Side Effects of Vasotec (enalapril)

Vasotec (enalapril) is an angiotensin converting enzyme (ACE) inhibitor used to treat high blood pressure (hypertension). 

ACE is an enzyme in the body that causes the formation of angiotensin II. Angiotensin II causes the arteries in the body to narrow, thereby elevating blood pressure. 

ACE inhibitors, such as Vasotec, lower blood pressure by preventing the formation of angiotensin II thereby relaxing the arteries. ACE inhibitors also improve the effectiveness of the heart function in patients with heart failure by reducing the blood pressure that the heart must maintain. 

Common side effects of Vasotec include

• dry and persistent cough,
• abdominal pain,
• diarrhea,
• dizziness,
• fatigue,
• headache,
• loss of appetite,
• nausea and vomiting,
• chest pain,
• fainting,
• numbness or tingling in the hands or feet,
• rash, and
• a sore or swollen throat.

Serious side effects of Vasotec include

• liver dysfunction and skin yellowing (jaundice),
• reduced kidney function, and
• hypersensitivity (allergic) reactions and angioedema (swelling of face, lips, tongue, throat).

Drug interactions of Vasotec include diuretics, because the combination may cause excessive reduction in blood pressure.

• Stopping the diuretic or increasing salt intake prior to taking Vasotec may prevent excessive blood pressure reduction.
• Vasotec may increase potassium levels (hyperkalemia) in blood. Therefore, there is an increased risk of hyperkalemia when enalapril is given with potassium supplements or drugs that increase potassium levels (for example, spironolactone).
• There have been reports of increased lithium levels when lithium is used in combination with ACE inhibitors, which may lead to toxicity from lithium.
• There have been reports that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, and naproxen may reduce the effects of ACE inhibitors.
• Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and low blood pressure) may occur when injectable gold (sodium aurothiomalate), used in the treatment of rheumatoid arthritis, is combined with ACE inhibitors, including Vasotec. 

ACE inhibitors, including Vasotec, can be harmful to the fetus and should not be taken by pregnant women. ACE inhibitors, including Vasotec, should be avoided in breastfeeding mothers.

Enalapril is generally well tolerated, and side effects usually are mild and transient. A dry, persistent cough has been reported commonly with the use of ACE inhibitors. Coughing resolves after discontinuing the medication.

Other important side effects include:

• abdominal pain,
• diarrhea,
• dizziness,
• fatigue,
• headache,
• loss of appetite,
• nausea and vomiting,
• chest pain,
• fainting,
• numbness or tingling in the hands or feet,
• rash, and a
• sore or swollen throat.

In rare instances, liver dysfunction and skin yellowing (jaundice) have been reported with ACE inhibitors. In susceptible individuals ACE inhibitors may reduce kidney function. Enalapril may cause hypersensitivity (allergic) reactions and angioedema (swelling of face, lips, tongue, throat).

Vasotec has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. Vasotec has been found to be generally well tolerated in controlled clinical trials involving 2987 patients. For the most part, adverse experiences were mild and transient in nature.

In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with Vasotec reporting adverse experiences was comparable to placebo.

Hypertension

Adverse experiences occurring in greater than one percent of patients with hypertension treated with Vasotec in controlled clinical trials are shown below. In patients treated with Vasotec, the maximum duration of therapy was three years; in placebo-treated patients the maximum duration of therapy was 12 weeks.

Heart Failure

Adverse experiences occurring in greater than one percent of patients with heart failure treated with Vasotec are shown below. The incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year).

In the placebo treated patients, the incidences reported are from the controlled trials (maximum duration of therapy is 12 weeks). The percentage of patients with severe heart failure (NYHA Class IV) was 29 percent and 43 percent for patients treated with Vasotec and placebo, respectively.

Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity.

Body As A Whole

• Anaphylactoid reactions.

Cardiovascular

• Cardiac arrest;
• myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients;
• pulmonary embolism and infarction;
• pulmonary edema;
• rhythm disturbances including atrial tachycardia and bradycardia;
• atrial fibrillation;
• palpitation, Raynaud's phenomenon.

Digestive

• Ileus,
• pancreatitis,
• hepatic failure,
• hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice),
• melena,
• anorexia,
• dyspepsia,
• constipation,
• glossitis,
• stomatitis,
• dry mouth.

Hematologic

• Rare cases of neutropenia, thrombocytopenia and bone marrow depression.

Musculoskeletal

• Muscle cramps.

Nervous/Psychiatric

• Depression,
• confusion,
• ataxia,
• somnolence,
• insomnia,
• nervousness,
• peripheral neuropathy (e.g., paresthesia, dysesthesia),
• dream abnormality.

Respiratory

• Bronchospasm,
• rhinorrhea,
• sore throat and hoarseness,
• asthma,
• upper respiratory infection,
• pulmonary infiltrates,
• eosinophilic pneumonitis.

Skin

• Exfoliative dermatitis,
• toxic epidermal necrolysis,
• Stevens-Johnson syndrome,
• pemphigus,
• herpes zoster,
• erythema multiforme,
• urticaria,
• pruritus,
• alopecia,
• flushing,
• diaphoresis,
• photosensitivity.

Special Senses

• Blurred vision, ta
• ste alteration,
• anosmia,
• tinnitus,
• conjunctivitis,
• dry eyes,
• tearing.

Urogenital

• Renal failure,
• oliguria,
• renal dysfunction,
• flank pain,
• gynecomastia,
• impotence.

Miscellaneous

• A symptom complex has been reported which may include some or all of the following:
  • a positive ANA,
  • an elevated erythrocyte sedimentation rate,
  • arthralgia/arthritis,
  • myalgia/myositis,
  • fever,
  • serositis,
  • vasculitis,
  • leukocytosis,
  • eosinophilia,
  • photosensitivity,
  • rash and other dermatologic manifestations.

Angioedema

• Angioedema has been reported in patients receiving Vasotec, 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 Vasotec should be discontinued and appropriate therapy instituted immediately.

Hypotension

• In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients following the initial dose or during extended therapy.
• Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients.
• Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure.

Cough

• See prescribing information.

Pediatric Patients

• The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.

Clinical Laboratory Test Findings

Serum Electrolytes

• Hyperkalemia,
• hyponatremia.

Creatinine, Blood Urea Nitrogen

• In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with Vasotec alone.
• Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis.
• In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of Vasotec and/or other concomitant diuretic therapy, were observed in about 11 percent of patients.
• Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients.

Hematology

• Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with Vasotec but are rarely of clinical importance unless another cause of anemia coexists.
• In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia.
• Hemolytic anemia, including cases of hemolysis in patients with G6PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded.

Liver Function Tests

• Elevations of liver enzymes and/or serum bilirubin have occurred.

To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Neprilysin Inhibitors

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

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.
• Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy.
• In general, avoid combined use of RAS inhibitors.
• Closely monitor blood pressure, renal function, and electrolytes in patients on Vasotec and other agents that affect the RAS.
• Do not coadminister aliskiren with Vasotec in patients with diabetes. Avoid use of aliskiren with Vasotec in patients with renal impairment (GFR <60 mL/min).

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 enalapril.
• The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril.
• If it is necessary to continue the diuretic, 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.

Agents Causing Renin Release

• The antihypertensive effect of Vasotec is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

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, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure.
• These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy.
• In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving Vasotec. In this study there was no evidence of a blunting of the antihypertensive action of Vasotec. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors.

Other Cardiovascular Agents

• Vasotec has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions.

Agents Increasing Serum Potassium

• Vasotec attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, 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.
• Potassium-sparing agents should generally not be used in patients with heart failure receiving Vasotec.

Lithium

• Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors.
• A few cases of lithium toxicity have been reported in patients receiving concomitant Vasotec and lithium and were reversible upon discontinuation of both drugs.
• It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.

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 Vasotec.

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.