Enanorm (Tablets) Instructions for Use

Marketing Authorization Holder

Ferrer Internacional, S.A. (Spain)

ATC Code

C09BB06 (Enalapril and Nitrendipine)

Active Substances

Enalapril (Rec.INN registered by WHO)

Nitrendipine (Rec.INN registered by WHO)

Dosage Form

Enanorm

Tablets 10 mg+20 mg: 30, 60 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are yellow, oblong, biconvex, with an imprint on one side “E/N”.

Excipients: sodium bicarbonate – 5 mg, microcrystalline cellulose – 20 mg, corn starch – 20 mg, sodium lauryl sulfate – 8 mg, povidone K25 – 6 mg, magnesium stearate – 1.2 mg, lactose monohydrate – 63.58 mg.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + ACE inhibitor)

Pharmacological Action

It is a combined antihypertensive agent, consisting of two antihypertensive drugs with complementary mechanisms for lowering blood pressure: enalapril is an ACE inhibitor and Nitrendipine is a slow calcium channel blocker.

Enalapril is a prodrug. As a result of its hydrolysis, an active metabolite, enalaprilat, is formed, which inhibits ACE. The mechanism of action is associated with a decrease in the formation of angiotensin II from angiotensin I, a decrease in the content of which leads to a direct decrease in aldosterone secretion. This reduces total peripheral vascular resistance, systolic and diastolic blood pressure, afterload and preload on the myocardium.

Enalapril dilates arteries to a greater extent than veins, and no reflex increase in heart rate is noted.

The antihypertensive effect is more pronounced with high plasma renin activity than with normal or reduced activity. A decrease in blood pressure within therapeutic limits does not affect cerebral circulation: blood flow in the cerebral vessels is maintained at a sufficient level even against the background of reduced blood pressure. It increases coronary and renal blood flow.

With long-term use, it reduces hypertrophy of the left ventricular myocardium and myocytes of the walls of resistive-type arteries, prevents the progression of heart failure and slows the development of left ventricular dilation. Enalapril improves blood supply to the ischemic myocardium.

The onset of the antihypertensive effect after oral administration is 1 hour, reaches a maximum after 4-6 hours and lasts for 24 hours.

Nitrendipine is a slow calcium channel blocker from the group of dihydropyridine derivatives, it has an antihypertensive effect. It reduces the flow of calcium ions into the smooth muscle cells of the coronary and peripheral arteries. It causes some increase in the excretion of sodium and water. It reduces afterload and myocardial oxygen demand, does not depress cardiac muscle conduction.

It reduces the number of functioning channels without affecting the time of their activation, inactivation and recovery. It uncouples the processes of excitation and contraction in the myocardium, mediated by tropomyosin and troponin, and in vascular smooth muscles, mediated by calmodulin. In therapeutic doses, it normalizes the transmembrane current of calcium ions, impaired in a number of pathological conditions, primarily in arterial hypertension.

Pharmacokinetics

Enalapril

After oral administration, it is absorbed from the gastrointestinal tract by 60%. The bioavailability of enalapril is 40%. C_max of enalapril in blood plasma is reached after 1 hour, of enalaprilat – after 3-4 hours. Food intake does not affect the absorption of enalapril. The binding of enalapril to plasma proteins is 50-60%. Enalaprilat easily passes through histohematic barriers, except for the blood-brain barrier. A small amount penetrates the placental barrier and into breast milk. Enalapril is rapidly metabolized in the liver to form an active metabolite, enalaprilat. T_1/2 of enalaprilat is about 11 hours. Enalapril is excreted mainly by the kidneys – 60% (20% as enalapril and 40% as enalaprilat), through the intestine – 33% (6% as enalapril and 27% as enalaprilat). It is removed by hemodialysis (rate 62 ml/min) and peritoneal dialysis.

Nitrendipine

It is rapidly absorbed from the gastrointestinal tract by 88%. Bioavailability is 20-30% due to a pronounced first-pass effect through the liver. T_max in blood plasma is 1-3 hours after administration. Binding to plasma proteins (albumin) is 96-98%. V_d at equilibrium is 5-9 l/kg, so hemodialysis and plasmapheresis are ineffective. Nitrendipine and its metabolites do not accumulate in the body. It is metabolized in the liver, mainly by oxidation. Metabolites are pharmacologically inactive. T_1/2 of nitrendipine after oral administration is 8-12 hours. Nitrendipine is excreted mainly by the kidneys: approximately 77% of the administered dose is excreted as metabolites, less than 0.1% of the administered dose is excreted unchanged. The rest of nitrendipine is excreted through the intestine.

In elderly patients, T_1/2 increases.

In liver cirrhosis, C_max in plasma and AUC increase.

In patients with impaired renal function, dose adjustment is not required.

A study of the interaction of enalapril and nitrendipine in healthy volunteers did not reveal changes in the pharmacokinetics of nitrendipine. As for enalaprilat, its bioavailability increases somewhat with simultaneous use with nitrendipine, but this apparently has no clinical significance. The bioavailability of nitrendipine when using the combined drug is higher than when using the two drugs separately.

Indications

Essential hypertension (for patients who require combination therapy).

ICD codes

Dosage Regimen

Orally, no more than 1 fixed dose once a day.

It is recommended to individually select the doses of the components.

For patients with mild to moderate hepatic impairment, monotherapy with either enalapril or nitrendipine is not contraindicated, but since there is no experience with the use of Enanorm in such patients, the drug should be prescribed with caution.

In patients with moderate renal failure (creatinine clearance >30 ml/min, serum creatinine ≤3 mg/ml), there is no need for dose adjustment; renal function should be monitored during treatment.

Adverse Reactions

Enalapril + Nitrendipine

From the cardiovascular system frequent – flushing, peripheral edema; infrequent – tachycardia, dizziness, pronounced decrease in blood pressure; very rare – peripheral circulatory disorders, dyspnea.

From the nervous system frequent – headache; very rare – asthenia, hypothermia, drowsiness, paresthesia, tremor, convulsions.

From the respiratory system frequent – cough; very rare – pharyngitis, tracheitis, dyspnea.

From the digestive system infrequent – nausea, dyspepsia; very rare – flatulence, increased activity of liver transaminases.

From the skin and subcutaneous tissues: infrequent – erythematous rash.

From the urinary system very rare – hematuria.

From the musculoskeletal system very rare – muscle spasm.

From metabolism very rare – hypokalemia.

The following adverse reactions have been observed with drugs containing similar components.

Enalapril

From the cardiovascular system infrequent, especially at the beginning of treatment and in patients with reduced blood volume and/or salts – worsening of Raynaud’s disease, in patients with heart failure, severe arterial hypertension or renal hypertension after increasing the dose of enalapril and/or using diuretics and/or in a standing position – dizziness, weakness, visual disturbances; rare – fainting; very rare – in connection with the enhancement of the antihypertensive effect, tachycardia, palpitations, atrial bradycardia, atrial fibrillation, chest pain, angina pectoris, myocardial infarction, transient cerebrovascular accident occurred; cardiac arrest, pulmonary embolism and infarction, pulmonary edema.

From the urinary system infrequent – appearance or intensification of renal function disorders, increased concentration of urea, creatinine, increased renal excretion of albumin (especially in patients with impaired renal function, severe heart failure, renovascular hypertension); very rare – acute renal failure; rare – oliguria, proteinuria, in some cases with concomitant deterioration of renal function, pain in the iliac region.

From the respiratory system infrequent – dry cough, sore throat, hoarseness, bronchitis; rare – dyspnea, sinusitis, rhinitis; very rare – bronchospasm/bronchial asthma attack, pulmonary infiltrates, stomatitis, glossitis, dry mouth, pneumonia.

From the digestive system infrequent – nausea, pain in the upper abdomen, indigestion; rare – vomiting, diarrhea, constipation, loss of appetite, change or transient loss of taste sensations, anosmia; very rare – increased concentration of bilirubin and increased activity of liver transaminases, pancreatitis, intestinal obstruction, stomatitis, glossitis, impaired liver function, hepatitis, liver failure, a syndrome starting with cholestatic jaundice and progressing to liver necrosis, in some cases with a fatal outcome.

From the nervous system infrequent – headache, weakness; rare – dizziness, depression, sleep disorders, impotence, peripheral neuropathy with paresthesia, imbalance, muscle cramps, nervousness, confusion.

From the sense organs rare – tinnitus, blurred vision, dry eyes, increased lacrimation.

From the endocrine system very rare – gynecomastia.

From the skin and subcutaneous tissues infrequent – exanthema; very rare – severe skin reactions, for example, pemphigus, pemphigoid, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome or toxic epidermal necrolysis; phenomena resembling psoriasis, photosensitivity, flushing, increased sweating, alopecia, onycholysis. Skin manifestations may be accompanied by fever, myalgia/myositis, arthralgia/arthritis, vasculitis, serositis, eosinophilia, leukocytosis, increased ESR and/or the appearance of antinuclear antibody titers. If a severe skin reaction is suspected, treatment should be discontinued.

Allergic reactions rare – urticaria, skin itching, angioedema of the lips, face and/or upper and lower extremities; very rare – angioedema involving the pharynx, larynx and/or tongue and in some cases leading to death (more often in patients of the Black race).

From the hematopoietic system infrequent – decrease in hemoglobin, hematocrit, leukocytes or platelets; rare – anemia, thrombocythemia, neutropenia, eosinophilia (in some cases agranulocytosis or pancytopenia), especially in patients with impaired renal function, with systemic connective tissue diseases, patients receiving allopurinol, procainamide or immunosuppressants; very rare – hemolysis/hemolytic anemia (also in combination with glucose-6-phosphate dehydrogenase deficiency).

From metabolism infrequent – increased potassium content in blood serum, decreased sodium content in blood serum, hyperkalemia (in patients with diabetes mellitus).

Nitrendipine

From the immune system infrequent – flu-like syndrome.

From the cardiovascular system infrequent – arrhythmia, tachycardia, palpitations, peripheral edema, flushing, increased symptoms of vasodilation; rare – pronounced decrease in blood pressure, angina pectoris, chest pain.

From the digestive system infrequent – nausea, diarrhea; rare – abdominal pain, constipation, dyspepsia, vomiting; very rare – gingival hyperplasia, increased activity of liver enzymes.

From the endocrine system very rare – gynecomastia.

From the hematopoietic system very rare – leukopenia, agranulocytosis.

From the musculoskeletal system rare – myalgia.

From the nervous system infrequent – headache, asthenia; rare – nervousness, paresthesias, tremor, dizziness.

From the respiratory system rare – dyspnea.

From the skin and subcutaneous tissues rare – skin itching, rash, urticaria.

From the organ of vision rare – visual disturbances.

From the urinary system: very rare – increased frequency of urination, polyuria.

If any of the side effects listed in the instructions get worse, or the patient notices any other side effects not listed in the instructions, you should inform your doctor.

Contraindications

A history of angioedema associated with ACE inhibitor treatment; hereditary or idiopathic angioedema; shock, collapse; acute heart failure; various pathological syndromes (decompensated chronic heart failure requiring inotropic therapy) and conditions if their course is accompanied by unstable hemodynamics (for example, cardiovascular shock, acute heart failure, acute coronary syndrome, acute period of stroke); severe arterial hypotension (systolic blood pressure less than 90 mm Hg); under conditions of unstable hemodynamics: acute myocardial infarction (within the first 4 weeks after myocardial infarction), chronic heart failure of functional class III-IV (according to NYHA classification); hemodynamically significant stenosis of the aortic or mitral valve and hypertrophic obstructive cardiomyopathy; bilateral renal artery stenosis or stenosis of the artery of a single kidney; severe renal impairment (creatinine clearance less than 10 ml/min) and hemodialysis; severe hepatic impairment; pregnancy, lactation (breastfeeding); age under 18 years; hypersensitivity to the components of the combination; hypersensitivity to other dihydropyridine derivatives.

With caution should be used for aortic stenosis, cerebrovascular diseases (including cerebrovascular insufficiency), coronary artery disease, coronary insufficiency, severe autoimmune systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), bone marrow hematopoiesis depression, diabetes mellitus, hyperkalemia, condition after kidney transplantation, renal failure, mild or moderate hepatic impairment, conditions accompanied by a decrease in blood volume (including diarrhea, vomiting), adherence to a salt-restricted diet, in elderly patients.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindications: severe hepatic impairment.

For patients with mild to moderate hepatic impairment, monotherapy with either enalapril or nitrendipine is not contraindicated, but since there is no experience with the use of this combination in such patients, the drug should be prescribed with caution.

Use in Renal Impairment

Contraindications: bilateral renal artery stenosis or stenosis of the artery of a single kidney; severe renal impairment (creatinine clearance less than 10 ml/min) and hemodialysis.

The drug should be used with caution in the condition after kidney transplantation, renal failure.

In patients with moderate renal failure (creatinine clearance >30 ml/min, serum creatinine ≤3 mg/ml), there is no need for dose adjustment; renal function should be monitored during treatment.

Pediatric Use

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

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

Use strictly as prescribed by a doctor.

Angioedema

When using ACE inhibitors, especially in the first weeks, as well as in rare cases after long-term use, angioedema of the extremities, face, lips, mucous membranes, tongue, larynx or pharynx may develop. In such cases, treatment should be discontinued immediately.

Angioedema of the tongue, larynx or pharynx can be fatal; in these cases, emergency therapy with hospitalization of the patient should be carried out, the patient should be observed for at least 12-24 hours, and he can be discharged from the hospital only after the symptoms have completely disappeared.

Neutropenia/agranulocytosis

Enalapril should be used with extreme caution in patients with systemic connective tissue diseases, in patients receiving immunosuppressants, allopurinol or procainamide, or their combination, especially in the presence of impaired renal function. When using the drug Enanorm in such patients, it is recommended to monitor the leukocyte formula. During treatment, patients should be instructed to report any signs of infection to the doctor. Enanorm should be discontinued if neutropenia is detected or suspected (neutrophil count less than 1000/µl).

Renal function disorders

In patients with impaired renal function, when using ACE inhibitors, renal function should be monitored, especially in the first weeks of treatment. Caution should be exercised regarding patients with an activated renin-angiotensin system.

For patients with moderate renal impairment (creatinine clearance >30 ml/min, serum creatinine ≤3 mg/ml), dose adjustment is not required, but renal function must be monitored.

In some patients, a pronounced decrease in blood pressure at the beginning of treatment with ACE inhibitors may lead to a slight further deterioration in renal function. Under such circumstances, cases of acute renal failure have been observed, which were usually reversible.

There is no experience with the use of the drug Enanorm in patients who have recently undergone kidney transplantation.

Proteinuria

In patients with impaired renal function, proteinuria has rarely developed. In patients with clinically significant proteinuria (>1 g/day), Enanorm can be used only after a careful assessment of the risk-benefit ratio of therapy and under regular monitoring of clinical and biochemical blood parameters.

Patients with impaired liver function

There is no experience with the use of Enanorm in patients with mild or moderate hepatic impairment; therefore, this drug should be used with caution in such patients if indicated.

Since isolated cases of a syndrome beginning with cholestatic jaundice and progressing to fatal liver necrosis have been described, treatment should be discontinued and patients monitored if jaundice or a marked increase in liver transaminases occurs.

Orthostatic hypotension

In some cases, Enanorm may cause orthostatic hypotension, the risk of which is increased in patients with activated RAAS. For example, in patients with reduced blood volume or impaired water-electrolyte balance, or salt deficiency due to the use of diuretics, a low-salt diet, hemodialysis, diarrhea or vomiting, as well as in patients with impaired left ventricular function and renovascular hypertension. In such patients, blood volume or salt concentration should first be corrected. In patients with heart failure (with or without concomitant renal impairment), symptomatic arterial hypotension may develop. The risk of arterial hypotension in such patients is increased in cases of severe heart failure, the use of high doses of “loop” diuretics, and the presence of hyponatremia or renal impairment.

A transient hypotensive reaction is not a contraindication to continued use of Enanorm and usually does not cause difficulties after restoration of blood volume and blood pressure.

Aortic stenosis

ACE inhibitors should be used with caution in patients with aortic stenosis. Enalapril is contraindicated in cases of hemodynamically significant stenosis.

Primary hyperaldosteronism

The use of enalapril in patients with primary aldosteronism is not recommended.

Patients on hemodialysis

The use of Enanorm during dialysis with high-flux membranes (made of polyacrylonitrile, sodium methylallyl sulfonate, e.g., AN69) may lead to anaphylactic reactions, including facial edema, facial flushing, severe orthostatic hypotension, and dyspnea within minutes of starting dialysis. Therefore, such combinations should be avoided.

Anaphylactoid reactions during LDL apheresis and desensitization to hymenoptera venom

The use of ACE inhibitors during LDL apheresis with dextran sulfate may be accompanied by life-threatening anaphylactoid reactions. The use of ACE inhibitors during specific immunotherapy (desensitization) to insect venoms (bees, wasps) may be accompanied by anaphylactoid reactions, which in some cases can be life-threatening. If LDL apheresis or specific immunotherapy (desensitization) to insect venoms is necessary, ACE inhibitors should be temporarily replaced with other agents for the treatment of arterial hypertension or heart failure.

Surgery/Anesthesia

During major surgery or anesthesia using agents that cause orthostatic hypotension, enalapril leads to blockade of angiotensin II synthesis due to compensatory renin release. In such cases, if orthostatic hypotension develops (and it is assumed that it occurs by this mechanism), it should be corrected by increasing blood plasma volume.

Effect on male fertility

In isolated cases of in vitro fertilization, slow calcium channel blockers similar to nitrendipine have caused reversible biochemical changes in sperm heads, which may lead to impaired sperm function. In cases of repeated unsuccessful attempts at artificial insemination, in addition to other factors, the man’s use of slow calcium channel blockers, such as Nitrendipine, should be taken into account.

Racial differences

Like other ACE inhibitors, enalapril as a component of a fixed-dose combination is likely to be less effective in reducing blood pressure in Black patients than in patients of other races. This may be due to the higher prevalence of low renin activity in Black patients with arterial hypertension.

Use in pediatrics

Enanorm should not be prescribed to children and adolescents under 18 years of age due to a lack of data on its use.

Effect on ability to drive and operate machinery

Caution should be exercised when driving vehicles and operating complex machinery while using Enanorm.

Drug Interactions

The antihypertensive effect of Enanorm may be enhanced when used concomitantly with other antihypertensive agents, such as diuretics, beta-blockers, or alpha-blockers.

Enalapril

Combinations to be used with caution

Potassium-sparing diuretics and potassium supplements. ACE inhibitors reduce diuretic-induced potassium loss. Potassium-sparing diuretics, potassium supplements, and other agents that can increase serum potassium levels (e.g., heparin) may have an additive effect on serum potassium levels, especially in patients with renal impairment. If concomitant use of such drugs is necessary, for example, to correct hypokalemia, caution should be exercised and serum potassium levels should be monitored frequently.

Lithium. The use of enalapril in combination with lithium is not recommended due to the risk of a significant increase in serum lithium concentration with subsequent severe neurotoxicity. If concomitant use of these drugs is necessary, serum lithium concentration should be carefully monitored.

NSAIDs and ACE inhibitors additively increase serum potassium levels, which can lead to worsening of renal function. In elderly patients and patients with reduced blood volume, this combination can cause acute renal failure due to a direct effect on the glomerular filtration rate. Moreover, NSAIDs may weaken the antihypertensive effect of ACE inhibitors.

Oral hypoglycemic agents. Enalapril may enhance the hypoglycemic effect of these drugs, so blood glucose concentration should be carefully monitored.

Baclofen may enhance the antihypertensive effect. If concomitant use is necessary, blood pressure should be monitored and the dose adjusted.

Concomitant use of Enanorm with antipsychotics may cause orthostatic hypotension.

Concomitant use with tricyclic antidepressants may cause orthostatic hypotension.

Allopurinol, cytostatics, immunosuppressants, systemic corticosteroids (administered parenterally or orally), procainamide. Concomitant use with Enanorm may lead to leukopenia.

Combinations to be considered

Concomitant use of Enanorm with amifostine enhances the antihypertensive effect.

Nitrendipine

Cimetidine and, to a lesser extent, ranitidine, can increase the plasma concentration of nitrendipine, but the clinical significance of these data is unknown.

Digoxin. Enalapril has been used concomitantly with digoxin without any signs of clinically significant adverse interaction. Concomitant use of nitrendipine and digoxin may lead to an increase in digoxin plasma concentration. Therefore, symptoms of digoxin overdose should be monitored or, if necessary, digoxin plasma concentration should be monitored.

Muscle relaxants. The use of nitrendipine may increase the duration and severity of the effects of muscle relaxants, such as pancuronium bromide.

Grapefruit juice inhibits the oxidative metabolism of nitrendipine. Taking the latter with grapefruit juice increases the plasma concentration of nitrendipine, which may enhance its antihypertensive effect.

Nitrendipine is metabolized by the CYP3A4 isoenzyme in the intestinal mucosa and liver. Inducers of the CYP3A4 isoenzyme, such as anticonvulsants (phenytoin, phenobarbital, carbamazepine) and rifampicin, can significantly reduce the bioavailability of nitrendipine. Inhibitors of the CYP3A4 isoenzyme, such as antifungal imidazoles (including itraconazole) may increase the plasma concentration of nitrendipine.

Nitrendipine and beta-blockers act synergistically. This may be of particular importance for patients in whom additional beta-adrenergic blockade does not allow compensation for sympathetic vascular reactions, and caution is recommended regarding such patients.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.