complicated by polyarthritis has been associated with lisinopril.

Psychiatric side effects

Psychiatric complications have rarely been attributed to use of ACE inhibitors, including memory impairment, confusion, somnolence, irritability, and nervousness. A single case of mania has been associated with the use of lisinopril in an elderly woman who had previously tolerated enalapril.

Although angiotensin converting enzymes are found in many areas of the central nervous system, the mechanism for ACE inhibitor-induced mania is unclear. They are lipophilic and are not known to cross the blood-brain barrier. ACE inhibitors have been shown to alter the metabolism of enkephalins and modulate cholinergic activity. Interestingly, one case of captopril-induced hallucinations was successfully treated with naloxone.

Hepatic side effects

Hepatic side effects associated with the use of ACE inhibitors have included a rare syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. Experts recommend discontinuation of therapy with this drug if jaundice or markedly elevated hepatic serum enzymes develop.

Endocrine side effects

Endocrine side effects including case reports indicating development of the syndrome of inappropriate secretion of antidiuretic hormone have been reported.

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