Prilenap^® (Tablets) Instructions for Use

Marketing Authorization Holder

Hemofarm, A.D. (Serbia)

ATC Code

C09BA02 (Enalapril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Enalapril (Rec.INN registered by WHO)

Dosage Forms

	Prilenap®	Tablets 10 mg+12.5 mg: 20 pcs.
		Tablets 10 mg+25 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, biconvex, from white to almost white in color, with a score on one side.

Excipients: lactose monohydrate, magnesium carbonate, gelatin, crospovidone, magnesium stearate.

10 pcs. – blisters (2) – cardboard packs.

Tablets are round, biconvex, from white to almost white in color, with a score on one side.

Excipients: lactose monohydrate, magnesium carbonate, gelatin, crospovidone, magnesium stearate.

10 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

Antihypertensive drug. Contains Enalapril and Hydrochlorothiazide.

Enalapril is an ACE inhibitor. It is a prodrug: the metabolite enalaprilat, which is formed as a result of the hydrolysis of enalapril, has pharmacological activity.

Hydrochlorothiazide is a thiazide diuretic. It acts at the level of the distal renal tubules, increasing the excretion of sodium and chloride ions.

At the beginning of treatment with the drug, due to the hydrochlorothiazide it contains, the volume of fluid in the vessels decreases as a result of increased excretion of sodium and fluid, which leads to a decrease in blood pressure and a decrease in cardiac output. Due to hyponatremia and a decrease in body fluid, the RAAS is activated. The reactive increase in angiotensin II concentration partially limits the decrease in blood pressure. With continued therapy, the hypotensive effect of hydrochlorothiazide is based on a decrease in total peripheral vascular resistance. The result of RAAS activation is metabolic changes in the electrolyte balance of the blood, the content of uric acid, glucose and lipids, which partially neutralizes the effectiveness of antihypertensive treatment. Despite effective blood pressure reduction, thiazide diuretics do not reduce structural changes in the heart and blood vessels.

Enalapril enhances the antihypertensive effect – it inhibits the RAAS, i.e., the production of angiotensin II and its effects. Additionally, it reduces aldosterone production and enhances the action of bradykinin and the release of prostaglandins. Since Enalapril has its own diuretic effect, this may enhance the effect of hydrochlorothiazide. Enalapril reduces pre- and afterload, reduces the load on the left ventricle, reduces myocardial hypertrophy and collagen proliferation, and prevents damage to myocardial cells. As a result, the heart rate slows down and the load on the heart decreases (in chronic heart failure), coronary blood flow improves and oxygen consumption by cardiomyocytes decreases. Thus, the heart’s sensitivity to ischemia is reduced.

It has a beneficial effect on cerebral blood flow in patients with arterial hypertension and chronic cardiovascular diseases. It prevents the development of glomerulosclerosis, maintains and improves kidney function and slows the progression of chronic kidney diseases even in those patients who have not yet developed arterial hypertension.

It is known that the antihypertensive effect of ACE inhibitors is higher in patients with hyponatremia, hypovolemia and elevated serum renin levels, whereas the effect of hydrochlorothiazide does not depend on the serum renin level. Therefore, the simultaneous administration of enalapril and hydrochlorothiazide contributes to an additional antihypertensive effect. In addition, Enalapril prevents or attenuates the metabolic effects of diuretic therapy and has a beneficial effect on structural changes in the heart and blood vessels.

Simultaneous administration of an ACE inhibitor and hydrochlorothiazide is used when each drug alone is insufficiently effective or when monotherapy is carried out using maximum doses of the drug, which increases the frequency of adverse effects.

The antihypertensive effect of the combination usually lasts for 24 hours.

Pharmacokinetics

Enalapril

Absorption and Metabolism

Enalapril is rapidly absorbed from the gastrointestinal tract (60%). Food intake does not affect the absorption of enalapril. C_max is reached after 1 hour. In the liver, Enalapril is hydrolyzed to the active metabolite – enalaprilat. C_max of enalaprilat in blood serum is reached after 3-6 hours.

Distribution

Enalaprilat penetrates into most body tissues, mainly the lungs, kidneys and blood vessels. Plasma protein binding is 50-60%. Enalaprilat is not subject to further metabolism.

Enalapril and enalaprilat cross the placental barrier and are excreted in breast milk.

Excretion

Enalapril is excreted in the urine (60%) and feces (33%) mainly as enalaprilat.

The renal clearance of enalapril and enalaprilat is 0.005 ml/s (18 L/h) and 0.00225-0.00264 ml/s (8.1-9.5 L/h), respectively. T_1/2 of enalaprilat from blood serum is approximately 11 hours.

Pharmacokinetics in Special Clinical Situations

Enalaprilat is removed from the bloodstream during hemodialysis or peritoneal dialysis. Hemodialysis clearance of enalaprilat is 0.63-1.03 ml/s (38-62 ml/min); serum concentration of enalaprilat after 4 hours of hemodialysis decreases by 45-57%.

In patients with reduced renal function, excretion is slowed, which requires dose adjustment according to renal function, especially in patients with severe renal failure.

In patients with hepatic impairment, the metabolism of enalapril may be slowed without changing its pharmacodynamic effect.

In patients with heart failure, the absorption and metabolism of enalaprilat are slowed, and V_d is also reduced. Since these patients may develop renal failure, the excretion of enalapril may be slowed.

The pharmacokinetics of enalapril may also change in elderly patients, largely due to concomitant diseases.

Hydrochlorothiazide

Absorption

It is absorbed mainly in the duodenum and proximal small intestine. Absorption is 70% and increases by 10% when taken with food. C_max is reached in 1.5-5 hours.

Distribution

V_d is about 3 L/kg. Plasma protein binding is 40%. The drug accumulates in erythrocytes; the mechanism of accumulation is not known.

It crosses the placental barrier and accumulates in the amniotic fluid. The serum concentration of hydrochlorothiazide in umbilical vein blood is practically the same as in maternal blood. The concentration in amniotic fluid exceeds that in umbilical vein serum (by 19 times). The concentration of hydrochlorothiazide in breast milk is very low. Hydrochlorothiazide was not detected in the serum of breastfed infants whose mothers took Hydrochlorothiazide during breastfeeding.

Excretion

It is not metabolized in the liver, excreted mainly by the kidneys (95% unchanged and about 4% as the hydrolyzate 2-amino-4-chloro-m-benzenedisulfonamide). The renal clearance of hydrochlorothiazide in healthy volunteers and patients with arterial hypertension is approximately 5.58 ml/s (335 ml/min). Hydrochlorothiazide has a biphasic excretion profile. T_1/2 in the initial phase is 2 hours, in the terminal phase (10-12 hours after administration) it is about 10 hours.

Pharmacokinetics in Special Clinical Situations

In elderly patients, Hydrochlorothiazide does not have a negative effect on the pharmacokinetics of enalapril, but the serum concentration of enalaprilat increases.

When hydrochlorothiazide was prescribed to patients with heart failure, its absorption was found to decrease proportionally to the severity of the disease – by 20-70%. T_1/2 of hydrochlorothiazide increases to 28.9 hours; renal clearance is 0.17-3.12 ml/s (10-187 ml/min), average values 1.28 ml/s (77 ml/min).

In patients who have undergone intestinal bypass surgery for obesity, the absorption of hydrochlorothiazide may be reduced by 30%, and the serum concentration by 50% compared to healthy volunteers.

Simultaneous administration of enalapril and hydrochlorothiazide does not affect the pharmacokinetics of each of them.

Indications

• Treatment of arterial hypertension when combination therapy is required.

ICD codes

Dosage Regimen

The dose of the drug and the duration of therapy are set individually.

It is recommended to take the drug 1 tablet/day (10 mg + 12.5 mg) or, if the therapeutic effect is insufficient, 10 mg + 25 mg.

The tablets should be taken whole during or after meals with a small amount of liquid.

If there is no therapeutic effect, it is recommended to add another drug or change the therapy.

In patients on diuretic therapy, it is recommended to discontinue or reduce the dose of diuretics at least 3 days before starting treatment with Prilenap^® to prevent the development of symptomatic hypotension. Renal function should be examined before starting treatment.

For patients with CrCl > 30 ml/min or serum creatinine < 265 µmol/L (3 mg/dL), the usual dose of Prilenap^® (10 mg +12.5 mg) may be prescribed.

Adverse Reactions

From the cardiovascular system: palpitations, various cardiac arrhythmias, marked decrease in blood pressure, orthostatic hypotension, cardiac arrest, myocardial infarction, cerebrovascular stroke, angina pectoris, Raynaud’s syndrome.

From the digestive system: dry mouth, glossitis, stomatitis, inflammation of the salivary glands, anorexia, nausea, vomiting, diarrhea, constipation, flatulence, epigastric pain, intestinal colic, ileus, pancreatitis, hepatic failure, hepatitis, jaundice, melena, increased activity of liver enzymes, hyperbilirubinemia.

From the respiratory system: rhinitis, sinusitis, pharyngitis, hoarseness, bronchospasm, asthma, pneumonia, pulmonary infiltrates, eosinophilic pneumonia, pulmonary embolism, pulmonary infarction, pulmonary edema, respiratory distress, including pneumonitis and pulmonary edema, non-productive cough.

From the genitourinary system: oliguria, gynecomastia, decreased potency, renal failure, impaired renal function, interstitial nephritis.

From the sensory organs: visual impairment, taste disturbance, smell disturbance, tinnitus, conjunctivitis, dry conjunctiva, lacrimation.

From the central and peripheral nervous system: depression, ataxia, drowsiness, insomnia, anxiety, nervousness, peripheral neuropathy (paresthesia, dysesthesia), dizziness.

From the hematopoietic system: leukocytosis, eosinophilia, neutropenia, leukopenia, agranulocytosis, anemia, hypoglobinemia, pancytopenia, decreased hematocrit.

Allergic reactions: urticaria, itching, angioedema, anaphylactic reactions.

Dermatological reactions: increased sweating, rash, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, alopecia, photosensitivity.

Laboratory parameters: hypokalemia, hyperkalemia, hypomagnesemia, hypercalcemia, hyponatremia, hypochloremic alkalosis, hyperglycemia, glucosuria, hyperuricemia, hypercholesterolemia, hypertriglyceridemia.

Other: herpes zoster, lupus-like syndrome (fever, myalgia and arthralgia, serositis, vasculitis, increased erythrocyte sedimentation rate, leukocytosis and eosinophilia, skin rash, positive test for antinuclear antibodies), muscle cramps, gout, thrombocytopenic purpura, necrotizing angiitis, fever.

Contraindications

• Anuria;
• Severe renal impairment (CrCl < 30 ml/min);
• History of angioedema associated with previous use of ACE inhibitors;
• Hereditary or idiopathic angioedema;
• Primary hyperaldosteronism;
• Addison’s disease;
• Porphyria;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the components of the drug or sulfonamides.

With caution, the drug should be prescribed for bilateral renal artery stenosis or stenosis of the artery of a single kidney, impaired renal function (CrCl 30-75 ml/min), severe aortic orifice stenosis or idiopathic hypertrophic subaortic stenosis, coronary artery disease, cerebrovascular diseases (including cerebrovascular insufficiency), chronic heart failure, severe autoimmune systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), bone marrow depression, diabetes mellitus, hyperkalemia, condition after kidney transplantation, severe impairment of liver and/or kidney function, conditions accompanied by a decrease in circulating blood volume (as a result of diuretic therapy, salt restriction, diarrhea and vomiting), gout, elderly patients.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy. If pregnancy occurs, the drug should be discontinued immediately.

If it is necessary to prescribe the drug during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Use with caution in severe hepatic impairment.

Use in Renal Impairment

For patients with CrCl greater than 30 ml/min or serum creatinine less than 265 µmol/L (3 mg/dL), the usual dose of Prilenap^® (10 mg +12.5 mg) may be prescribed.

Contraindicated in severe renal impairment (CrCl less than 30 ml/min).

Pediatric Use

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

Geriatric Use

With caution, the drug should be prescribed to elderly patients.

Special Precautions

At the beginning of treatment, the development of arterial hypotension is possible (in patients with severe heart failure, hyponatremia, severe renal failure, arterial hypertension or left ventricular dysfunction and, especially, in patients with hypovolemia as a result of diuretic therapy, salt-free diet, diarrhea, vomiting or hemodialysis). Arterial hypotension after the first dose and its more serious consequences are a rare and transient phenomenon. It can be avoided by discontinuing diuretics, if possible, before starting treatment with Prilenap^®.

In case of arterial hypotension, the patient should be placed on his back with a low headboard and, if necessary, the circulating blood volume should be corrected by infusion of saline. Transient arterial hypotension is not a contraindication to continue treatment. After normalization of blood pressure and replenishment of circulating blood volume, patients usually tolerate subsequent doses well.

The drug should be prescribed with caution to patients with impaired renal function (CrCl 30-75 ml/min). In patients taking Hydrochlorothiazide, azotemia may develop. In patients with impaired renal function, signs of drug accumulation may appear. If necessary, a combination of enalapril with a lower amount of hydrochlorothiazide can be used, or combination therapy with enalapril and hydrochlorothiazide should be discontinued.

Prilenap^® should be avoided in patients with bilateral renal artery stenosis or stenosis of the renal artery of a single kidney, as deterioration of renal function up to the development of acute renal failure (effect of enalapril) is possible. Therefore, monitoring of renal function before and during treatment is necessary.

The drug should be prescribed with caution to patients with coronary artery disease, severe cerebrovascular diseases, aortic stenosis or other stenosis that impedes the outflow of blood from the left ventricle, severe atherosclerosis, and elderly patients due to the risk of developing arterial hypotension and deterioration of perfusion of the heart, brain and kidneys.

Regular monitoring of serum electrolyte concentrations is necessary during treatment with Prilenap^® to identify possible imbalance and take necessary measures in a timely manner. Determination of serum electrolyte concentrations is mandatory for patients with prolonged diarrhea, vomiting and those receiving intravenous infusions.

In patients taking Prilenap^®, signs of electrolyte imbalance should be identified, such as dry mouth, thirst, weakness, drowsiness, lethargy, agitation, muscle pain and cramps (mainly in the calf muscles), decreased blood pressure, tachycardia, oliguria and gastrointestinal disorders (nausea, vomiting).

Prilenap^® should be prescribed with caution to patients with hepatic insufficiency or progressive liver diseases, as Hydrochlorothiazide can cause hepatic coma even with minimal electrolyte disturbances.

During treatment with Prilenap^®, hypomagnesemia and sometimes hypercalcemia may occur, resulting from increased excretion of magnesium and slowed excretion of calcium in the urine under the influence of hydrochlorothiazide. A significant increase in serum calcium levels may be a symptom of latent hyperparathyroidism.

In some patients, as a result of the action of hydrochlorothiazide, hyperuricemia or worsening of gout may be observed. If an increase in serum uric acid concentration is noted, treatment should be discontinued. It can be resumed after normalization of laboratory parameters and subsequently carried out under their control.

Caution is necessary in all patients receiving treatment with oral hypoglycemic agents or insulin, as Hydrochlorothiazide may weaken, and Enalapril may enhance their effect. Patients with diabetes mellitus should be under observation; if necessary, dose adjustment of hypoglycemic agents may be required.

In the event of angioneurotic edema of the face or neck, it is usually sufficient to discontinue therapy and administer antihistamines to the patient. In more severe cases (edema of the tongue, pharynx, and larynx), epinephrine should be administered and airway patency must be maintained (by intubation or laryngotomy).

The antihypertensive effect of Prilenap^® may be enhanced after sympathectomy.

Due to an increased risk of anaphylactic reactions, Prilenap^® should not be prescribed to patients undergoing hemodialysis with polyacrylonitrile membranes, undergoing apheresis with dextran sulfate, and immediately before desensitization procedures to wasp or bee venom.

During treatment with Prilenap^®, hypersensitivity reactions may occur in patients without a prior history of allergy or bronchial asthma.

Worsening of systemic lupus erythematosus has been reported.

Several cases of acute liver failure with cholestatic jaundice, liver necrosis, and a fatal outcome have been reported during treatment with ACE inhibitors. The cause of these syndromes is not fully understood. If jaundice occurs and liver enzyme activity increases, treatment should be discontinued immediately, and patients should be placed under observation.

Caution is also necessary in patients taking sulfonamides or oral hypoglycemic agents from the sulfonylurea group (due to possible cross-hypersensitivity).

In patients taking antihypertensive drugs, after extensive surgical operations under general anesthesia, Enalapril may block the formation of angiotensin II, secondary to the compensatory release of renin. If the physician suspects this mechanism of arterial hypotension, treatment may be aimed at increasing the circulating blood volume.

Periodic monitoring of the leukocyte count is required during treatment, especially in patients with connective tissue diseases or kidney diseases.

Periodic monitoring of serum concentrations of electrolytes, glucose, urea, creatinine, liver enzyme activity, and urine protein is necessary during treatment.

Treatment with Prilenap^® should be discontinued before conducting tests of parathyroid gland function.

Effect on the Ability to Drive Vehicles and Operate Machinery

Prilenap^® does not affect the ability to drive a car or operate machinery; however, some patients, mainly at the beginning of treatment, may experience arterial hypotension and dizziness, which may reduce the ability to drive a car and operate machinery. Therefore, at the beginning of treatment, it is recommended to avoid driving, operating machinery, and performing other work requiring concentration until the response to treatment is established.

Overdose

Symptoms increased diuresis, pronounced decrease in blood pressure with bradycardia or other cardiac rhythm disorders, convulsions, paresis, paralytic ileus, impaired consciousness (including coma), renal failure, acid-base balance disorder, blood electrolyte balance disorders.

Treatment the patient is placed in a horizontal position with the head lowered. In mild cases, gastric lavage and oral administration of saline are indicated; in more serious cases, measures aimed at stabilizing blood pressure – intravenous administration of saline, plasma substitutes. It is necessary to monitor the level of blood pressure, heart rate, respiratory rate, serum concentration of urea, creatinine, electrolytes, and diuresis; if necessary – intravenous administration of angiotensin II, hemodialysis (elimination rate of enalaprilat – 62 ml/min).

Drug Interactions

Concomitant use of other antihypertensive agents, barbiturates, tricyclic antidepressants, phenothiazines, opioid analgesics, ethanol enhances the antihypertensive effect of Prilenap^®.

Analgesics and NSAIDs, a large amount of salt in food, concomitant use of cholestyramine or colestipol reduce the effect of Prilenap^®.

Concomitant use of Prilenap^® and lithium preparations may lead to lithium intoxication, because Enalapril and Hydrochlorothiazide reduce the excretion of lithium. Monitoring of serum lithium concentration and, if necessary, dose adjustment is required. If possible, concomitant treatment with Prilenap^® and lithium preparations should be avoided.

Concomitant use of Prilenap^® and NSAIDs and analgesics (due to inhibition of prostaglandin synthesis) may reduce the effectiveness of enalapril and increase the risk of worsening renal function and/or the course of heart failure. In some patients, the antihypertensive effect of enalapril may also be reduced, so monitoring is indicated if this combination is necessary.

Concomitant use with potassium-sparing diuretics (spironolactone, amiloride, triamterene) or potassium preparations may lead to hyperkalemia.

Concomitant use with allopurinol, cytostatics, immunosuppressants, or systemic corticosteroids may lead to the development of leukopenia, anemia, or pancytopenia, so periodic monitoring of the hemogram is required.

The development of acute renal failure has been reported in two patients after kidney transplantation who were simultaneously receiving Enalapril and cyclosporine. It is assumed that acute renal failure was the result of reduced renal blood flow caused by cyclosporine and decreased glomerular filtration caused by enalapril. Therefore, caution is necessary when using enalapril and cyclosporine concomitantly.

Concomitant use of sulfonamides and oral hypoglycemic agents from the sulfonylurea group may cause hypersensitivity reactions (cross-hypersensitivity is possible).

Caution is necessary when using Prilenap^® concomitantly with cardiac glycosides. Possible hypovolemia, hypokalemia, and hypomagnesemia may increase the toxicity of glycosides.

Concomitant use of Prilenap^® with corticosteroids increases the risk of hypokalemia.

When Prilenap^® and theophylline are used concomitantly, Enalapril may reduce the T_1/2 of theophylline.

When Prilenap^® and cimetidine are used concomitantly, an increase in the T_1/2 of enalapril is possible.

The risk of arterial hypotension increases during general anesthesia or the use of non-depolarizing muscle relaxants (e.g., tubocurarine).

Storage Conditions

The drug should be stored in a dry place, protected from moisture, out of the reach of children, at a temperature from 15°C (59°F) to 25°C (77°F).

Shelf Life

Shelf life – 2 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.