Triapin (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis Deutschland, GmbH (Germany)

ATC Code

C09BB05 (Ramipril and Felodipine)

Active Substances

Felodipine (Rec.INN registered by WHO)

Ramipril (Rec.INN registered by WHO)

Dosage Forms

	Triapin	Extended-release film-coated tablets, 2.5 mg+2.5 mg: 20, 28, 30 or 42 pcs.
		Extended-release film-coated tablets, 5 mg+5 mg: 20, 28, 30 or 42 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – PVC/aluminum foil blisters (2) – cardboard packs.
10 pcs. – PVC/aluminum foil blisters (3) – cardboard packs.
14 pcs. – PVC/aluminum foil blisters (2) – cardboard packs.
14 pcs. – PVC/aluminum foil blisters (3) – cardboard packs.

10 pcs. – PVC/aluminum foil blisters (2) – cardboard packs.
10 pcs. – PVC/aluminum foil blisters (3) – cardboard packs.
14 pcs. – PVC/aluminum foil blisters (2) – cardboard packs.
14 pcs. – PVC/aluminum foil blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + ACE inhibitor)

Pharmacological Action

Both medicinal products included in the combination: the CCB – Felodipine and the ACE inhibitor – Ramipril, lower blood pressure (BP) through dilation of peripheral blood vessels.

CCBs dilate the arterial bed, whereas ACE inhibitors dilate both the arterial and venous beds. Vasodilation and, consequently, BP reduction can activate the sympathetic nervous system and the renin-angiotensin-aldosterone system.

Inhibition of ACE leads to a decrease in the plasma concentration of angiotensin II.

The antihypertensive effect of a single dose of Triapin develops within 1-2 hours. The maximum antihypertensive effect is achieved within 2-4 weeks and is maintained during long-term treatment. The antihypertensive effect is maintained with a 24-hour dosing interval.

Felodipine is a ‘slow’ calcium channel blocker that reduces BP by decreasing total peripheral vascular resistance through a direct relaxing effect on vascular smooth muscle.

Due to its selective effect on arteriolar smooth muscle, therapeutic doses of felodipine do not affect myocardial contractility and conduction.

Felodipine reduces vascular resistance in the kidneys. This does not affect normal glomerular filtration. In cases of impaired renal function, glomerular filtration may increase.

Felodipine has a weak natriuretic and diuretic effect; fluid retention in the body does not occur.

Ramipril. The active metabolite of ramipril formed under the action of ‘hepatic’ enzymes – ramiprilat – is a long-acting ACE inhibitor.

In blood plasma and tissues, ACE catalyzes the conversion of angiotensin I to angiotensin II (an active vasoconstrictor) and the breakdown of the active vasodilator – bradykinin.

Therefore, when taking ramipril, the formation of angiotensin II is reduced and bradykinin accumulates, leading to vasodilation and a decrease in BP, and also contributes to the cardioprotective effect of ramipril and its endothelial protective effect, due to the induction of nitric oxide (NO) formation in endothelial cells as a result of prostaglandin system activation and increased prostaglandin synthesis under the influence of increased kallikrein-kinin system activity in the blood and tissues.

Angiotensin II stimulates the release of aldosterone, so taking ramipril leads to a decrease in aldosterone secretion and an increase in serum potassium ion concentrations.

Due to the negative feedback between the concentration of angiotensin II and renin secretion, a decrease in the concentration of angiotensin II leads to an increase in plasma renin activity.

It is also assumed that the increase in bradykinin activity is partially associated with the occurrence of some adverse reactions (dry cough).

Pharmacokinetics

Felodipine (extended-release dosage form) bioavailability is about 15% and does not depend on food intake.

C_max is reached in 3 – 5 hours. Plasma protein binding is 99%. V_d at steady state is 10 L/kg. T_1/2 of felodipine is approximately 25 hours; steady state is reached after 5 days.

During long-term treatment, there is no risk of accumulation. The clearance of felodipine averages 1200 ml/min. In elderly patients, a decrease in clearance leads to an increase in the plasma concentration of felodipine. Age is only a partial explanation for interindividual differences in felodipine plasma concentrations.

Felodipine is metabolized in the liver, and all its known metabolites lack vasodilatory action.

Approximately 70% of the administered dose is excreted as metabolites by the kidneys, and about 10% through the intestines.

Less than 0.5% of the dose is excreted unchanged by the kidneys. Impaired renal function does not affect the plasma concentrations of felodipine.

Ramipril: after oral administration, Ramipril is rapidly absorbed from the gastrointestinal tract (50-60%). Food slows its absorption but does not affect the extent of absorption.

Ramipril undergoes intensive presystemic metabolism/activation (mainly in the liver by hydrolysis), resulting in the formation of its only active metabolite – ramiprilat, whose ACE inhibitory activity is approximately 6 times greater than that of ramipril.

In addition, as a result of ramipril metabolism, a diketopiperazine is formed, which lacks pharmacological activity, and is then conjugated with glucuronic acid; ramiprilat is also glucuronidated and metabolized to diketopiperazine acid.

The bioavailability of ramipril after oral administration ranges from 15% (for a 2.5 mg dose) to 28% (for a 5 mg dose). The bioavailability of the active metabolite – ramiprilat – after oral administration of 2.5 mg and 5 mg of ramipril is approximately 45% (compared to intravenous administration of the same doses of ramipril).

After oral administration of ramipril, maximum plasma concentrations of ramipril and ramiprilat are reached after 1 and 2-4 hours, respectively. The decrease in plasma concentration of ramiprilat occurs in several stages: a distribution and elimination phase with a T_1/2 of ramiprilat of approximately 3 hours, then an intermediate phase with a T_1/2 of ramiprilat of approximately 15 hours, and a terminal phase with a very low plasma concentration of ramiprilat and a T_1/2 of ramiprilat of approximately 4-5 days.

This terminal phase is due to the slow release of ramiprilat from a strong bond with ACE receptors.

Despite the prolonged terminal phase, with a single daily dose of ramipril of 2.5 mg or more, the steady-state plasma concentration of ramiprilat is reached approximately 4 days after the start of treatment.

During course use of the drug, the ‘effective’ T_1/2 depending on the dose is 13-17 hours.

Plasma protein binding is approximately 73% for ramipril and 56% for ramiprilat.

After intravenous administration, the volume of distribution of ramipril and ramiprilat is approximately 90 L and 500 L, respectively.

Approximately 80-90% of metabolites in urine and bile were identified as ramiprilat and its metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10-20% of the total metabolites in urine, and the content of unmetabolized ramipril in urine is approximately 2%.

In cases of impaired renal function (creatinine clearance less than 60 ml/min), the renal excretion of ramiprilat and its metabolites is slowed. This leads to an increase in the plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.

Bioequivalence of the fixed combination (Felodipine+Ramipril) and simultaneously administered individual preparations of felodipine and ramipril

The pharmacokinetics of ramipril, ramiprilat, and felodipine of the drug Triapin^® do not change significantly compared to those of the individual preparations of felodipine and ramipril: extended-release felodipine tablets and ramipril tablets.

Felodipine does not affect the ACE inhibition caused by ramiprilat.

Thus, the fixed combination tablets Felodipine+Ramipril are bioequivalent to the simultaneously administered individual components of this combination (extended-release felodipine and ramipril).

Indications

• Essential arterial hypertension.

ICD codes

Dosage Regimen

Swallow tablets whole with a sufficient amount of liquid; do not divide, crush, or chew.

Administer once daily, regardless of meals.

Initiate therapy with the 2.5 mg + 2.5 mg strength. The recommended starting dose is one tablet per day.

The maximum daily dose for the 2.5 mg + 2.5 mg strength is two tablets.

For the 5 mg + 5 mg strength, the recommended dose is one tablet per day. Do not exceed one tablet daily.

Titrate the dose based on individual therapeutic response and tolerability. The maximum antihypertensive effect is typically achieved within 2 to 4 weeks.

For patients with impaired renal function (creatinine clearance 20-50 ml/min), exercise caution and monitor renal function and serum potassium.

In elderly patients, use with caution due to the potential for a more pronounced hypotensive effect; consider a lower starting dose.

Prior to switching to this fixed-dose combination, achieve stable blood pressure control using the individual components at equivalent doses.

If a dose is missed, take it as soon as remembered unless it is almost time for the next dose; do not double the dose.

Adverse Reactions

The adverse effects listed below are presented according to the following frequency gradations: very common (≥ 10%), common (≥1%, <10); uncommon (≥0.1%, < 1%); rare (≥0.01%, < 0.1%) and very rare, including isolated reports (<0.01%), unknown frequency (cannot be estimated from the available data).

The following adverse reactions may develop due to the intake of ramipril

Nervous system and sensory organs

Uncommon – headache, feeling of fatigue, balance disorder, allergic conjunctivitis.

Rare – drowsiness, depressed mood, sleep disorders, impotence, decreased libido, confusion, feeling of restlessness, irritability, tremor, hearing disorders (e.g., ringing in the ears), decreased visual acuity, taste and smell disorders, temporary loss of taste sensations.

Very rare – paresthesia.

Cardiovascular system

Uncommon – excessive decrease in BP (arterial hypotension, orthostatic reaction), accompanied by symptoms such as dizziness, decreased ability to concentrate, increased sweating, weakness, visual impairment (these phenomena are more often observed at the beginning of treatment and in patients with hyponatremia and hypovolemia, heart failure – especially after acute myocardial infarction, severe arterial hypertension, as well as when increasing the dose of ramipril and (or) diuretics); peripheral edema (in the ankle area).

Rare – loss of consciousness (fainting).

The following adverse reactions may be associated with a pronounced decrease in BP

Uncommon – tachycardia

Rare – palpitation sensation, angina pectoris.

Very rare – myocardial infarction, transient cerebrovascular accident, ischemic stroke; rhythm disturbances (appearance or intensification), worsening of circulatory disorders against the background of stenosing vascular lesions.

Respiratory system

Common – dry, non-productive cough, more frequent in women and non-smoking patients, worsening at night and in a horizontal lying position.

Rare – bronchospasm, shortness of breath, bronchitis, sinusitis, rhinitis.

Very rare – angioedema involving the larynx, pharynx and/or tongue (see section ‘Special Instructions’), more common in patients of the Black race.

Gastrointestinal tract

Uncommon – nausea, decreased appetite.

Rare – epigastric pain with increased activity of ‘hepatic’ enzymes, dyspeptic disorders, vomiting, diarrhea or constipation, inflammation of the gastrointestinal mucosa, including the oral mucosa and tongue, dry mouth, thirst.

Very rare – pancreatitis, angioedema of the small intestine, partial or complete intestinal obstruction.

Liver

Very rare – impaired liver function (including the development of acute liver failure), hepatitis; cases of liver injury syndrome beginning with cholestatic jaundice and progressing to hepatic necrosis (sometimes fatal) have been described with ACE inhibitors.

Skin and mucous membranes; allergic reactions

Uncommon – allergic reactions (skin rash, itching, urticaria, angioedema involving the lips, face, and/or extremities), upon occurrence of which ramipril should be discontinued.

Very rare – severe skin reactions (multiforme erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis), maculopapular exanthema and enanthema, pemphigus, worsening of psoriasis, psoriasiform, pemphigoid and lichenoid lesions of the skin and mucous membranes, photosensitivity, alopecia, onycholysis, vasculitis and exacerbation or development of Raynaud’s syndrome. If serious skin reactions are suspected, the patient should immediately inform the doctor and stop taking ramipril.

Some skin reactions may be accompanied by fever, myalgia, arthralgia (or) arthritis, vasculitis, eosinophilia and/or an increase in the titer of antinuclear antibodies.

Kidneys

Uncommon – impaired renal function or worsening of pre-existing impaired renal function.

Very rare – acute renal failure; proteinuria, sometimes with decreased renal function.

Musculoskeletal system and others

Very rare – muscle cramps, myalgia, arthralgia, fever.

Blood picture and laboratory parameters

Uncommon – increased serum concentrations of urea and creatinine (especially in patients with impaired renal function), increased bilirubin concentration and activity of ‘hepatic’ enzymes.

Rare – decreased hemoglobin concentration, decreased hematocrit, leukopenia, anemia, thrombocytopenia, eosinophilia, increased potassium ion concentration (especially in patients with diabetes mellitus), decreased sodium ion concentration, increased activity of pancreatic enzymes.

Very rare – agranulocytosis or pancytopenia (especially in patients with impaired renal function, connective tissue diseases or concurrent treatment with allopurinol, procainamide and some immunosuppressive agents), increased titer of antinuclear antibodies, hemolysis/hemolytic anemia, including due to glucose-6-phosphate dehydrogenase deficiency, proteinuria.

Adverse effects on the fetus

Impaired development of fetal kidneys, decreased BP in the fetus and newborns, impaired renal function, hyperkalemia, skull hypoplasia, oligohydramnios, limb contractures, skull bone deformities, lung hypoplasia.

The following adverse reactions may develop due to the intake of felodipine.

Nervous system and sensory organs

Common – headache.

Uncommon – dizziness, paresthesia.

Cardiovascular system

Common – facial flushing, peripheral edema.

Uncommon – tachycardia, sensation of palpitations.

Rare – loss of consciousness (fainting).

Very rare – leukocytoclastic vasculitis, extrasystole, pronounced decrease in BP.

Gastrointestinal tract and liver

Uncommon – nausea, epigastric pain.

Rare – vomiting, gum hyperplasia, tongue mucosal hyperplasia, gingivitis.

Very rare – increased activity of ‘hepatic’ transaminases.

Skin and mucous membranes; allergic reactions

Uncommon – skin rash, itching.

Rare – urticaria.

Very rare – angioedema of the lips or tongue, photosensitivity reactions, hypersensitivity reactions.

Kidneys

Rare – frequent urination.

Musculoskeletal system

Rare – myalgia, arthralgia.

Other

Uncommon – fatigue.

Rare – impotence, sexual disorders.

Very rare – fever, hyperglycemia.

Contraindications

• History of angioedema (risk of rapid development of angioedema);
• Hemodynamic instability: cardiogenic shock, decompensated chronic heart failure, acute myocardial infarction, unstable angina, stroke;
• Atrioventricular block II and III degree;
• Hemodynamically significant stenosis of the aortic or mitral valve or hypertrophic obstructive cardiomyopathy;
• Renal artery stenosis (bilateral or unilateral in the case of a single kidney);
• Condition after kidney transplantation;
• Primary hyperaldosteronism;
• Severe hepatic insufficiency;
• Severe renal insufficiency (creatinine clearance less than 20 ml/min) or hemodialysis (insufficient clinical experience);
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces, such as hemodialysis or hemofiltration with certain high-flux membranes (polyacrylonitrile membranes) and low-density lipoprotein apheresis with dextran sulfate (high risk of severe anaphylactoid reactions);
• Lactase deficiency, galactose intolerance, or glucose-galactose malabsorption syndrome (due to the lactose content in the drug);
• Hypersensitivity to felodipine (or other dihydropyridine derivatives), ramipril, other ACE inhibitors, or to any of the excipients of the drug.

With caution

• Conditions in which an excessive decrease in BP is particularly dangerous (stenosing lesions of the coronary and cerebral arteries, severe ventricular arrhythmias);
• Conditions accompanied by increased activity of the renin-angiotensin-aldosterone system, in which ACE inhibition carries a risk of a sharp decrease in BP with worsening renal function (severe arterial hypertension, moderate chronic heart failure, hemodynamically significant unilateral renal artery stenosis in the presence of two kidneys, prior diuretic use, water-electrolyte imbalance, diarrhea, vomiting);
• Renal impairment (creatinine clearance 20-50 ml/min) (risk of hyperkalemia and decreased leukocyte count);
• Systemic connective tissue diseases (including systemic lupus erythematosus; scleroderma);
• Concomitant therapy with glucocorticosteroids, immunomodulators, cytostatics, antimetabolites, allopurinol, procainamide, and lithium salts, bone marrow depression (risk of impaired immune reactions, neutropenia or agranulocytosis); diabetes mellitus (risk of hyperkalemia); elderly age (risk of more pronounced hypotensive effect); hyperkalemia.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency.

Use in Renal Impairment

Contraindicated: severe renal failure (creatinine clearance less than 20 ml/min) or hemodialysis (insufficient clinical experience); status after kidney transplantation.

Use with caution: Renal impairment (creatinine clearance 20-50 ml/min) (risk of hyperkalemia and decreased leukocyte count).

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Use with caution in the elderly (risk of more pronounced hypotensive effect).

Special Precautions

If edema occurs, for example, of the face (lips, eyelids) or tongue, or difficulty swallowing or breathing, the patient should immediately discontinue the drug.

Angioedema of the tongue, pharynx, or larynx (possible symptoms: difficulty swallowing or breathing) can be life-threatening and requires emergency care (immediate subcutaneous injection of 1:1000 epinephrine (adrenaline) solution (0.3-0.5 ml) or slow intravenous administration of 1 mg/ml epinephrine (note the dilution instructions) under ECG and blood pressure monitoring.

The patient should be hospitalized and observed for at least 12-24 hours until symptoms completely resolve.

If there is a history of angioedema not associated with ACE inhibitor use, such patients still have an increased risk of its development when taking Triapin.

Intestinal angioedema has been reported in patients treated with ACE inhibitors.

Such patients experienced abdominal pain (with or without nausea and vomiting); in some cases without preceding facial edema and with normal C₁-esterase activity.

This condition was diagnosed during computed tomography or ultrasound of the abdomen or during surgery; symptoms resolved after discontinuation of the ACE inhibitor.

In patients taking an ACE inhibitor and having abdominal pain, intestinal angioedema should be included in the differential diagnosis.

When treated with ACE inhibitors, angioedema is more frequently reported in Black patients compared to Caucasian patients.

Monitoring of renal function is necessary, especially during the first weeks of treatment and particularly carefully in patients with concomitant circulatory failure, renal vascular disease (e.g., with clinically insignificant renal artery stenosis, or with unilateral hemodynamically significant renal artery stenosis, since even a slight increase in serum creatinine concentration may indicate unilateral reduction in renal function) in cases of pre-existing renal impairment.

In some patients treated with ACE inhibitors, including ramipril, an increase in serum potassium concentration has been observed.

Patients at risk for hyperkalemia include those with renal failure, diabetes mellitus, or patients concurrently using potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes, as well as patients taking other drugs associated with increased serum potassium concentrations (e.g., heparin).

If concomitant use of these drugs is necessary, serum potassium levels should be monitored regularly.

The likelihood of developing proteinuria is higher in patients with impaired renal function or with relatively high doses of ACE inhibitors.

There is an increased risk of severe arterial hypotension and renal failure if a patient with renovascular hypertension and established bilateral renal artery stenosis or stenosis of the artery to a solitary kidney is treated with an ACE inhibitor.

In patients with unilateral renal artery stenosis (with two kidneys), a decrease in renal function may occur with only minor changes in serum creatinine concentration.

There is no experience with the use of Triapin in patients with recently transplanted kidneys.

In rare cases, the use of ACE inhibitors has been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis (sometimes fatal).

The mechanism of this syndrome is unknown.

If jaundice or a marked increase in liver enzymes occurs, the ACE inhibitor should be discontinued and appropriate medical care provided.

During major surgery or during anesthesia with agents known to cause hypotension, arterial hypotension may develop, which can be corrected by volume expansion.

ACE inhibitors should be used with caution in patients with significant hemodynamic impairment of left ventricular function (e.g., aortic or mitral valve stenosis, obstructive cardiomyopathy).

Close medical supervision is required during the initial phase of treatment.

In some patients, mainly those with chronic heart failure (with or without concomitant renal impairment), receiving high doses of loop diuretics, in case of hyponatremia or decreased renal function, symptomatic arterial hypotension may develop after the first dose.

Therefore, prescribing Triapin to such patients should only be done after additional assessment of their condition and proper titration of the individual components.

Triapin should only be administered under stable hemodynamic conditions.

In patients with arterial hypertension without cardiac or renal failure, arterial hypotension may develop, mainly in case of reduced blood volume due to diuretic therapy, salt-restricted diet, diarrhea, or vomiting.

Patients for whom a decrease in blood pressure poses a particular risk (e.g., patients with coronary or cerebrovascular insufficiency) should start treatment and have the necessary doses of this combination selected using individual preparations of felodipine and ramipril.

If satisfactory and stable blood pressure control is achieved with doses of ramipril and felodipine equal to those contained in Triapin, the patient can be switched to the fixed combination.

In some cases, Felodipine may cause arterial hypotension with tachycardia, which may provoke an exacerbation of angina pectoris.

Triapin can cause agranulocytosis and neutropenia.

These adverse reactions have been demonstrated with other ACE inhibitors: less frequently in uncomplicated patients, and more frequently in patients with renal impairment, especially when the latter is accompanied by a systemic connective tissue disease (e.g., systemic lupus erythematosus or scleroderma) during treatment with immunosuppressive drugs.

White blood cell count monitoring should be ensured in patients with systemic connective tissue diseases (collagenoses), especially if the disease is accompanied by impaired renal function.

After discontinuation of the ACE inhibitor, neutropenia and agranulocytosis are reversible.

If symptoms such as fever, swollen lymph nodes and/or sore throat develop during treatment with Triapin^®, a doctor should be consulted and the white blood cell count checked immediately.

During treatment with an ACE inhibitor, a dry cough may appear, which disappears after discontinuation of the drug.

Concomitant treatment with ACE inhibitors and hypoglycemic agents (insulin and oral hypoglycemic agents) may enhance the hypoglycemic effect with a risk of hypoglycemia.

This effect is most pronounced at the beginning of treatment and in patients with impaired renal function.

Felodipine is metabolized by the CYP3A4 isoenzyme.

Therefore, combinations with drugs that are potent inhibitors or inducers of the CYP3A4 isoenzyme should be avoided.

For the same reason, simultaneous intake of grapefruit juice should be avoided (see section “Drug Interactions”).

Combining lithium preparations with an ACE inhibitor is not recommended.

In patients undergoing hemodialysis using certain high-flux membranes (e.g., polyacrylonitrile membranes) while taking ACE inhibitors (see also membrane manufacturers’ instructions), life-threatening, rapidly developing, allergy-like (anaphylactoid) hypersensitivity reactions, sometimes progressing to shock, have been described.

The combined use of Triapin and such membranes, for example, for emergency hemodialysis or hemofiltration, should be avoided.

In this case, the use of other membranes or discontinuation of ACE inhibitors is preferable.

Similar reactions have been observed during low-density lipoprotein apheresis with dextran sulfate.

Therefore, this method should not be used for patients being treated with ACE inhibitors.

As with other ACE inhibitors, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom during desensitization (e.g., bees, wasps) is increased.

This medicine contains lactose.

It should not be taken by patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Effect on ability to drive and use machines

Some side effects (e.g., symptoms associated with decreased blood pressure, such as dizziness) may impair the ability to concentrate and slow psychomotor reactions, which may increase the risk in situations where this is particularly important, such as when driving or operating machinery.

Overdose

Overdose may cause excessive peripheral vasodilation with marked decrease in blood pressure, bradycardia (sometimes tachycardia), atrioventricular block I-III degree, hypokalemia, ventricular extrasystole, ventricular fibrillation, shock, electrolyte imbalance, and renal failure.

Primary detoxification by, for example, gastric lavage, administration of adsorbents and/or laxatives (if possible within the first 30 minutes).

In case of marked decrease in blood pressure: in addition to volume and salt replacement, administration of α₁-adrenergic sympathomimetics and angiotensin II may be required.

For bradycardia, atrioventricular block, or excessive vagal excitation, administer atropine.

The specific antidote for felodipine is calcium preparations (in case of overdose, slow intravenous administration of 10% calcium chloride or calcium gluconate is indicated, followed by switching to a prolonged infusion).

There is no experience regarding the effectiveness of forced diuresis, urine pH change, hemofiltration, or dialysis for the purpose of accelerating the elimination of ramipril or ramiprilat.

Drug Interactions

Combinations not recommended

• Potassium salts, potassium-sparing diuretics (e.g., amiloride, triamterene, spironolactone) – more pronounced increase in serum potassium ion concentration (careful monitoring of serum potassium ion concentration is required during concomitant use);

Felodipine is a substrate of the CYP3A4 isoenzyme. Drugs that induce or inhibit the CYP3A4 isoenzyme have a significant effect on the plasma concentration of felodipine.

Drugs that enhance the metabolism of felodipine by inducing the CYP 3 A 4 isoenzyme include carbamazepine, phenytoin, phenobarbital and rifampicin, as well as St. John’s wort (Hypericum perforatum).

When felodipine is administered concomitantly with carbamazepine, phenytoin, phenobarbital, the AUC (area under the concentration-time curve) decreases by 93%, and C_max by 82%.

A similar effect is possible with St. John’s wort.

Combinations with inducers of the CYP3A4 isoenzyme should be avoided.

Potent inhibitors of the CYP3A4 isoenzyme include azole antifungals, macrolide antibiotics, telithromycin and HIV protease inhibitors.

When felodipine is used concomitantly with itraconazole, C_max increases 8-fold, and AUC 6-fold.

During concomitant use of felodipine with erythromycin, C_max and AUC increased almost 2.5-fold.

Combinations with potent inhibitors of the CYP3A4 isoenzyme should be avoided.

Grapefruit juice inhibits the CYP 3 A 4 isoenzyme.

Concomitant intake of felodipine with grapefruit juice increases the C_max and AUC of felodipine by approximately 2-fold.

This combination should be avoided.

Combinations requiring caution

• Antihypertensive agents (especially diuretics) and other drugs that lower blood pressure (nitrates, tricyclic antidepressants) – potentiation of hypotensive effects;
• Hypnotics, narcotics, and analgesics – may cause a more pronounced decrease in blood pressure;
• Vasopressor adrenomimetics (epinephrine) may cause a weakening of the effect of ramipril;
• Allopurinol, procainamide, cytostatics, immunosuppressants, systemic glucocorticosteroids and other drugs that may affect hematological parameters — concomitant use increases the risk of leukopenia;
• Lithium – increased serum lithium concentration and enhanced cardio- and neurotoxic effects of lithium;
• Oral hypoglycemic agents (sulfonylurea derivatives, biguanides), insulin – due to the reduction of insulin resistance under the influence of ramipril, the hypoglycemic effect of these agents may be enhanced, up to the development of hypoglycemia;
• Non-steroidal anti-inflammatory drugs (indomethacin, acetylsalicylic acid) – possible weakening of the effect of ramipril, increased risk of renal impairment and increased serum potassium ion concentration;
• Heparin – possible increase in serum potassium ion concentration;
• Sodium chloride – weakening of the hypotensive effect of ramipril and less effective treatment of heart failure symptoms;
• Ethanol – enhancement of vasodilation;
• Estrogens – weakening of the hypotensive effect of ramipril (fluid retention);
• Theophylline – concomitant treatment with felodipine and oral theophylline reduces the absorption of theophylline by approximately 20%. This phenomenon is probably of minor clinical significance;
• Tacrolimus – Felodipine may increase the concentration of tacrolimus. During concomitant use, serum tacrolimus concentration should be monitored; adjustment of the tacrolimus dose may be required.

Storage Conditions

For 2.5 mg+2.5 mg dosage: at a temperature not exceeding 30°C (86°F). For 5 mg+5 mg dosage: at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life: for 2.5 mg+2.5 mg tablets — 2 years, for 5 mg+5 mg tablets — 2.5 years.

Dispensing Status

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.