Lotensin (Tablets) Instructions for Use

ATC Code

C09AA07 (Benazepril)

Active Substance

Benazepril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE blocker

Pharmacological Action

ACE inhibitor. Lotensin (benazepril hydrochloride) is a prodrug that, after hydrolysis, is converted into the active metabolite, benazeprilat, which inhibits ACE and thus blocks the conversion of angiotensin I to angiotensin II.

This reduces the vasoconstrictive effect of angiotensin II and its stimulating effect on the production of aldosterone, which promotes the reabsorption of sodium and water in the renal tubules and also increases cardiac output. Lotensin reduces peripheral vascular resistance and cardiac afterload.

Due to its venodilatory action, Lotensin also reduces cardiac preload. During the use of Lotensin, no reflex increase in heart rate in response to a decrease in total peripheral resistance is observed.

After a single dose of Lotensin, the hypotensive effect is noted after 1 hour, reaches a maximum after 2-4 hours, and lasts up to 24 hours. With systematic use, a persistent decrease in blood pressure is noted after 1 week.

The severity of the hypotensive effect does not depend on age, race, or baseline plasma renin activity. Sudden withdrawal of the drug does not cause a sharp increase in blood pressure.

In patients with chronic heart failure, the addition of Lotensin to standard therapy led to an increase in cardiac output, improved exercise tolerance, decreased pulmonary capillary wedge pressure, systemic blood pressure, and reduced symptoms of heart failure.

In patients with impaired renal function (creatinine clearance 30-60 ml/min), with kidney diseases of various origins, long-term treatment with Lotensin led to a reduction in proteinuria and a 53% decrease in the risk of further deterioration of renal function.

Pharmacokinetics

Absorption

At least 37% of the orally administered dose of benazepril hydrochloride is absorbed from the gastrointestinal tract. The prodrug is rapidly converted into the pharmacologically active metabolite, benazeprilat.

After taking benazepril hydrochloride on an empty stomach, the C_max of benazepril and benazeprilat in blood plasma is reached after 30 and 60-90 minutes, respectively.

After oral administration of benazepril hydrochloride, the bioavailability of the metabolite, benazeprilat, is about 28%. Taking the tablets after a meal slows down absorption, but the amount of benazepril absorbed and converted to benazeprilat does not change.

Therefore, benazepril hydrochloride can be taken either with food or on an empty stomach.

In the dose range from 5 mg to 20 mg, the AUC and C_max of benazepril and benazeprilat are approximately proportional to the dose size.

Small but statistically significant deviations from the proportional dose-dependence were noted when using a wider dose range of 2-80 mg. This may be explained by saturable binding of benazeprilat to ACE.

When using multiple doses of the drug (5-20 mg once daily), the pharmacokinetic parameters did not change. No accumulation of benazepril was noted. Benazeprilat accumulates only to a small extent; the AUC at steady-state is approximately 20% greater than after the first dose of the drug.

The T_1/2 of benazeprilat is 10-11 hours. Steady-state plasma concentration is reached after 2-3 days.

Distribution

About 95% of benazepril and benazeprilat bind to plasma proteins (mainly albumin). The degree of binding does not change with age. The V_d of benazeprilat at steady-state is about 9 L.

Metabolism

Benazepril is extensively metabolized. The main metabolite is benazeprilat. This conversion is believed to occur through enzymatic hydrolysis, mainly in the liver.

Two subsequent metabolites are acyl glucuronide conjugates of benazepril and benazeprilat.

Excretion

Benazeprilat is excreted by the kidneys and with bile; in patients with normal renal function, renal excretion predominates.

In urine, the amount of benazepril is less than 1%, and the amount of benazeprilat is about 20% of the drug dose. The elimination of benazepril from plasma ends after 4 hours.

The elimination of benazeprilat proceeds in two phases, the T_1/2 of the initial phase (α-phase) is about 3 hours, and the terminal phase (β-phase) is about 22 hours.

The presence of a terminal elimination phase indicates strong binding of benazeprilat to ACE.

Pharmacokinetics in Special Clinical Cases

In patients with arterial hypertension, the steady-state concentration of benazeprilat depends on the size of the daily dose of the drug.

In patients with chronic heart failure, the absorption of benazepril and its conversion to benazeprilat do not change.

Due to some slowing of the elimination of the active substance in this group of patients compared to healthy individuals or patients with arterial hypertension, the steady-state concentration of benazeprilat is somewhat higher.

The pharmacokinetic parameters of benazepril and benazeprilat in the elderly, in patients with mild or moderate renal impairment (creatinine clearance 30-80 ml/min), or with nephrotic syndrome do not change significantly.

In cases of impaired liver function (due to liver cirrhosis), the pharmacokinetic parameters of benazeprilat do not change, so in such patients there is no need to adjust the dosage regimen.

In severe renal failure (creatinine clearance <30 ml/min), the elimination of benazeprilat is slowed and, as a result, accumulation of the drug is possible; therefore, a dose reduction may be required.

Benazepril and benazeprilat are eliminated from plasma even in patients with end-stage renal disease; the pharmacokinetic parameters in these cases are the same as in patients with severe renal impairment.

Extrarenal clearance (e.g., metabolic or biliary excretion) partially compensates for the reduced renal clearance.

Regular hemodialysis initiated at least 2 hours after taking benazepril hydrochloride does not significantly change the plasma concentrations of benazepril and benazeprilat.

This means that there is no need to take an additional dose of the drug after hemodialysis. Hemodialysis removes only a very small amount of benazeprilat from the body.

The pharmacokinetics of benazepril hydrochloride do not change when used concomitantly with the following drugs: hydrochlorothiazide, furosemide, chlorthalidone, digoxin, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine.

In turn, the use of benazepril hydrochloride does not lead to significant changes in the pharmacokinetics of the aforementioned drugs.

Indications

• Arterial hypertension;
• Chronic heart failure (as part of combination therapy).

ICD codes

Dosage Regimen

Tablets

For arterial hypertension, the recommended initial dose for patients not receiving thiazide diuretics is 10 mg once daily. The dose can be increased to 20 mg/day.

The dose is adjusted based on blood pressure dynamics, usually at intervals of 1-2 weeks. In some patients, the antihypertensive effect may decrease by the end of this interval.

The total daily dose may subsequently be divided into 2 equal doses. The maximum daily dose of Lotensin in patients with arterial hypertension is 40 mg in 1 or 2 doses.

If monotherapy with Lotensin does not lead to sufficient blood pressure reduction, another antihypertensive drug may be additionally prescribed, for example, a thiazide diuretic or a calcium channel blocker (initially in a small dose).

If diuretic therapy is conducted before prescribing Lotensin, it should be discontinued 2-3 days before starting Lotensin, and then, if necessary, resumed.

To prevent excessive blood pressure reduction in cases where it is not possible to discontinue diuretic treatment, the initial dose of Lotensin should be reduced (to 5 mg instead of 10 mg).

For patients with creatinine clearance greater than 30 ml/min, Lotensin is prescribed at a standard dose.

For patients with creatinine clearance less than 30 ml/min, the initial dose is 5 mg. It can be increased to a maximum of 10 mg/day.

To achieve a pronounced reduction in blood pressure, combined administration with non-thiazide diuretics or another antihypertensive drug is recommended.

For chronic heart failure, the recommended initial dose is 2.5 mg once daily. To prevent the risk of a sharp decrease in blood pressure in response to the first dose of the drug (first-dose effect), the patient should be under close observation.

After 2-4 weeks, if the desired clinical response is not achieved, and provided the patient does not have clinically significant arterial hypotension or other unacceptable side effects, the drug dose can be increased to 5 mg/day (in one dose).

Depending on the clinical effect, the drug dose can be increased at appropriate intervals to 10 mg and, in extreme cases, to 20 mg/day (in one dose).

In most patients, taking the drug once daily is effective. In some patients, better results are achieved by taking the drug twice daily.

Controlled clinical studies have shown that patients with severe heart failure usually require lower doses of Lotensin than patients with mild to moderate heart failure.

The safety and efficacy of Lotensin in children have not currently been established.

Recommendations for the dosage regimen and precautions for elderly patients do not differ from those for adults.

Adverse Reactions

The frequency of occurrence is estimated as follows: very rare – <0.01%, rare – from ≥0.01% to <0.1%, uncommon – from ≥0.1% to <1%, common – from ≥1% to <10%, very common – ≥10%.

In general, Lotensin is well tolerated. Side effects that occur during the use of Lotensin and are characteristic of other ACE inhibitors are listed below.

From the cardiovascular system: common – palpitations, orthostatic hypotension; rare – clinically significant arterial hypotension, chest pain, angina pectoris, arrhythmias; very rare – myocardial infarction.

From the gastrointestinal tract: common – dyspeptic symptoms; rare – diarrhea, constipation, nausea, vomiting, abdominal pain; very rare – pancreatitis.

From the liver and biliary tract: rare – hepatitis (predominantly cholestatic), cholestatic jaundice.

Dermatological reactions: common – rash, facial flushing, itching, photosensitivity; rare – pemphigus; very rare – Stevens-Johnson syndrome.

From the urinary system: common – increased frequency of urination; rare – increased levels of blood urea nitrogen and serum creatinine; very rare – renal function disorders.

From the respiratory system: common – non-productive cough, which can lead to irritation of the pharynx and larynx and hoarseness of the voice.

From the central and peripheral nervous system: common – headache, dizziness, increased fatigue; rare – drowsiness, insomnia, increased nervous excitability, paresthesia.

From the hematopoietic system: very rare – hemolytic anemia, thrombocytopenia.

From the sensory organs: very rare – tinnitus, taste disturbances.

Allergic reactions: rare – angioedema, swelling of the lips and/or face.

From the musculoskeletal system: rare – arthralgia, arthritis, myalgia.

From laboratory parameters: in less than 0.1% of patients with essential hypertension receiving Lotensin as monotherapy, as well as during treatment with other ACE inhibitors, a slight increase in blood urea nitrogen and serum creatinine levels was observed, which resolved after discontinuation of treatment.

An increase in these parameters is more likely in patients with renal artery stenosis who are also receiving diuretics.

Contraindications

• History of angioedema during therapy with ACE inhibitors;
• Pregnancy;
• Lactation (breastfeeding);
• Hypersensitivity to benazepril and other components of the drug.

Use in Pregnancy and Lactation

Lotensin is contraindicated for use during pregnancy.

ACE inhibitors, when administered to pregnant women, can cause fetal and neonatal pathology and lead to their death. Several such cases have been reported in the world literature.

If pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.

The use of ACE inhibitors in the second and third trimesters of pregnancy was accompanied by the development of fetal and neonatal pathology, including arterial hypotension, skull hypoplasia in newborns, anuria, reversible and irreversible renal failure, and death.

Oligohydramnios has also been described, presumably due to impaired fetal renal function; oligohydramnios in such cases was accompanied by the development of limb joint contractures, craniofacial deformation, and lung hypoplasia in the fetus.

Furthermore, premature birth, delayed intrauterine fetal development, and premature closure of the ductus arteriosus have been reported, although in these cases the connection of the pathological phenomena with the use of ACE inhibitors is unclear.

It has been established that Benazepril and benazeprilat are excreted in breast milk, but their maximum concentration is 0.3% of the concentration in blood plasma.

The fraction of benazepril entering the systemic circulation of the infant should be insignificant. However, despite the very low probability of side effects in the breastfed child, the use of Lotensin during lactation (breastfeeding) is not recommended.

Use in Hepatic Impairment

In cases of impaired liver function (due to liver cirrhosis), the pharmacokinetic parameters of benazeprilat do not change, so in such patients there is no need to adjust the dosage regimen.

Rare cases of hepatitis (predominantly cholestatic) and isolated cases of acute liver failure, some of which were fatal, have been described in patients taking ACE inhibitors.

The mechanism of such complications is unclear. If jaundice occurs in patients taking ACE inhibitors or if there is a significant increase in serum liver enzyme levels, these drugs should be discontinued and the patient should be under close medical supervision.

Use in Renal Impairment

For patients with creatinine clearance greater than 30 ml/min, Lotensin is prescribed at a standard dose.

For patients with creatinine clearance less than 30 ml/min, the initial dose is 5 mg. It can be increased to a maximum of 10 mg/day.

To achieve a pronounced reduction in blood pressure, combined administration with non-thiazide diuretics or another antihypertensive drug is recommended.

Pediatric Use

The safety and efficacy of Lotensin in children have not currently been established.

Geriatric Use

Recommendations for the dosage regimen and precautions for elderly patients do not differ from those for adults.

Special Precautions

In patients taking ACE inhibitors (including Lotensin), due to their possible effect on the metabolism of eicosanoids and polypeptides, including bradykinin, serious side effects (including anaphylactoid and similar reactions) may develop.

In patients receiving ACE inhibitors, including Lotensin, the development of angioedema of the face, lips, tongue, vocal cords, and larynx has been reported.

In such cases, Lotensin should be discontinued immediately, appropriate treatment should be administered, and regular monitoring should be ensured until complaints and symptoms are completely and stably resolved.

In cases where the edema is limited to the face and lips, this complication usually resolves after the administration of antihistamines or even without treatment.

Angioedema involving the larynx can be fatal. In cases where the tongue, vocal cords, or larynx are involved, appropriate therapy should be immediately prescribed, including a subcutaneous injection of epinephrine 1:1000 (0.3-0.5 ml) and/or measures to ensure airway patency should be taken.

It has been reported that the frequency of angioedema during treatment with ACE inhibitors is higher in patients of African descent with black skin color.

In two patients undergoing desensitizing therapy with hymenoptera venom during treatment with ACE inhibitors, life-threatening anaphylactoid reactions developed.

In these same patients, such reactions were avoided after preliminary temporary discontinuation of ACE inhibitors, but when treatment was mistakenly resumed, anaphylactoid reactions occurred again.

The development of anaphylactoid reactions has been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes.

The development of anaphylactoid reactions has also been reported in patients undergoing LDL apheresis using dextran sulfate for adsorption.

In rare cases, as with treatment with other ACE inhibitors, clinically significant arterial hypotension has been described, usually developing in patients with reduced blood volume or low blood sodium levels due to long-term diuretic therapy, salt restriction in the diet, dialysis, diarrhea, or vomiting.

Before starting treatment with Lotensin, blood volume and/or blood sodium levels must be corrected. If arterial hypotension has already developed, the patient should be placed in a supine position and, if necessary, intravenous physiological saline should be administered.

Treatment with Lotensin can be resumed only after blood pressure and blood volume have normalized.

In patients with severe chronic heart failure, treatment with ACE inhibitors can be complicated by excessive arterial hypotension, which in some cases is accompanied by oliguria and/or azotemia, and (rarely) acute renal failure.

In such patients, treatment should be initiated under strict medical supervision; careful monitoring should continue during the first 2 weeks of treatment and each time the doses of Lotensin or diuretics are increased.

It has been established that another ACE inhibitor, captopril, can cause agranulocytosis and bone marrow suppression; these complications developed more frequently in patients with renal impairment, especially if they also had diffuse connective tissue diseases such as systemic lupus erythematosus or systemic sclerosis.

Currently, there are no reports of the development of such phenomena with the use of Lotensin. Nevertheless, for patients with diffuse connective tissue diseases, especially in cases of renal involvement, the need for regular monitoring of the white blood cell count in peripheral blood should be kept in mind.

In patients taking ACE inhibitors, rare cases of hepatitis (predominantly cholestatic) and isolated cases of acute liver failure, some of which were fatal, have been described. The mechanism of such complications is unclear. If jaundice occurs in patients taking ACE inhibitors or if there is a significant increase in serum liver enzyme levels, these drugs should be discontinued, and the patient should be under careful medical supervision.

In case of corresponding predisposition, patients may develop impaired renal function. In patients with severe chronic heart failure, renal function may depend on the activity of the renin-angiotensin-aldosterone system. Consequently, treatment with ACE inhibitors in these patients may be accompanied by the development of oliguria and/or progressive azotemia, as well as (rarely) acute renal failure. In a small study on arterial hypertension due to unilateral or bilateral renal artery stenosis, treatment with Lotensin was accompanied by a transient increase in serum urea nitrogen and creatinine levels; these abnormalities are reversible upon discontinuation of Lotensin or the diuretic, or both drugs. In such patients, renal function should be regularly monitored during the first few weeks of ACE inhibitor therapy. An increase in serum urea nitrogen and creatinine (usually slight and transient) developed in some patients with arterial hypertension without pre-existing renal vascular disease, especially in cases where Lotensin was used together with a diuretic. However, the development of such disorders is more likely in patients with pre-existing renal impairment. In such cases, a reduction in the dose of Lotensin and/or discontinuation of the diuretic may be required. Medical supervision of a patient with arterial hypertension should always include an assessment of renal function.

In patients taking ACE inhibitors, the development of a persistent non-productive cough has been reported, presumably due to the inhibition of endogenous bradykinin degradation. This type of cough always resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of this pathological condition.

Before surgery, the anesthesiologist should be informed that the patient is taking ACE inhibitors, because anesthetic agents that cause arterial hypotension may be used, leading to increased renin production. ACE inhibitors can block the secondary formation of angiotensin II due to a compensatory increase in renin secretion. Therefore, arterial hypotension arising through this mechanism should be corrected by increasing the circulating blood volume.

In rare cases, an increase in serum potassium levels has been observed during treatment with ACE inhibitors. In clinical trials for arterial hypertension, no cases of Lotensin discontinuation due to hyperkalemia were reported. Risk factors for the development of hyperkalemia include renal failure, diabetes mellitus, and the concomitant use of agents for correcting hypokalemia. Isolated cases of treatment discontinuation due to hyperkalemia were noted in one study that included patients with progressive chronic kidney diseases. In patients with progressive chronic kidney diseases, serum potassium levels should be monitored regularly.

As with the use of other vasodilators, special caution is required in patients with aortic orifice stenosis or mitral stenosis.

Use in Pediatrics

The safety and efficacy of Lotensin in children have not been currently established.

Effect on the Ability to Drive and Operate Machinery

As with the use of other antihypertensive agents, caution is recommended when driving vehicles and/or operating machinery.

Overdose

Although there are no data on Lotensin overdose, the main possible symptom is pronounced arterial hypotension.

Treatment: in case of recent drug intake, gastric lavage should be performed (induce vomiting). Although the active metabolite, benazeprilat, is dialyzed only to a small extent, this procedure may be indicated in case of overdose in patients with significantly impaired renal function, in order to maintain normal elimination. In case of pronounced arterial hypotension, intravenous infusion of isotonic sodium chloride solution is performed.

Drug Interactions

In cases where ACE inhibitor therapy is initiated in patients taking diuretics or in a state of dehydration, an excessive decrease in blood pressure may sometimes develop. The likelihood of arterial hypotension in such patients can be minimized by discontinuing diuretic therapy 2-3 days before starting treatment with Lotensin.

In patients receiving ACE inhibitors, the concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium preparations, or potassium-containing salt substitutes is not recommended, as this may lead to a significant increase in serum potassium concentration. If such a combination of drugs is deemed necessary, more frequent monitoring of serum potassium levels is recommended.

In patients receiving lithium preparations, cases of increased serum lithium levels and the occurrence of signs of lithium toxicity have been reported when ACE inhibitors were prescribed. These drugs should be used concomitantly with caution, and frequent determination of serum lithium levels is recommended. The risk of lithium toxic effects may increase if a diuretic drug is used concomitantly.

It has been shown that the hypotensive effect of ACE inhibitors may be reduced when used concomitantly with indomethacin. In controlled clinical trials, indomethacin did not affect the antihypertensive effect of Lotensin.

Storage Conditions

The drug should be stored in the original packaging, in a place inaccessible to children, at a temperature not exceeding 30°C (86°F); protect from moisture.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.