Diropress (Tablets) Instructions for Use

Marketing Authorization Holder

Lek d.d. (Slovenia)

Manufactured By

Salutas Pharma, GmbH (Germany)

ATC Code

C09AA03 (Lisinopril)

Active Substance

Lisinopril (Rec.INN registered by WHO)

Dosage Forms

	Diropress	Tablets 5 mg: 7, 10, 14, 20, 21, 28, 30, 35, 40 or 50 pcs.
		Tablets 10 mg: 7, 10, 14, 20, 21, 28, 30, 35, 40 or 50 pcs.
		Tablets 20 mg: 7, 10, 14, 20, 21, 28, 30, 35, 40 or 50 pcs.

Dosage Form, Packaging, and Composition

Tablets brownish-pink, round, convex, with a score on one side, with inclusions of lighter and darker color.

Excipients: calcium hydrogen phosphate dihydrate, mannitol, corn starch, croscarmellose sodium, magnesium stearate, iron oxide red dye (E172).

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (3) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.

Tablets brownish-pink, round, convex, with a score on one side, with inclusions of lighter and darker color.

Excipients: calcium hydrogen phosphate dihydrate, mannitol, corn starch, croscarmellose sodium, magnesium stearate, iron oxide red dye (E172).

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (3) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.

Tablets brownish-pink, round, convex, with a score on one side, with inclusions of lighter and darker color.

Excipients: calcium hydrogen phosphate dihydrate, mannitol, corn starch, croscarmellose sodium, magnesium stearate, iron oxide red dye (E172).

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (3) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE blocker

Pharmacological Action

An ACE inhibitor, it reduces the formation of angiotensin II from angiotensin I. The decrease in angiotensin II content 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 pressure, causes an increase in cardiac output and an increase in myocardial tolerance to stress in patients with chronic 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, slow the progression of left ventricular dysfunction in patients who have had myocardial infarction without clinical manifestations of heart failure. The antihypertensive effect begins approximately after 6 hours and persists for 24 hours. The duration of the effect also depends on the dose. The onset of action is within 1 hour. The maximum effect is determined after 6-7 hours. In arterial hypertension, the effect is noted in the first days after the start of treatment, a stable effect develops after 1-2 months.

No marked increase in blood pressure was observed upon abrupt withdrawal of the drug.

In addition to lowering blood pressure, Lisinopril reduces albuminuria. In patients with hyperglycemia, it promotes the normalization of the function of damaged glomerular endothelium.

Lisinopril does not affect blood glucose concentration in patients with diabetes mellitus and does not lead to an increased incidence of hypoglycemia.

Pharmacokinetics

Absorption

After oral administration of the drug, about 25% of lisinopril is absorbed from the gastrointestinal tract. C_max is reached in 7 hours and is 90 ng/ml.

Food intake does not affect drug absorption. Absorption averages 30%, bioavailability is 29%.

Distribution

It is almost not bound to plasma proteins. Permeability through the blood-brain barrier and placental barrier is low.

Metabolism

Lisinopril is not biotransformed in the body.

Excretion

It is excreted by the kidneys unchanged. T_1/2 is 12 hours.

Pharmacokinetics in special clinical cases

In patients with chronic heart failure, the absorption and clearance of lisinopril are reduced.

In patients with renal failure, the concentration of lisinopril is several times higher than the concentrations in the blood plasma of volunteers, and an increase in the time to reach C_max in plasma and an increase in T_1/2 are noted.

In elderly patients, the plasma concentration of the drug and AUC are 2 times greater than in young patients.

Indications

• Arterial hypertension (as monotherapy or in combination with other antihypertensive agents);
• Chronic heart failure (as part of combination therapy for the treatment of patients taking digitalis preparations and/or diuretics);
• Early treatment of acute myocardial infarction (within the first 24 hours with stable hemodynamic parameters to maintain these parameters and prevent left ventricular dysfunction and heart failure);
• Diabetic nephropathy (reduction of albuminuria in insulin-dependent patients with normal blood pressure and non-insulin-dependent patients with arterial hypertension).

ICD codes

Dosage Regimen

The drug is taken orally, regardless of meals.

For arterial hypertension, patients not receiving other antihypertensive agents are prescribed 5 mg once a day. If there is no effect, the dose is increased every 2-3 days by 5 mg to an average therapeutic dose of 20-40 mg/day (increasing the dose beyond 40 mg/day usually does not lead to a further decrease in blood pressure). The usual daily maintenance dose is 20 mg. The maximum daily dose is 40 mg.

The full effect usually develops after 2-4 weeks from the start of treatment, which should be taken into account when increasing the dose. If the clinical effect is insufficient, it is possible to combine the drug with other antihypertensive agents.

If the patient received prior treatment with diuretics, then the intake of such drugs must be discontinued 2-3 days before starting the use of Diropress. If this is not feasible, then the initial dose of Diropress should not exceed 5 mg/day. In this case, medical supervision is recommended for several hours after taking the first dose (maximum action is reached in about 6 hours), as a marked decrease in blood pressure may occur.

For renovascular hypertension or other conditions with increased activity of the renin-angiotensin-aldosterone system, it is advisable to prescribe the drug in the same low dose – 2.5-5 mg/day, under enhanced medical supervision (control of blood pressure, renal function, serum potassium concentration). The maintenance dose under strict medical supervision should be determined depending on the dynamics of blood pressure.

In renal failure, since Lisinopril is excreted by the kidneys, the initial dose should be determined depending on the creatinine clearance. Further dose adjustment should be carried out depending on the individual response under frequent monitoring of renal function, serum potassium and sodium levels.

For persistent arterial hypertension, long-term maintenance therapy of 10-15 mg/day is indicated.

For chronic heart failure, the initial dose is 2.5 mg once a day, followed by an increase in the dose by 2.5 mg after 3-5 days to the usual, maintenance daily dose of 5-20 mg. The dose should not exceed 20 mg/day.

In elderly people, a more pronounced prolonged hypotensive effect is often observed, which is associated with a decrease in the excretion rate of lisinopril (it is recommended to start treatment with 2.5 mg/day).

For acute myocardial infarction (as part of combination therapy) on the first day – 5 mg orally, then 5 mg every other day, 10 mg after two days and then 10 mg once a day. In patients with acute myocardial infarction, the drug should be used for at least 6 weeks. At the beginning of treatment or within the first 3 days after acute myocardial infarction in patients with low systolic blood pressure (120 mm Hg or lower), the drug should be prescribed at a lower dose – 2.5 mg. In case of a decrease in blood pressure (systolic blood pressure below or equal to 100 mm Hg), the daily dose of 5 mg can, if necessary, be temporarily reduced to 2.5 mg. In case of a prolonged marked decrease in blood pressure (systolic blood pressure below 90 mm Hg for more than 1 hour), treatment with Diropress should be discontinued.

For diabetic nephropathy in patients with insulin-dependent diabetes mellitus, Diropress is prescribed at a dose of 10 mg once a day. The dose can, if necessary, be increased to 20 mg once a day to achieve sitting diastolic blood pressure values below 75 mm Hg. In patients with non-insulin-dependent diabetes mellitus, the dose is the same, to achieve sitting diastolic blood pressure values below 90 mm Hg.

Adverse Reactions

Definition of frequency of adverse effects: frequent (≥1%), rare (< 1%).

Most frequently dizziness, headache, increased fatigue, dry cough, nausea, diarrhea.

From the immune system: (0.1%) angioedema (face, lips, tongue, larynx or epiglottis, upper and lower extremities).

From the cardiovascular system frequent – marked decrease in blood pressure, orthostatic hypotension; rare – chest pain, tachycardia, bradycardia, worsening of heart failure symptoms, AV conduction disturbance, myocardial infarction.

From the CNS: frequent – paresthesia, mood lability, confusion, drowsiness, convulsive twitching of limb and lip muscles; rare – asthenic syndrome.

From the hematopoietic system: rare – leukopenia, neutropenia, agranulocytosis, thrombocytopenia, with long-term treatment – anemia (slight decrease in hemoglobin concentration and hematocrit, erythrocytopenia).

From the respiratory system rare – dyspnea, bronchospasm.

Laboratory parameters frequent – hyperkalemia, hyponatremia; sometimes – hyperbilirubinemia, increased activity of liver enzymes, increased serum urea and creatinine.

From the digestive system rare – dry mouth, anorexia, dyspepsia, taste changes, abdominal pain, pancreatitis, hepatocellular or cholestatic jaundice, hepatitis.

Dermatological reactions: rare – urticaria, increased sweating, skin itching, alopecia, photosensitivity.

From the urinary system: rare – impaired renal function, oliguria, anuria, acute renal failure, uremia, proteinuria.

Allergic reactions: rare – angioedema of the face, extremities, lips, tongue, epiglottis and/or larynx, skin rashes, itching, fever, positive antinuclear antibody test results, increased ESR, eosinophilia, leukocytosis; very rare – interstitial angioedema.

Other: rare – decreased potency, myalgia, arthralgia/arthritis, vasculitis.

Contraindications

• History of angioedema, including from the use of ACE inhibitors;
• Hereditary angioedema;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other ACE inhibitors.

With caution, the drug should be used in patients with severe renal impairment, bilateral renal artery stenosis or stenosis of the artery of a single kidney with progressive azotemia, in the state after kidney transplantation, with renal failure, azotemia, hyperkalemia, aortic stenosis, hypertrophic obstructive cardiomyopathy, with primary hyperaldosteronism, arterial hypotension, cerebrovascular diseases (including cerebral circulation insufficiency), with coronary artery disease, coronary insufficiency, autoimmune systemic connective tissue diseases (including scleroderma, systemic lupus erythematosus); with bone marrow hematopoiesis suppression; against the background of a sodium-restricted diet, in hypovolemic conditions, (including as a result of diarrhea, vomiting); in elderly patients.

Use in Pregnancy and Lactation

The use of Diropress during pregnancy is contraindicated.

Lisinopril crosses the placental barrier. When pregnancy is established, the drug should be discontinued as soon as possible. The use of ACE inhibitors in the II and III trimester of pregnancy has an adverse effect on the fetus (possible marked decrease in blood pressure, renal failure, hyperkalemia, skull hypoplasia, intrauterine fetal death). There are no data on the negative effects of the drug on the fetus in case of use during the first trimester.

Newborns and infants who have been exposed to ACE inhibitors in utero are recommended to be carefully monitored for the timely detection of marked hypotension, oliguria, hyperkalemia.

It is not known whether Lisinopril is excreted in breast milk. Breastfeeding should be discontinued during treatment with the drug.

Use in Renal Impairment

With caution, the drug should be used in patients with severe renal impairment, bilateral renal artery stenosis or stenosis of the artery of a single kidney with progressive azotemia, in the state after kidney transplantation, with renal failure, azotemia.

Pediatric Use

Contraindication: age under 18 years (efficacy and safety not established).

Geriatric Use

In elderly people, a more pronounced prolonged hypotensive effect is often observed, which is associated with a decrease in the excretion rate of lisinopril (it is recommended to start treatment with 2.5 mg/day).

Special Precautions

Symptomatic hypotension

Most often, a marked decrease in blood pressure 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 or without concomitant renal failure, a marked decrease in blood pressure is possible.

Diropress should be prescribed under strict medical supervision to patients with coronary artery disease, cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke.

Transient arterial hypotension is not a contraindication for taking the next dose of the drug.

When using Diropress in some patients with chronic heart failure, but with normal or low blood pressure, a decrease in blood pressure may be noted, which is usually not a reason to discontinue treatment.

Before starting treatment with Diropress, if possible, the sodium concentration should be normalized and/or the circulating blood volume should be replenished, and the effect of the initial dose of Diropress on the patient should be carefully monitored.

In the case of renal artery stenosis (especially with bilateral stenosis, or with stenosis of the artery of a single kidney), as well as in circulatory insufficiency due to sodium and/or fluid deficiency, the use of Diropress may lead to impaired renal function, acute renal failure, which is usually irreversible after drug withdrawal.

In acute myocardial infarction

The use of standard therapy (thrombolytics, acetylsalicylic acid, beta-blockers) is indicated. Diropress can be used in conjunction with intravenous administration or with the use of therapeutic transdermal nitroglycerin systems.

Surgery/general anesthesia

During major surgical interventions, as well as when using other drugs that cause a decrease in blood pressure, Lisinopril, by blocking the formation of angiotensin II, can cause a marked unpredictable decrease in blood pressure.

In elderly patients the same dose leads to a higher concentration of the drug in the blood, so special caution is required when determining the dose.

Since the potential risk of agranulocytosis cannot be excluded, periodic monitoring of the blood picture is required. When using the drug under dialysis conditions with a polyacrylonitrile membrane, anaphylactic shock may occur, so either a different type of dialysis membrane is recommended, or other antihypertensive agents are prescribed.

Effect on the Ability to Drive Vehicles and Mechanisms

There are no data on the effect of the drug Diropress on the ability to drive vehicles and mechanisms when used in therapeutic doses; however, it is necessary to consider that dizziness may occur, so caution should be exercised.

Overdose

Symptoms (occur when taking a single dose of 50 mg): pronounced decrease in BP; dry mouth, drowsiness, urinary retention, constipation, anxiety, increased irritability. A specific antidote is absent.

Treatment: gastric lavage, administration of enterosorbents and laxatives, intravenous administration of 0.9% sodium chloride solution. In the case of treatment-resistant bradycardia, the use of a pacemaker is necessary. Control of BP, water-electrolyte balance is necessary. Lisinopril can be removed from the body by hemodialysis.

Drug Interactions

With the simultaneous use of the drug Diropress with potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium preparations, salt substitutes containing potassium, with cyclosporine, the risk of hyperkalemia increases, especially in cases of impaired renal function. The necessity for concomitant administration is decided by the physician individually under regular monitoring of serum potassium levels and renal function.

When lisinopril is used in combination with beta-blockers, slow calcium channel blockers, diuretics, tricyclic antidepressants and other agents that lower BP, it increases the severity of the BP reduction.

Lisinopril slows the excretion of lithium. Therefore, when used concomitantly with lithium preparations, it is necessary to regularly monitor the serum lithium concentration.

Antacids and cholestyramine reduce the absorption of lisinopril from the gastrointestinal tract.

With simultaneous use with insulin and oral hypoglycemic agents, there is a risk of hypoglycemia.

NSAIDs (including selective COX-2 inhibitors), estrogens, adrenergic stimulants reduce the antihypertensive effect of lisinopril.

With simultaneous use of ACE inhibitors and gold preparations (sodium aurothiomalate), a symptom complex including facial flushing, nausea, vomiting, and decreased BP has been described.

With simultaneous use with selective serotonin reuptake inhibitors, pronounced hyponatremia is possible.

Concomitant use with allopurinol, procainamide, cytostatics may lead to leukopenia.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 4 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.