Enanorm, tablets 20 mg+10 mg 30 pcs

Pharmacodynamics

Enanorm is a combination of two hypotensive agents that complement each other by a mechanism of blood pressure (BP) reduction: enalapril: angiotensin-converting enzyme (ACE) and nitrendipine: slow calcium channel blocker (CMCB).

ENALAPRIL

Enalapril is a prodrug that hydrolyzes to form the active metabolite, enaprilate, which inhibits ACE. Its mechanism of action is related to the reduction of angiotensin I angiotensin II formation, the decrease of which leads to a fivefold decrease of aldosterone secretion. In this case total peripheral vascular resistance (TPR), systolic and diastolic BP, postload and preload of myocardium are decreased.

Enalapril dilates arteries more than veins, and there is no reflex increase in heart rate (HR).

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

Long-term use decreases left ventricular myocardial hypertrophy and arterial wall myocytes resistance, prevents the progression of heart failure and slows the development of left ventricular dilatation. Enalapril improves the blood supply to the ischemic myocardium.

The time of onset of antihypertensive effect when taken orally is 1 hour, reaches a maximum after 4-6 hours and lasts for 24 hours.

Nitrandipine BMCC from the group of dihydropyridine derivatives has an angihypertensive effect. It reduces the flow of calcium ions into the smooth muscle cells of coronary and peripheral arteries. Causes some increase in sodium and water excretion. Reduces post-load and myocardial oxygen demand, does not inhibit conduction of the heart muscle.

Decreases the number of functioning channels without affecting the time of their activation, inactivation and recovery. Separates the processes of excitation and contraction in myocardium mediated by tropomyosin and troponin and in vascular smooth muscle mediated by calmodulin. In therapeutic doses it normalizes the transmembrane flow of calcium ions which is impaired in a number of pathological conditions, especially in arterial hypertension.

The results of a clinical study of Enanorm in patients with arterial hypertension who have not achieved satisfactory BP control with enalapril monotherapy 10 mg or nitrendipine 20 mg have shown that Enanorm has more pronounced action with regard to both diastolic and systolic BP reduction and degree of therapeutic response to therapy.

Pharmacokinetics

Enalapril

After oral administration, it is 60% absorbed from the gastrointestinal tract. Food intake has no effect on the absorption of enalapril.

Enalapril binding to plasma proteins is 50 – 60%. Enalapril is rapidly metabolized in the liver to form the active metabolite, enalaprilate. Biodistulence of enalapril is 40%.

The maximum concentration of enalapril in blood plasma is reached after 1 hour, of enalaprilat – 3-4 hours. Enalaprilat easily passes through the histoematic barriers, excluding the blood-brain barrier, a small amount penetrates through the placenta and into the breast milk.

The elimination half-life (T1/2) of enalaprilat is about 1 hour. Enalapril is excreted mainly by the kidneys – 60% (20% as enalapril and 40% as enalaprilat), through the intestine – 33% (6% as enapril and 27% as enalaprilat).

It is eliminated by hemodialysis (rate 62 ml/min) and peritoneal dialysis.

Nitrandipine

It is rapidly absorbed from the gastrointestinal tract by 88%. Bioavailability is 20-30% due to a pronounced effect of “primary passage” through the liver, The binding to plasma proteins (albumin) is 96-99%. Hemodialysis is ineffective. Time of reaching maximum concentration in blood plasma 1-3 hours after administration.

The volume of distribution in equilibrium is 5-9 l/kg, therefore hemodialysis and plasmapheresis are ineffective.

It is metabolized in the liver mainly by oxidation. Metabolites are pharmacologically inactive. Nitrendipine is excreted mainly through the kidneys: about 77% of the dose taken is excreted as metabolites, less than 0.1% of the dose taken is excreted unchanged. The rest of nitrendipine is excreted through the intestine.

The T1/2 of nitrendipine after oral administration is 8-12 hours. Neither nitrendipine nor its metabolites cumulate in the body. The T1/2 is increased in elderly patients, the area under the “concentration-time curve” (AUC) and the maximum plasma concentration is increased in cirrhosis.

Dose adjustment is not required in patients with impaired renal function.

Studies of interactions of enalapril and nitrendipine in healthy volunteers have shown no changes in the pharmacokinetics of nitrendipine. As for enalaprilat, its bioavailability is slightly increased by concomitant use with nitrendipine, but this does not seem to be clinically relevant. The bioavailability of nitrendipine is higher with the combined drug than with the two drugs alone.

Indications

Essential hypertension (patients who are indicated for combination therapy).

Active ingredient

Composition

1 tablet contains:

acting ingredients:

nitrendipine – 20 mg,

enalapril maleate – 10 mg;

excipients:

sodium bicarbonate – 5.00 mg,

microcrystalline cellulose – 20.00 mg,

corn starch – 20.00 mg,

sodium lauryl sulfate – 8.00 mg,

povidone K25 – 6.00 mg,

/p>

magnesium stearate – 1.20 mg,

lactose monohydrate – 63.58 mg.

How to take, the dosage

Enanorm is prescribed orally, not more than 1 tablet a day. The tablets should be swallowed whole, without breaking or chewing, with plenty of water.

It is recommended that the doses of the ingredients be adjusted on an individual basis.

Patients with impaired liver function

Enanorm is contraindicated in patients with severe liver function impairment. In patients with mild to moderate hepatic impairment, monotherapy with either enalapril or nitrendipine is not contraindicated, but due to the lack of experience with Enanorm in these patients, the drug should be prescribed with caution.

Patients with impaired renal function

Enanorm is contraindicated in patients with severe renal impairment (CKR less than 10 ml/min) and in patients on hemodialysis. In patients with moderate renal insufficiency (CKD more than 30 ml/min, serum creatinine less than 3 mg/ml) there is no need in dose adjustment; at the same time during the treatment period renal function should be assessed.

Children and adolescents

The drug Enanorm should not be used in children and adolescents under 18 years of age due to lack of data on its use.

Interaction

The antihypertensive effect of Enanorm may be enhanced when used simultaneously with other hypotensive agents, e.g. diuretics, beta-adrenoblockers or alpha-adrenoblockers. In addition, when used concomitantly, certain components of the drug may exhibit the following interactions:

ENALAPRIL

Combinations to be used with caution:

Calcium-saving diuretics and potassium preparations

Angiotensin-converting enzyme inhibitors (ACE inhibitors) reduce diuretic-induced potassium loss. Potassium-saving diuretics, potassium preparations, and other drugs that can increase serum potassium (e.g., heparin) may have an additive effect on serum potassium, especially in patients with impaired renal function. If co-administration of these drugs is necessary, e.g. to reverse hypokalemia, caution should be exercised and serum potassium levels monitored frequently.

Lithium

The use in combination with lithium is not recommended due to the risk of significant increases in serum lithium concentration with subsequent development of severe nephotoxicity. If co-administration of these drugs is necessary, serum lithium concentrations should be monitored carefully.

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) and ACE inhibitors additively increase serum potassium levels, which may lead to impaired renal function. In elderly patients and patients with decreased OBC, this combination may cause acute renal failure by directly affecting glomerular filtration rate. Moreover, NSAIDs may weaken the antihypertensive effect of ACE inhibitors.

Special Instructions

Use strictly as directed by the physician.

Queen’s edema

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

In cases of angioedema of the tongue, larynx or pharynx, it can be fatal; in these cases, emergency treatment must be given with hospitalization, observation of the patient for at least 12-24 hours, and the patient must be discharged from the hospital only after symptoms have completely resolved.

Neutropenia/agranulocytosis

Enalapril should be used with extreme caution in patients with systemic connective tissue disease, in patients receiving immunosuppressants, allopurinol or procainamide, or a combination of these, especially if renal function is impaired. When using Enanorm in such patients, it is recommended to monitor the leukocyte count. During the treatment period, patients should be instructed to inform the physician about any signs of infection. Enanorm should be discontinued if neutropenia is present or suspected (neutrophil count less than 1000/mmZ).

Renal dysfunction

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

In patients with moderate renal dysfunction (creatinine clearance greater than 30 ml/min, serum creatinine ≤Z mg/mL), no dose adjustment is required, but renal function monitoring is necessary.

In some patients, a marked decrease in BP at the start of treatment with ACE inhibitors may lead to a slight further deterioration of renal function. Cases of acute renal failure have been observed in such circumstances, which have usually been reversible.

There is no experience with Enanorm in patients who have recently undergone renal transplantation.

Proteinuria

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

Patients with hepatic impairment

There is no experience with Enanorm in patients with mild to moderate hepatic impairment, so the drug should be used with caution in these patients if indicated.

As there have been some cases of syndrome starting with cholestatic jaundice and progressing to hepatic necrosis with fatal outcome described, it is necessary to stop treatment and monitor the patients if jaundice or marked liver transaminase activity appears.

Orthostatic hypotension

In some cases Enanorm may cause orthostatic hypotension, the risk of which is increased in patients with an activated renin-angiotensin-aldosterone system. For example, in patients with decreased blood volume or impaired blood-water-electrolyte balance or salt deficiency due to diuretics, low-salt diet, hemodialysis, diarrhea or vomiting, impaired left ventricular function, and renovascular hypertension. In such patients, blood volume or salt concentrations should be corrected first. Patients with heart failure (with or without concomitant renal impairment) may develop symptomatic hypotension. The risk of hypotension in such patients is increased in severe heart failure, when using high doses of loop diuretics and in the presence of hyponatremia or renal dysfunction.

Transient hypotensive reaction is not a contraindication for continued use of Enanorm, and it is usually not difficult after recovery of circulating blood volume and blood pressure.

Aortic valve stenosis

In patients with aortic valve stenosis, ACE inhibitors should be used with caution. Enalapril is contraindicated in hemodynamically significant stenosis.

Primary hyperaldosteronism

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

Patients on hemodialysis

Patients on hemodialysis. The use of Enanorm in dialysis through high-strength membranes (polyacrylonitrile, sodium methylallyl sulfonate, such as AN69) can lead to anaphylactic reactions, including facial edema, “flushes to the skin, marked orthostatic hypotension and shortness of breath within minutes of starting dialysis, so these combinations should be avoided.

Anaphylactoid reactions during LDL apheresis and desensitization to hymenopteran venom

The use of ACE during low-density lipoprotein (LDL) apheresis with dextran sulfate can 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 may be life-threatening. If LDL apheresis or specific immunotherapy (desensitization) to insect venoms is necessary, AGIF should be temporarily replaced by other means of treatment of high blood pressure or heart failure.

Surgery/anesthesia

In major surgery or anesthesia with orthostatic drugs, enalapril results in blocking angiotensin II synthesis, due to compensatory renin release. In such cases, if orthostatic hypotension develops (and it is assumed that the development of orthostatic hypotension occurs by this mechanism), it should be corrected by increasing blood plasma volume.

Contraindications

Side effects

Classification of undesirable adverse reactions (ADRs):

The adverse reactions observed with Enanorm are similar to the reactions to taking each of the components of the drug individually.

Cardiovascular system disorders: often – flushing of the skin, peripheral edema; infrequent – tachycardia, dizziness, marked BP decrease; very rare – peripheral circulatory disorders, dyspnea.

Nervous system disorders: frequently – headache; very rarely – asthenia, hypothermia, somnolence, paresthesia, tremor, convulsions.

Respiratory system: often – cough; very rarely – pharyngitis, tracheitis, dyspnea.

The digestive system: infrequent – nausea, dyspepsia; very rare – flatulence.

Skin and subcutaneous tissue: infrequent erythematous rash.

Renal and urinary tract: very rare – hematuria.

Skeletal, muscular and connective tissue disorders: very rare – muscle spasm.

Laboratory and instrumental data: very rarely – increase of liver transaminases activity, hypokalemia.

The following adverse adverse reactions have been reported when taking drugs containing similar components:

ENALAPRIL

Cardiovascular adverse reactions: infrequent-especially at the start of treatment and in patients with decreased OBC and/or saline, worsening of Raynaud’s disease, heart failure, severe arterial hypertension or renal hypertension, and after increasing the dose of enalapril and/or using diuretics u/ or standing position have been noted: dizziness, weakness, visual disturbances; rarely – fainting; very rarely – tachycardia, palpitations, atrial bradycardia, atrial fibrillation, chest pain, angina, myocardial infarction, transient cerebral circulatory disorders due to increased antihypertensive effect occurred. Cardiac arrest, pulmonary embolism and infarction, pulmonary edema.

Renal and urinary tract disorders: infrequent – appearance or increase of renal function disorders; very rare – acute renal failure; rare – oliguria, proteinuria in some cases with associated deterioration of renal function, pain in the iliac region.

Respiratory system disorders: Infrequent – dry cough, sore throat, hoarseness, bronchitis; rare – shortness of breath, sinusitis, rhinitis; very rare – bronchospasm, bronchial asthma attack, pulmonary infiltrates, stomatitis, glottitis, dry mouth, pneumonia, angioedema involving the pharynx, larynx and/or tongue and leading to death in some cases; more frequent in nonhyroid patients.

The digestive system: infrequent – nausea, upper abdominal pain, digestive disorders; rare – vomiting, diarrhea, constipation, loss of appetite, altered or transient loss of taste sensation, anosmia; very rare – pancreatitis, intestinal obstruction, stomatitis, glossitis.

Hepatic and biliary tract disorders: very rare – hepatitis, hepatic insufficiency, syndrome starting with cholestatic jaundice and progressing to liver necrosis, in some cases with fatal outcome.

Endocrine system disorders: very rare gynecomastia.

Skin and subcutaneous tissue: infrequent – exanthem; rare – urticaria, skin itching, angioedema of the lips, face and/or upper and lower extremities; very rare – severe skin reactions, such as pemphigus, erythema multiforme vesicularis, exfoliative dermatitis, Stevens-Johnson syndrome or toxic epidermal necrolysis; psoriasis-like phenomena, photosensitivity, blood flushes to the face, increased sweating, alopecia, onycholysis. Cutaneous manifestations may be accompanied by fever, myalgia/myositis, arthralgia/arthritis, vasculitis, serositis, eosinophilia, leukocytosis, increased erythrocyte sedimentation rate and/or antinuclear antibody titers. If a severe skin reaction is suspected, treatment should be discontinued.

Nervous system disorders: infrequent – headache, weakness; rarely – dizziness, depression, sleep disturbances, impotence, peripheral neuropathy with paresthesia, balance disorders, muscle spasms, nervousness, confusion.

Hearing organ: rarely – tinnitus.

An organ of vision: rarely – blurred vision, dry eyes, increased lacrimation.

Laboratory and instrumental data: 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; increased serum concentrations of urea, creatinine, and potassium, decreased serum sodium, hyperkalemia (in diabetic patients), increased renal albumin excretion, especially in patients with impaired renal function, severe heart failure), renovascular hypertension; very rarely – hemolysis/hemolytic anemia (also in combination with glucose-6-phosphate dehydrogenase deficiency), increased bilirubin concentration and increased asthma of “hepatic” transaminases.

Nitrandipine

Immune system disorders: infrequent flu-like syndrome.

Cardiovascular system: infrequent – arrhythmia, tachycardia, palpitations, peripheral edema, “rushes” of blood to the face, increasing symptoms of vasodilation; rarely – marked decrease of blood pressure, angina pectoris, chest pain.

Gastro-intestinal tract: infrequent – nausea, diarrhea, rarely – abdominal pain, constipation, dyspepsia, vomiting; very rare – gum hyperplasia.

Endocrine system: very rare – gynecomastia.

With the blood and lymphatic system: very rare – leukopenia, agranulocytosis.

Muscular and connective tissue: rarely – myalgia.

Nervous system disorders: infrequent – headache, asthenia; rarely – nervousness, paresthesia, tremor, dizziness.

Respiratory system disorders: rarely – shortness of breath.

Skin and subcutaneous tissue: rarely – skin itching, rash, urticaria.

An organ of vision: rarely – visual disturbances.

Renal and urinary tract: very rarely – increased frequency of urination, polyuria.

Laboratory and instrumental data: very rarely – increased activity of “liver” enzymes.

If any of the side effects listed in the instructions worsen, or if any other side effects not listed in the instructions are noticed, the physician should be informed.

Overdose

To date, overdose of this combination has not been reported.

Symptoms: the most likely manifestation of overdose of Enanorm will be a marked decrease in BP.

Treatment: there is no specific antidote. Gastric lavage, administration of adsorbents (if possible, in the first 30 minutes. Vital signs should be monitored.

If there is a significant decrease in BP, the patient should be transferred to a low lying, horizontal position. In mild cases gastric lavage and oral administration of sodium chloride saline are indicated, in more severe cases – measures aimed at stabilization of BP; intravenous infusion of 0.9% sodium chloride solution; plasma exchange solutions; angiotensin II infusion, hemodialysis if necessary (enalaprilat infusion rate – 62 ml/min).

Pregnancy use

Pregnancy

The use of ACE inhibitors in the first trimester of pregnancy is not recommended. Epidemiologic data on the risk of teratogenicity of ACE inhibitors in the first trimester of pregnancy are not conclusive; however, an increase in this risk cannot be excluded. If continued use of ACE inhibitors during pregnancy is not deemed absolutely necessary, patients should be switched to alternative therapies whose safety in pregnancy has been established. The use of ACE inhibitors during the second and third trimesters of pregnancy is known to have toxic effects on the fetus (impaired renal function, sedation, delayed cranial ossification) and the newborn (impaired renal function, arterial hypotension, hyperkalemia). If ACE inhibitors have been used in the second and third trimesters of pregnancy, an ultrasound examination is recommended to assess renal function and cranial bone condition. Newborns should also be closely monitored for arterial hypotension if the mother was taking ACE inhibitors.

Breastfeeding

Few pharmacokinetic data are available about the very low concentrations of enalapril in breast milk. Although these concentrations are clinically insignificant, it is not recommended for use in breastfed preterm infants or in the first few weeks after birth because of the theoretical possibility of cardiovascular and renal risks in neonates and the lack of sufficient clinical data. In older infants, breastfeeding women may be considered if such treatment is necessary for the mother and if the child is monitored for any adverse events.