Listril^® Plus (Tablets) Instructions for Use

Marketing Authorization Holder

Torrent Pharmaceuticals, Ltd. (India)

Contact Information

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

C09BA03 (Lisinopril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Lisinopril (Rec.INN registered by WHO)

Dosage Form

Listril® Plus

Tablets 5 mg+12.5 mg: 30 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are white or almost white, round, biconvex, with an embossed heart shape on one side and a score line on the other.

Excipients: mannitol, pregelatinized starch, sodium phosphate dibasic, magnesium stearate, talc, starch (dry).

10 pcs. – blister strips (3) – cardboard packs.
10 pcs. – blister strips (10) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

Combined antihypertensive drug. It has antihypertensive and diuretic effects.

Lisinopril is an ACE inhibitor, it reduces the formation of angiotensin II from angiotensin I.

The decrease in angiotensin II levels leads to a direct reduction in aldosterone secretion. It reduces the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces total peripheral vascular resistance, blood pressure, preload, pulmonary capillary wedge pressure, causes an increase in cardiac output and improves exercise tolerance in patients with heart failure. It dilates arteries to a greater extent than veins.

Some effects are explained by the impact on tissue renin-angiotensin systems. With long-term use, it reduces hypertrophy of the myocardium and walls of resistive arteries. It improves blood supply to the ischemic myocardium. ACE inhibitors prolong the life expectancy of patients with chronic heart failure and slow the progression of left ventricular dysfunction in patients who have had a myocardial infarction without clinical manifestations of heart failure.

The onset of action is within 1 hour, the maximum effect is observed in 6-7 hours, and the duration is 24 hours. In arterial hypertension, the effect is noted in the first days after starting treatment, and a stable effect develops after 1-2 months.

Hydrochlorothiazide is a thiazide diuretic, whose action is associated with impaired reabsorption of sodium, chloride, potassium, magnesium ions and water in the distal nephron. It delays the excretion of calcium ions and uric acid. It has antihypertensive properties: the hypotensive effect develops due to the dilation of arterioles. It has almost no effect on normal blood pressure. The diuretic effect occurs within 1-2 hours, reaches a maximum in 4 hours, and lasts for 6-12 hours. The antihypertensive effect occurs in 3-4 days, but it may take 3-4 weeks to achieve the optimal therapeutic effect.

Lisinopril and Hydrochlorothiazide, when used simultaneously, have an additive antihypertensive effect.

Pharmacokinetics

Lisinopril

Absorption, Distribution, Metabolism

After oral administration, Lisinopril is slowly absorbed from the gastrointestinal tract. Absorption averages 30%. Lisinopril is a primarily active ACE inhibitor and is not metabolized in the liver. C_max in blood plasma is reached in approximately 7 hours. Plasma protein binding is insignificant – 5%.

Elimination

It is excreted unchanged in the urine. In patients with normal renal function, T_1/2 is 12 hours. Lisinopril is removed from the body by hemodialysis.

Hydrochlorothiazide

Absorption

After oral administration, 60-80% of hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract.

Elimination

About 95% of hydrochlorothiazide is excreted unchanged, almost entirely by the kidneys. T_1/2 is 5.6-14.8 hours. A small amount of the drug is excreted in the bile.

Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk.

Indications

• Arterial hypertension (in patients for whom combination therapy is indicated).

ICD codes

Dosage Regimen

The drug should be taken orally once a day.

For arterial hypertension, the dose of the drug is set individually. The recommended dose is 1-2 tablets once a day.

For renal failure (CrCl 30-80 ml/min), the drug can be used only after titrating the dose of each of the components of the drug separately. The recommended initial dose of lisinopril in uncomplicated renal failure is 5-10 mg.

In case of prior diuretic therapy, symptomatic arterial hypotension may occur after taking the initial dose of the drug. Such cases occur more often in patients with fluid and electrolyte loss due to previous treatment with diuretics. Therefore, diuretic intake should be discontinued 2-3 days before starting treatment with Listril Plus.

Adverse Reactions

In most patients, adverse events were mild and transient. The most common were: dizziness, headache.

Less common adverse events

From the cardiovascular system: marked decrease in blood pressure, chest pain; rarely – orthostatic hypotension, tachycardia, bradycardia, appearance of symptoms of heart failure, impaired AV conduction, myocardial infarction.

From the digestive system: nausea, vomiting, abdominal pain, dry mouth, diarrhea, dyspepsia, anorexia, taste disturbance, pancreatitis, hepatitis (hepatocellular and cholestatic), jaundice.

From the central and peripheral nervous system: mood lability, impaired concentration, paresthesia, increased fatigue, drowsiness, convulsive twitching of the muscles of the limbs and lips; rarely – asthenic syndrome, confusion.

From the respiratory system: dyspnea, bronchospasm, apnea.

From the urinary system: uremia, oliguria/anuria, impaired renal function, acute renal failure.

From the hematopoietic system: leukopenia, thrombocytopenia, neutropenia, agranulocytosis, anemia (decrease in hemoglobin, hematocrit, erythrocytopenia).

Allergic reactions: urticaria, photosensitivity, angioedema of the face, extremities, lips, tongue, glottis and/or larynx, skin rash, itching, fever, vasculitis, positive results for antinuclear antibodies, increased ESR, eosinophilia.

Laboratory parameters: hyperkalemia and/or hypokalemia, hyponatremia, hypomagnesemia, hypochloremia, hyperuricemia, hyperglycemia, increased levels of urea and creatinine; rarely – increased activity of liver transaminases, hyperbilirubinemia, hypercholesterolemia, hypertriglyceridemia, decreased glucose tolerance.

Other: dry cough, arthralgia, arthritis, myalgia, exacerbation of gout, decreased potency, sweating, alopecia, impaired fetal kidney development.

Contraindications

• Anuria;
• Severe renal failure (CrCl<30 ml/min);
• Angioedema (including history from the use of ACE inhibitors);
• Hemodialysis using high-flux membranes;
• Hypercalcemia;
• Hyponatremia;
• Porphyria;
• Precoma;
• Hepatic coma;
• Diabetes mellitus (severe forms);
• Pregnancy;
• Lactation period (breastfeeding);
• Childhood and adolescence under 18 years (efficacy and safety not established);
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other ACE inhibitors;
• Hypersensitivity to sulfonamide derivatives.

The drug should be used with caution in bilateral renal artery stenosis, aortic stenosis/hypertrophic cardiomyopathy, stenosis of the artery of a single kidney with progressive azotemia, condition after kidney transplantation, renal failure (CrCl>30 ml/min), primary hyperaldosteronism, arterial hypotension, bone marrow hypoplasia, hyponatremia (increased risk of arterial hypotension in patients on a low-salt or salt-free diet), conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), connective tissue diseases (including SLE, scleroderma), diabetes mellitus, gout, hyperuricemia, hyperkalemia, coronary artery disease, cerebrovascular insufficiency, severe chronic heart failure, hepatic insufficiency, in elderly patients.

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

The use of the drug is contraindicated in porphyria, precoma, hepatic coma.

The drug should be used with caution in hepatic insufficiency.

Use in Renal Impairment

The use of the drug is contraindicated in anuria, severe renal failure (CrCl<30 ml/min).

The drug should be used with caution in bilateral renal artery stenosis, stenosis of the artery of a single kidney with progressive azotemia, condition after kidney transplantation, renal failure (CrCl<30 ml/min).

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated (efficacy and safety have not been established).

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

Symptomatic hypotension

Marked decrease in blood pressure most often occurs with a decrease in circulating blood volume caused by diuretic therapy, reduced salt intake in the diet, dialysis, diarrhea, or vomiting.

In patients with chronic heart failure with/without renal failure, symptomatic arterial hypotension may develop. It is more often detected in patients with severe forms of heart failure due to the use of high doses of diuretics, hyponatremia, or impaired renal function. In such patients, treatment should be started under strict medical supervision.

Similar rules should be followed when prescribing the drug to patients with coronary artery disease and cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke.

A transient hypotensive reaction is not a contraindication for taking the next dose of the drug.

Impaired renal function

In patients with chronic renal failure, a marked decrease in blood pressure after starting treatment with ACE inhibitors may lead to a further deterioration in renal function.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney who received ACE inhibitors, an increase in serum urea and creatinine was noted, usually reversible after discontinuation of treatment. This was more common in patients with renal failure.

Hypersensitivity/Angioedema

Angioedema can occur at any time during treatment. In such a case, treatment with lisinopril should be stopped immediately and the patient should be monitored until the symptoms completely regress. In cases where the edema is limited to the face and lips, the condition most often resolves without treatment, but antihistamines may be prescribed.

Cough

When using ACE inhibitors, a dry, prolonged cough may appear, which disappears after discontinuation of treatment. When making a differential diagnosis of cough, cough caused by the use of an ACE inhibitor should be considered.

Surgery/General anesthesia

When using blood pressure-lowering agents in patients undergoing major surgery or during general anesthesia, Lisinopril, by blocking the formation of angiotensin II, can lead to a marked decrease in blood pressure, which can be corrected by increasing the circulating blood volume.

Before surgery (including dentistry), the surgeon/anesthesiologist should be informed about the use of ACE inhibitors.

Serum potassium

Hyperkalemia may develop. Risk factors for the development of hyperkalemia: renal failure, diabetes mellitus, use of potassium preparations or drugs that cause an increase in potassium concentration in the blood (including heparin), especially in patients with impaired renal function.

In patients at risk of symptomatic arterial hypotension (on a low-salt or salt-free diet) with/without hyponatremia, as well as in patients receiving high doses of diuretics, fluid and salt loss must be compensated before starting treatment.

Metabolic and endocrine effects

Thiazide diuretics can affect glucose tolerance, so the doses of antidiabetic drugs should be adjusted. Thiazide diuretics can reduce the urinary excretion of calcium and cause hypercalcemia. Severe hypercalcemia may be a symptom of latent hyperparathyroidism; it is recommended to discontinue treatment with thiazide diuretics before conducting tests to assess parathyroid function.

During treatment with Listril Plus, regular monitoring of potassium, glucose, urea, lipids and creatinine in blood plasma is necessary; it is not recommended to consume alcoholic beverages, as alcohol enhances the hypotensive effect of the drug.

Caution should be exercised during physical exercise, in hot weather (risk of dehydration and excessive decrease in blood pressure due to a decrease in circulating blood volume).

Effect on ability to drive vehicles and operate machinery

During the treatment period, one should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, since dizziness is possible, especially at the beginning of the course of treatment.

Overdose

Symptoms: marked decrease in blood pressure.

Treatment: induce vomiting and/or perform gastric lavage, symptomatic therapy aimed at correcting dehydration and water-electrolyte balance disturbances is carried out. For arterial hypotension, intravenous infusion of isotonic solution is recommended. Monitor serum urea, creatinine and electrolyte concentrations, and diuresis indicators.

Drug Interactions

When Listril^® Plus is used concomitantly

• With potassium-sparing diuretics (including spironolactone, triamterene, amiloride), potassium preparations, salt substitutes containing potassium, the risk of hyperkalemia increases, especially in patients with impaired renal function;
• With vasodilators, barbiturates, phenothiazines, tricyclic antidepressants, ethanol, the hypotensive effect is enhanced;
• With NSAIDs (including indomethacin), estrogens, the antihypertensive effect of lisinopril is reduced;
• With lithium preparations, the excretion of lithium from the body is slowed down, thereby enhancing the cardiotoxic and neurotoxic effects of lithium;
• With antacids and cholestyramine, the absorption of lisinopril in the gastrointestinal tract is reduced.

Listril^® Plus enhances the neurotoxicity of salicylates, weakens the effect of oral hypoglycemic agents, norepinephrine, epinephrine and anti-gout agents, enhances the effects (including side effects) of cardiac glycosides, the action of peripheral muscle relaxants, and reduces the excretion of quinidine.

Listril^® Plus reduces the effect of oral contraceptives.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years.

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.