Sumilar n
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUMILAR H (SUMILAR H)
Composition:
Active substances: ramipril, amlodipine (as amlodipine besylate), hydrochlorothiazide;
One hard capsule contains:
5 mg ramipril, 6.934 mg amlodipine besylate equivalent to 5 mg amlodipine free base and 12.5 mg hydrochlorothiazide, or
10 mg ramipril, 13.868 mg amlodipine besylate equivalent to 10 mg amlodipine free base and 25 mg hydrochlorothiazide, or
10 mg ramipril, 6.934 mg amlodipine besylate equivalent to 5 mg amlodipine free base and 25 mg hydrochlorothiazide;
Excipients:
capsule contents: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, pregelatinized corn starch, low moisture pregelatinized corn starch, sodium starch glycolate (type A), sodium stearyl fumarate;
capsule shell:
5 mg/5 mg/12.5 mg: body: iron oxide black (E 172), titanium dioxide (E 171), gelatin; cap: iron oxide red (E 172), titanium dioxide (E 171), gelatin;
10 mg/10 mg/25 mg: body: iron oxide red (E 172), iron oxide yellow (E 172), titanium dioxide (E 171), gelatin; cap: iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172), titanium dioxide (E 171), gelatin;
10 mg/5 mg/25 mg: body: iron oxide yellow (E 172), titanium dioxide (E 171), gelatin; cap: iron oxide red (E 172), titanium dioxide (E 171), gelatin.
Pharmaceutical form. Hard capsules.
Main physicochemical properties:
5 mg/5 mg/12.5 mg: hard gelatin capsule, size № 3; body: light grey, opaque; cap: pink, opaque. Capsule contents: white or almost white granules;
10 mg/10 mg/25 mg: hard gelatin capsule, size № 1; body: caramel-colored, opaque; cap: brown, opaque. Capsule contents: white or almost white granules;
10 mg/5 mg/25 mg: hard gelatin capsule, size № 1; body: yellow, opaque; cap: dark pink, opaque. Capsule contents: white or almost white granules.
Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. Other combinations. ATC code C09BX03.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action of ramipril
Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme, kininase II), which catalyzes the conversion of tissue angiotensin I into the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduction in angiotensin II levels and inhibition of bradykinin degradation lead to vasodilation.
Since angiotensin II also stimulates aldosterone release, ramiprilat results in reduced aldosterone secretion. On average, the response to monotherapy with ACE inhibitors has been lower in patients of non-black race (from the Afro-Caribbean region) with hypertension (typically in groups with low renin levels and hypertension) compared to other races.
Pharmacodynamic effects
Administration of ramipril leads to a pronounced reduction in peripheral arterial resistance. Significant changes in renal plasma flow and glomerular filtration rate are usually not observed. In individuals with arterial hypertension, ramipril reduces arterial blood pressure both in the supine and upright positions without increasing heart rate.
In most patients, the antihypertensive effect begins within 1–2 hours after administration, reaches its maximum within 3–6 hours, and lasts for 24 hours.
Maximum reduction in blood pressure is usually achieved after 3–4 weeks of continuous treatment. The antihypertensive effect has been shown to be maintained during long-term therapy lasting up to 2 years.
Sudden discontinuation of ramipril does not lead to rapid or excessive rebound increase in blood pressure.
Mechanism of action of amlodipine
Amlodipine inhibits transmembrane influx of calcium ions into cardiac and vascular smooth muscle (a slow calcium channel blocker or calcium antagonist).
The antihypertensive mechanism of action of the drug is due to its relaxing effect on vascular smooth muscle.
The exact mechanism of action of amlodipine in angina is not fully established, but it is known that the drug reduces myocardial ischemia via two pathways:
- Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance. Since heart rate remains virtually unchanged, the reduced cardiac workload leads to decreased myocardial oxygen demand.
- By dilating major coronary arteries and coronary arterioles in both normal and ischemic myocardial regions, amlodipine improves oxygen delivery. Through this mechanism, it increases oxygen supply to the myocardium even in cases of coronary artery spasm (Prinzmetal's angina or variant angina).
Pharmacological Properties
In patients with arterial hypertension, once-daily dosing provides clinically significant reduction of arterial blood pressure throughout the entire 24-hour interval, both in the supine and upright positions. Due to its slow onset of action, acute arterial hypotension is not a characteristic of the drug's use.
In patients with angina pectoris, once-daily dosing increases total exercise duration, time to onset of angina, and time to significant ST-segment depression, as well as reduces both the frequency of angina attacks and the need for nitroglycerin.
The drug is not associated with any adverse metabolic effects: it has no influence on plasma lipid levels, blood glucose levels, or serum uric acid levels. The drug is suitable for use in patients with asthma.
Mechanism of action of hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully elucidated. Hydrochlorothiazide inhibits reabsorption of sodium and chloride ions in the distal tubules, resulting in excretion of approximately 15% of filtered sodium and chloride. Enhanced renal excretion of these ions is accompanied by increased urine output (due to osmotic water retention). Excretion of potassium and magnesium is also increased, whereas excretion of uric acid is reduced. With high-dose hydrochlorothiazide use, excretion of bicarbonate may be enhanced due to inhibition of carbonic anhydrase, leading to alkaline urine pH. Acidosis or alkalosis does not significantly affect the saluretic and diuretic effects of hydrochlorothiazide. Glomerular filtration rate decreases to a minimal level at the beginning of therapy. During prolonged hydrochlorothiazide therapy, renal excretion of calcium decreases. This mechanism may lead to hypercalcemia.
Possible mechanisms of hydrochlorothiazide’s hypotensive action include changes in sodium balance, reduction in extracellular fluid and plasma volume, changes in renal vascular resistance, or decreased responsiveness to norepinephrine and angiotensin II. A reduction in peripheral vascular resistance is also likely, probably due to decreased sodium concentration in vascular walls, leading to reduced vascular wall sensitivity to norepinephrine.
Pharmacodynamic effects
After administration, diuresis with hydrochlorothiazide begins approximately 2 hours after intake, maximum effect is reached about 4 hours later, and the effect lasts for 6–12 hours.
Antihypertensive effect begins 3–4 days after starting treatment and may persist for up to 1 week after discontinuation. During long-term use, the antihypertensive effect of hydrochlorothiazide in most patients is dose-dependent within the range of 12.5 mg/day to 50–75 mg/day.
The antihypertensive effect is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance, and plasma renin activity.
Beyond a certain dose, the therapeutic effect of thiazide diuretics remains unchanged, while adverse effects continue to intensify: if ineffective, the recommended dose should not be exceeded due to poor tolerability (see section "Dosage and administration").
In patients with nephrogenic diabetes insipidus, hydrochlorothiazide reduces urine output and increases urine osmolality.
Use of hydrochlorothiazide in patients with chronic renal impairment (creatinine clearance < 30 mL/min and/or serum creatinine > 1.8 mg/100 mL) is ineffective.
Pharmacokinetics
Ramipril
Absorption
Ramipril is rapidly absorbed after oral administration: maximum plasma concentration is reached within 1 hour. Based on urinary excretion data, the extent of absorption is at least 56%; food intake does not affect ramipril absorption. The bioavailability of the active metabolite, ramiprilat, after oral administration of 2.5 mg and 5 mg ramipril is 45%.
Maximum plasma concentrations of ramiprilat, the sole active metabolite of ramipril, are reached 2–4 hours after ramipril intake. Steady-state plasma concentrations of ramiprilat after once-daily administration of usual ramipril doses are achieved approximately on day 4 of treatment.
Distribution
Protein binding of ramipril to serum proteins is approximately 73%, and for ramiprilat it is approximately 56%.
Metabolism
Ramipril is almost completely metabolized to ramiprilat and to diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.
Excretion
Metabolites are primarily excreted by the kidneys.
Plasma concentrations of ramiprilat decline in multiple phases. Due to strong binding to ACE and slow dissociation from the enzyme, ramiprilat exhibits a prolonged terminal elimination phase at very low plasma concentrations.
After once-daily ramipril administration, the effective elimination half-life of ramiprilat is 13–17 hours with doses of 5–10 mg and longer with doses of 1.25–2.5 mg. This difference is related to the enzyme’s capacity to bind ramiprilat in a saturable manner.
After a single oral dose of ramipril (10 mg), its level in breast milk was below the limit of detection. However, the effect with repeated administration is unknown.
Patients with renal impairment
Renal excretion of ramiprilat is reduced in patients with impaired kidney function, and renal elimination of ramiprilat is proportional to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in patients with normal renal function.
Patients with hepatic impairment
In patients with impaired liver function, metabolism of ramipril to ramiprilat is slowed due to reduced hepatic esterase activity. Plasma levels of ramipril are elevated in these patients. However, maximum ramiprilat concentrations in these patients do not differ from those in patients with normal liver function.
Amlodipine
Absorption, distribution, protein binding
After oral administration in therapeutic doses, amlodipine is gradually absorbed into the plasma. Maximum plasma concentration is reached within 6–12 hours after administration. Absolute bioavailability of the unchanged molecule is approximately 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that amlodipine protein binding to plasma proteins is approximately 97.5%. Concomitant food intake does not affect amlodipine absorption.
Metabolism and excretion
Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites. The elimination half-life from plasma is approximately 35–50 hours, consistent with once-daily dosing. Amlodipine is primarily metabolized in the liver into inactive metabolites; 60% of metabolites are excreted in urine, 10% unchanged.
Patients with hepatic impairment
There is very limited clinical data on amlodipine use in patients with impaired liver function. In patients with hepatic insufficiency, amlodipine clearance is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.
Use in elderly patients
Time to reach maximum plasma concentration of amlodipine is similar in elderly and younger patients. Amlodipine clearance is generally somewhat reduced in elderly patients, resulting in increased area under the concentration-time curve (AUC) and prolonged elimination half-life. Increases in AUC and elimination half-life in patients with congestive heart failure were consistent with expectations for this patient age group.
Hydrochlorothiazide
Absorption
After oral administration, hydrochlorothiazide is rapidly absorbed (Tmax approximately 2 hours). The increase in mean AUC is linear and proportional to dose within the therapeutic range.
Food intake has minimal clinical effect on hydrochlorothiazide absorption. After oral administration, absolute bioavailability of hydrochlorothiazide is 70%.
Absorption of hydrochlorothiazide is impaired in patients with congestive heart failure.
Long-term use of the drug does not alter hydrochlorothiazide metabolism. After 3 months of daily 50 mg hydrochlorothiazide treatment, absorption, excretion, and elimination are similar to those observed during short-term treatment.
Distribution
Hydrochlorothiazide also accumulates in erythrocytes, reaching maximum concentration 4 hours after oral intake. After 10 hours, erythrocyte concentration is approximately three times higher than plasma concentration. Protein binding to plasma proteins has been reported as approximately 40–70%, and the confirmed volume of distribution is 4–8 L/kg.
Elimination half-life varies among individuals: it ranges from 6 to 25 hours.
Metabolism
Hydrochlorothiazide undergoes minimal hepatic metabolism; no induction or inhibition of CYP450 isoenzymes has been observed.
Excretion
Hydrochlorothiazide is eliminated from plasma primarily in unchanged form. Terminal elimination half-life is 6–15 hours. Within 72 hours, 60–80% of a single oral dose is excreted in urine, 95% unchanged and 4% as the hydrolysis product 2-amino-4-chloro-N-benzenedisulfonamide (ABCS). Up to 24% of the oral dose is excreted in feces, and a small amount in bile. In renal and cardiac insufficiency, renal clearance of hydrochlorothiazide is reduced and elimination half-life prolonged, as also observed in elderly patients, with a subsequent increase in maximum plasma concentration.
Cardiovascular insufficiency
Hydrochlorothiazide clearance may be reduced in patients with congestive heart failure.
Hepatic impairment
No significant changes in hydrochlorothiazide pharmacokinetics have been noted in liver cirrhosis.
Hydrochlorothiazide is contraindicated in hepatic coma and precomatose states and should be used with caution in patients with progressive liver disease.
Clinical characteristics.
Indications.
For the treatment of arterial hypertension in patients whose blood pressure is adequately controlled by concomitant administration of separate ramipril, amlodipine and hydrochlorothiazide preparations at the same doses as in the fixed combination.
Contraindications.
- Hypersensitivity to amlodipine or other dihydropyridine calcium channel blockers, ramipril or other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide or other thiazide diuretics, sulfonamides, or any excipients of the medicinal product.
- History of angioedema (hereditary, idiopathic, or previous angioedema during treatment with ACE inhibitors or angiotensin II receptor antagonists).
- Shock (including cardiogenic shock).
- Second and third trimesters of pregnancy.
- Breastfeeding period.
- Extracorporeal treatments involving contact of blood with negatively charged surfaces.
- Significant bilateral renal artery stenosis or stenosis of the renal artery of a single functioning kidney.
- Severe renal impairment (creatinine clearance < 30 ml/min).
- Hypotensive or hemodynamically unstable conditions.
- Refractory hypokalemia, hyponatremia, hypercalcemia, or symptomatic hyperuricemia.
- Obstruction of outflow from the left ventricle (e.g., severe aortic stenosis).
- Combination with angiotensin II receptor antagonists (ARAs) in patients with diabetic nephropathy.
- Concomitant use with sacubitril/valsartan. Sumilar N must not be used within 36 hours of prior sacubitril/valsartan administration (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
- Concomitant use of Sumilar N with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (eGFR < 60 ml/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
- Hepatic impairment.
Interaction with other medicinal products and other types of interactions.
No formal studies of interactions between Sumilar N and other medicinal products have been conducted. This section provides only known information on interactions with other medicinal products of the active substances contained in this medicinal product.
However, it is important to note that Sumilar N may potentiate the hypotensive effect of other antihypertensive agents (e.g., diuretics).
Table 1
Concomitant use not recommended
| Individual components of the medicinal product Sumilar N |
Interacting medicinal products |
Consequences of interaction with other medicinal products |
| Ramipril and hydrochlorothiazide |
Lithium salts |
ACE inhibitors and thiazides may reduce lithium excretion, which may lead to increased lithium toxicity. Therefore, the combination of ramipril and hydrochlorothiazide with lithium is not recommended. Thus, when used concomitantly, serum lithium levels must be closely monitored. |
| Ramipril |
High-flux dialysis or hemofiltration membranes |
Extracorporeal treatment methods that lead to blood contact with negatively charged surfaces, particularly dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents. |
| Ramipril |
Sacubitril/valsartan |
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special precautions"). Treatment with ramipril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of the medicinal product Sumilar N. |
| Amlodipine |
Grapefruit or grapefruit juice |
Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients the bioavailability of amlodipine may increase, thereby enhancing its hypotensive effect. |
Table 2
Concomitant use requiring precautions
| Individual components of the medicinal product Sumilar N |
Interacting medicinal products |
Consequences of interaction with other medicinal products |
||
| Ramipril and Hydrochlorothiazide Ramipril |
Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid |
A reduced antihypertensive effect of ramipril and hydrochlorothiazide is expected. Concurrent use of Sumilar N and NSAIDs may also be associated with an increased risk of worsening renal function and elevated blood potassium levels. Therefore, monitoring of renal function at the beginning of treatment and adequate hydration of the patient are recommended. |
||
| Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes, and other active substances that may increase potassium levels (including trimethoprim, tacrolimus) |
Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving this medicinal product. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. |
|||
| Caution should also be exercised when ramipril is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic, similar to amiloride. Therefore, combination of ramipril with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, treatment should be administered with caution and serum potassium levels should be frequently monitored. |
||||
| Cyclosporine |
Hyperkalemia may occur during concomitant use of ACE inhibitors with cyclosporine. Monitoring of serum potassium levels is recommended. |
|||
| Heparin |
Hyperkalemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium levels is recommended. |
|||
| Nitrates, tricyclic antidepressants, anesthetics, acute alcohol intoxication, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin |
An increased risk of arterial hypotension is expected (information on diuretics is provided in the section "Dosage and administration"). |
|||
| Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril |
Monitoring of blood pressure is recommended. Hydrochlorothiazide may reduce the effect of vasopressor sympathomimetics. |
|||
| Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may alter blood parameters |
Increased risk of hematological reactions (see section "Special precautions for use"). |
|||
| Antidiabetic agents, including insulin |
ACE inhibitors may reduce insulin resistance. In individual cases, such reduction may lead to hypoglycemic reactions in patients receiving antidiabetic agents concomitantly. Therefore, careful monitoring of blood glucose levels is recommended during the initial phase of concomitant therapy. |
|||
| Neprilysin inhibitors (NEP) (e.g., racecadotril), mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), or vildagliptin |
Concomitant use of ACE inhibitors with NEP inhibitors such as racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema. Therapy should be initiated with caution (see section "Special precautions for use"). |
|||
| Amlodipine |
CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) |
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors may lead to a significant increase in amlodipine exposure. The clinical significance of these pharmacokinetic changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary. |
||
| CYP3A4 inducers (e.g., rifampicin, St. John's wort) |
Plasma concentrations of amlodipine may change following concomitant use with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted accordingly during and after concomitant therapy, especially with strong CYP3A4 inducers (e.g., rifampicin, St. John's wort). |
|||
| Dantrolene (infusions) |
Ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed in animals after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia. |
|||
| Simvastatin |
Concomitant administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking amlodipine, the simvastatin dose should be limited to 20 mg daily. |
|||
| Cyclosporine |
No interaction studies between cyclosporine and amlodipine have been conducted in healthy volunteers or other groups, except in kidney transplant patients, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) were observed. For kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduced if necessary. |
|||
| Tacrolimus |
There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully established. To avoid tacrolimus toxicity during concomitant use with amlodipine, regular monitoring of blood tacrolimus levels and dose adjustment if necessary are required. |
|||
| Hydrochlorothiazide |
Medicinal products that may cause hypokalemia |
Hypokalemia is a factor predisposing to cardiac arrhythmias (including torsades de pointes) and increases the toxicity of certain medicinal products, such as digoxin. Several medicinal products may cause hypokalemia and are involved in numerous interactions. These include potassium-sparing diuretics (as monotherapy or in combination therapy), stimulant laxatives, glucocorticoids, tetracosactide, and intravenous amphotericin B. |
||
| Medicinal products that may cause hyponatremia |
Some medicinal products more frequently increase the risk of hyponatremia. These include diuretics, desmopressin, serotonin reuptake inhibitors, carbamazepine, and oxcarbazepine. Combination of these medicinal products increases the risk of hyponatremia. |
|||
| Medicinal products that may cause ventricular tachycardia |
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution when administered with medicinal products that may cause ventricular tachycardia of the torsades de pointes type, particularly class Ia and class III antiarrhythmics and certain antipsychotics. Hypokalemia should be corrected before administration, and clinical, electrolyte, and electrocardiographic monitoring should be performed. |
|||
| Antidiabetic agents, including insulin |
Hypoglycemic reactions may occur. Hydrochlorothiazide may reduce the effectiveness of antidiabetic agents. Therefore, blood glucose levels should be monitored closely at the beginning of concomitant therapy. |
|||
| Oral anticoagulants |
The anticoagulant effect may be reduced when used concomitantly with hydrochlorothiazide. |
|||
| Cardiac glycosides, active substances capable of prolonging the QT interval, antiarrhythmic agents |
Proarrhythmic effects may be enhanced and antiarrhythmic effects reduced in the presence of electrolyte imbalances (e.g., hypokalemia, hypomagnesemia). Serum potassium levels should be monitored, and clinical, electrolyte, and electrocardiographic monitoring should be performed. |
|||
| Potassium-sparing diuretics (as monotherapy and in combination therapy) |
This is a rational combination, beneficial for some patients, but does not exclude the possibility of hypokalemia or, particularly in renal insufficiency and diabetes, hyperkalemia. Serum potassium levels should be monitored, an electrocardiogram should be performed, and treatment reconsidered if necessary. |
|||
| Calcium salts and medicinal products that increase plasma calcium levels |
An increase in serum calcium concentration may be expected when used concomitantly with hydrochlorothiazide; therefore, serum calcium levels should be carefully monitored. |
|||
| Medicinal products causing orthostatic hypotension |
Antihypertensive agents may cause orthostatic hypotension. These include nitrates, phosphodiesterase type 5 inhibitors, alpha-adrenoblockers, and agents for the treatment of urological disorders (alfuzosin, doxazosin, prazosin, silodosin, tamsulosin, terazosin), tricyclic antidepressants, phenothiazine neuroleptics, agonists |
|||
| dopamine, levodopa, baclofen, amifostine. |
||||
| Carbamazepine |
There is a potential risk of hyponatremia due to additive effects with hydrochlorothiazide. Clinical and biological monitoring should be performed. |
|||
| Bile acid sequestrants (cholestyramine-type resins) |
Bile acid sequestrants bind thiazide diuretics in the intestine and reduce their gastrointestinal absorption by 43–85%. Administration of thiazide 4 hours after a bile acid sequestrant reduced hydrochlorothiazide absorption by 30–35%. Thiazide should be administered 2–4 hours before or 6 hours after the bile acid sequestrant. Follow the recommended sequence. Monitor blood pressure and, if necessary, increase the thiazide dose. |
|||
| Iodinated contrast agents |
In cases of dehydration caused by diuretics, including hydrochlorothiazide, there is an increased risk of acute renal failure, especially with high doses of iodinated contrast agents. Rehydration should be performed prior to administration of iodine-containing compounds. |
|||
| Cyclosporine |
There is a risk of increased blood creatinine levels without changes in circulating cyclosporine concentration, even in the absence of water and sodium deficiency. Complications such as hyperuricemia and gout may also occur. |
|||
Double blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren
Clinical data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to treatment with a single agent acting on the RAAS.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
If such dual blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor antagonists must not be used concomitantly in patients with diabetic nephropathy.
mTOR inhibitors (mammalian target of rapamycin) or vildagliptin. There may be an increased risk of angioedema in patients receiving concomitant treatment with mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Such therapy should be initiated with caution (see section "Special precautions for use").
Neprilysin inhibitors. There have been reports of a potentially increased risk of angioedema with concomitant use of ACE inhibitors and neprilysin inhibitors (NEP), for example, racecadotril (see section "Special precautions for use").
Sacubitril/valsartan. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema.
Blood pressure, renal function, and electrolytes should be monitored in patients taking ramipril and other agents affecting the RAAS.
Regarding ramipril.
Dual blockade of the renin-angiotensin system (RAS) with ACE inhibitors (angiotensin-converting enzyme inhibitors), ARBs (angiotensin receptor blockers), or aliskiren.
Concomitant use of ACE inhibitors, including ramipril, or ARBs with aliskiren is contraindicated in patients with moderate to severe renal impairment (GFR < 60 mL/min).
Special precautions for use.
The safety and efficacy of amlodipine in hypertensive crisis have not been evaluated.
Special patient groups
Pregnant women
ACE inhibitors such as ramipril or angiotensin II receptor antagonists should not be initiated during pregnancy. If continuation of therapy with an ACE inhibitor/angiotensin II receptor antagonist is considered necessary, women planning pregnancy should switch to an alternative antihypertensive agent with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use in pregnancy or breastfeeding").
Patients at special risk of arterial hypotension
Patients with an activated renin-angiotensin-aldosterone system are at risk of acute marked reduction in blood pressure and worsening renal function due to ACE inhibition, particularly when the ACE inhibitor or concomitant diuretic is used for the first time or during initial dose escalation.
Significant activation of the renin-angiotensin-aldosterone system and medical monitoring, including blood pressure monitoring, should be anticipated in patients with:
- severe hypertension;
- decompensated congestive heart failure;
- hemodynamically significant obstruction of inflow and outflow from the left ventricle (aortic or mitral valve stenosis);
- unilateral renal artery stenosis with a functioning contralateral kidney;
- hepatic cirrhosis and/or ascites;
- existing or potential dehydration and/or salt depletion (including patients taking diuretics);
- following major surgery or during anesthesia with agents causing arterial hypotension;
- transient or persistent heart failure;
- post-myocardial infarction state;
- risk of developing cardiac or cerebral ischemia in case of acute hypotension;
- elderly age.
Prior to initiating treatment, dehydration, hypovolemia, or excessive salt loss should be corrected (however, in patients with heart failure, the possibility of such corrective measures should be carefully weighed against the risk of volume overload).
Initial treatment requires special medical supervision.
Patients with heart failure
Patients with heart failure should be treated with caution. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher in the amlodipine group than in the placebo group (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used cautiously in patients with congestive heart failure, as they may increase the risk of future cardiovascular complications and increase mortality.
Patients with hepatic impairment
The elimination half-life of amlodipine is prolonged and AUC values are increased in patients with hepatic impairment. Therefore, treatment with amlodipine should be initiated at the lower end of the dosing range, and caution should be exercised both at the beginning of treatment and during dose escalation.
Thiazide diuretics should be used with caution in patients with hepatic impairment or progressive liver disease, as minor changes in fluid and electrolyte balance may precipitate hepatic coma.
In patients with hepatic impairment, the maximum daily dose of ramipril should not exceed 2.5 mg. Sumilar H should not be used in patients with hepatic impairment, as the ramipril content exceeds the maximum daily dose (2.5 mg) permitted for use in this condition.
Patients with renal impairment
Renal function should be assessed before and during treatment with Sumilar H. Dose adjustment is required, especially during the first weeks of treatment. Close monitoring is necessary in patients with renal impairment (see section "Dosage and administration"). Thiazide diuretics may induce azotemia in patients with chronic renal impairment. Periodic monitoring of serum electrolytes (including potassium levels), serum urea, and creatinine is recommended in patients with renal impairment receiving Sumilar H. Sumilar H is contraindicated in patients with severe renal impairment, bilateral renal artery stenosis, or renal artery stenosis of a single functioning kidney. This medicinal product is also not recommended if there is only one functioning kidney or in case of hypokalemia.
There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation.
Surgery
It is recommended to discontinue treatment with ACE inhibitors such as ramipril, if possible, one day before surgery.
Hypersensitivity / angioedema
Angioedema
Angioedema has been reported in patients taking ACE inhibitors, including ramipril.
If angioedema occurs, ramipril should be discontinued.
Concomitant use of ramipril with sacubitril/valsartan is contraindicated, as it may increase the risk of angioedema. Sacubitril/valsartan should be initiated 36 hours after the last dose of ramipril. If treatment with sacubitril/valsartan is discontinued, ramipril therapy should not be started earlier than 36 hours after the last dose of sacubitril/valsartan. Concomitant use of ACE inhibitors with neprilysin inhibitors (NEP) (e.g., racecadotril), selective mTOR (mammalian target of rapamycin) inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Patients already taking an ACE inhibitor should start therapy with racecadotril, selective mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin with caution.
If angioedema develops, ramipril should be discontinued and emergency measures should be taken immediately. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.
Angioedema of the intestine has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). Patients complained of abdominal pain (with or without nausea/vomiting).
Anaphylactic reactions during desensitization
The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased with ACE inhibitor use. Temporary discontinuation of ramipril therapy should be considered before desensitization.
Electrolyte balance monitoring
Serum potassium levels. Hyperkalemia has occurred in some patients receiving ACE inhibitors, including ramipril.
ACE inhibitors can cause hyperkalemia because they inhibit aldosterone release. This effect is usually minor in patients with normal renal function. However, in patients with renal impairment, patients over 70 years of age, patients with uncontrolled diabetes mellitus, or patients with conditions such as dehydration, acute heart decompensation, metabolic acidosis, and/or patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics, and other agents that increase plasma potassium levels (trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, and especially aldosterone antagonists or angiotensin receptor antagonists), hyperkalemia may occur. If concomitant use of the above-mentioned agents is considered appropriate, regular monitoring of serum potassium levels is recommended. Potassium-sparing diuretics and angiotensin receptor antagonists should be used with caution in patients taking ACE inhibitors, and serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").
Hyponatremia due to inappropriate antidiuretic hormone secretion (SIADH) has been observed in some patients receiving ramipril, leading to subsequent hyponatremia. Regular monitoring of serum sodium levels is recommended in elderly patients and other patients at risk of hyponatremia.
Treatment with Sumilar H should be initiated only after correction of existing hyponatremia and any associated hypomagnesemia. Thiazides and other thiazide diuretics may cause hypokalemia or exacerbate existing hypokalemia. Thiazide diuretics should be used with caution in patients with conditions involving potassium loss, such as salt-wasting nephropathy or prerenal (cardiogenic) renal impairment.
The risk of hypokalemia (< 3.5 mmol/L) should be prevented in certain high-risk patient groups, particularly in elderly patients and/or poorly nourished patients and/or patients taking multiple medications, patients with cirrhosis with edema and ascites, and patients with coronary artery disease and heart failure.
Hypokalemia increases the cardiotoxicity of digitalis agents and the risk of cardiac arrhythmias.
Patients with prolonged QT interval, whether congenital or iatrogenic, are at risk. Hypokalemia, like bradycardia, predisposes to serious cardiac arrhythmias, especially ventricular fibrillation/tachycardia, potentially fatal, especially in the presence of bradycardia.
Hypokalemia and hypomagnesemia should be corrected before initiating treatment with thiazide diuretics.
The first measurement of plasma potassium concentration should be performed within the first week of treatment. Therefore, regular monitoring of serum potassium levels is recommended. All patients receiving thiazide diuretics should have electrolyte balance monitored, particularly serum potassium levels. During long-term treatment, serum potassium levels should be monitored at the beginning of treatment and consideration given to monitoring after 3–4 weeks, depending on risk factors. Thus, regular monitoring is recommended, especially in high-risk patients.
Serum sodium levels should be checked before starting treatment and then regularly at certain intervals. Thiazide diuretics may cause or exacerbate existing hyponatremia. In patients with significant reduction in serum sodium levels and/or dehydration (e.g., in individuals receiving high doses of diuretics), symptomatic hypotension may rarely occur after initiation of hydrochlorothiazide therapy.
Plasma sodium reduction may initially be asymptomatic, so regular monitoring is necessary. Monitoring should be performed more frequently in elderly patients, poorly nourished patients, and patients with cirrhosis (see sections "Adverse reactions" and "Overdose").
Treatment with thiazide diuretics, including hydrochlorothiazide, is associated with the development of hyponatremia and hypochloremic alkalosis or exacerbation of existing hyponatremia. Hyponatremia accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Hydrochlorothiazide treatment should be initiated only after correction of existing hyponatremia. If severe or rapidly developing hyponatremia occurs during treatment, the drug should be discontinued until sodium levels normalize.
Thiazides, including hydrochlorothiazide, enhance urinary magnesium excretion, which may lead to hypomagnesemia. Thiazide diuretics reduce calcium excretion, which may lead to hypercalcemia. All patients receiving thiazide diuretics should undergo periodic monitoring of electrolyte levels, particularly potassium, sodium, and magnesium.
Hypercalcemia
Hydrochlorothiazide stimulates calcium reabsorption in the kidneys and may cause hypercalcemia. This may affect parathyroid function test results.
Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide was identified in two pharmacoepidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be the mechanism underlying NMSC development.
Patients taking hydrochlorothiazide should be informed about the risk of NMSC, the need for regular skin examination, and to promptly report any suspicious skin lesions to their physician. To reduce the risk of skin cancer, patients should be advised about possible preventive measures, such as limiting exposure to sunlight and UV radiation, and, if exposure occurs, the need for adequate skin protection. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy material. Patients who have previously experienced NMSC may also require a review of hydrochlorothiazide use (see also section "Adverse reactions").
Neutropenia/agranulocytosis
Rare cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been reported, and bone marrow suppression has also been reported. Monitoring of leukocyte count is recommended to detect possible leukopenia. More frequent monitoring is recommended at the beginning of treatment or in case of renal impairment, presence of concomitant collagen diseases (e.g., systemic lupus erythematosus or scleroderma), or concomitant use of other medicinal products that may cause blood count changes.
Racial differences
ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. As with other ACE inhibitors, ramipril may be less effective in reducing blood pressure in black patients than in patients of other races, possibly due to the higher prevalence of low-renin states among hypertensive patients in this group.
Cough
Cough has been reported with ACE inhibitor use. In typical cases, it was characterized as non-productive, persistent, and resolving after discontinuation of treatment. Cough due to ACE inhibitor therapy should be considered in the differential diagnosis of cough.
The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section "Adverse reactions").
If photosensitivity reactions occur during drug intake, discontinuation of treatment is recommended. If resumption of diuretic use is considered necessary, protection of exposed skin areas from sunlight and artificial ultraviolet radiation is recommended.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Hydrochlorothiazide, a sulfonamide derivative, may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms are characterized by acute onset of decreased visual acuity or eye pain and typically develop within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial management includes prompt discontinuation of hydrochlorothiazide. Risk factors for acute angle-closure glaucoma include a history of sulfonamide use or penicillin allergy.
Glycemia and lipidemia
Thiazide therapy may alter glucose tolerance and increase cholesterol and triglyceride levels. Diabetics should consider adjusting insulin or oral hypoglycemic agent doses.
Uric acid
Hydrochlorothiazide, like other diuretics, may increase serum uric acid concentration due to reduced urinary excretion and, consequently, may cause or exacerbate existing hyperuricemia, potentially triggering gout attacks in predisposed patients.
Dose adjustment should be performed according to plasma uric acid levels.
Antihypertensive combinations
Dose reduction is advisable when used in combination with other antihypertensive agents, at least initially.
The antihypertensive effect of ACE inhibitors, angiotensin II receptor antagonists, or direct renin inhibitors is enhanced by agents that increase plasma renin activity (diuretics).
ACE inhibitors, angiotensin II receptor antagonists, or direct renin inhibitors should be used with caution concomitantly with hydrochlorothiazide, especially in patients with dehydration and/or hypovolemia.
Acute respiratory toxicity
Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been observed after hydrochlorothiazide administration. Pulmonary edema typically develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening lung function, and hypotension. If ARDS is suspected, the combination of ramipril + amlodipine + hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who have previously experienced ARDS after hydrochlorothiazide.
Professional sports
Athletes should pay special attention to the fact that Sumilar H contains active substances that may cause a positive doping test during anti-doping control.
Other
Systemic lupus erythematosus: exacerbation or activation of systemic lupus erythematosus has been reported with thiazide diuretics, including hydrochlorothiazide.
Hypersensitivity reactions to hydrochlorothiazide occur more frequently in patients with allergies and asthma.
Sumilar H contains less than 1 mmol sodium (23 mg) per capsule, i.e., practically sodium-free.
Use during pregnancy or breastfeeding.
Data on the use of Sumilar H in pregnant women are lacking. The medicinal product should not be used in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.
Regarding ramipril
Epidemiological data on teratogenic risk after ACE inhibitor use in the first trimester of pregnancy were not conclusive; however, a slight increase in risk cannot be excluded. If continuation of ACE inhibitor therapy is considered necessary, patients planning pregnancy should switch to an alternative antihypertensive agent with an established safety profile during pregnancy. If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and alternative therapy initiated if necessary.
It is known that use of ACE inhibitors/angiotensin II receptor antagonists during the second and third trimesters causes fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) in humans. Infants whose mothers received ACE inhibitors in the second trimester require ultrasound assessment of renal function and skull ossification. Infants whose mothers received ACE inhibitors require careful monitoring for arterial hypotension, oliguria, and hyperkalemia.
Regarding amlodipine
The safety of amlodipine use in women during pregnancy has not been established.
Reproductive toxicity has been demonstrated in animal studies at high doses. Use during pregnancy is recommended only when no safer alternative exists and the risk associated with the disease itself exceeds the potential harm of treatment to the mother and fetus.
Regarding hydrochlorothiazide
Prolonged use of hydrochlorothiazide during the third trimester of pregnancy may cause fetoplacental ischemia and fetal growth retardation. Additionally, hypoglycemia and thrombocytopenia have rarely been observed in newborns. Hydrochlorothiazide may cause reduced circulating blood volume and uteroplacental perfusion.
Breastfeeding
Use of Sumilar H is contraindicated during breastfeeding. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from treatment with Sumilar H, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.
The combination of ramipril and hydrochlorothiazide is contraindicated during breastfeeding. The amount of ramipril and hydrochlorothiazide transferred into breast milk is such that an infant on breastfeeding may be affected when therapeutic doses of ramipril and hydrochlorothiazide are used. As adequate data on ramipril use during breastfeeding are lacking, it is preferable to use other medicinal products with a safer profile during breastfeeding, especially when breastfeeding newborns or premature infants. Hydrochlorothiazide passes into breast milk. Use of thiazides in breastfeeding women has been associated with reduced or even complete cessation of breast milk production. Increased sensitivity to sulfonamide derivatives, hypokalemia, and nuclear jaundice may occur. Since use of both active substances may lead to serious adverse effects in breastfed infants, a decision should be made whether to discontinue breastfeeding or treatment, depending on the importance of this therapy for the woman.
Amlodipine is excreted in breast milk. The ratio of the dose received by the newborn from the mother is estimated at 3–7%, maximum 15%, in the interquartile range. The effect of amlodipine on infants is unknown.
Fertility.
Regarding amlodipine
Reversible biochemical changes in the sperm head have been reported in some patients receiving calcium channel blockers. Clinical information on the potential effect of amlodipine on fertility is insufficient.
Regarding hydrochlorothiazide
There are no data on the effect of hydrochlorothiazide on human fertility.
Animal studies have demonstrated that hydrochlorothiazide does not affect fertility or conception.
Ability to affect reaction speed when driving or operating machinery.
Some adverse effects (e.g., symptoms of reduced blood pressure such as dizziness) may impair the patient's ability to concentrate and affect reaction speed, which is risky in situations where these qualities are particularly important (e.g., when driving vehicles or operating machinery).
This is especially relevant at the beginning of treatment or when switching to other medications. After taking the first dose or subsequent dose increase, driving vehicles or operating machinery is not recommended for several hours.
Method of Administration and Dosage
Dosage
The recommended daily dose is one capsule.
Sumilar N should be taken once daily, at the same time each day, with or without food, as food does not affect the bioavailability of the medicinal product. Fixed-dose combination therapy is not suitable for initial treatment.
Symptomatic hypotension may occur in patients concurrently taking ramipril, amlodipine, and diuretics.
If dose adjustment is required, the dose of each individual component may be modified, and after establishing appropriate doses, transition to a new fixed-dose combination may be considered.
Special Patient Populations
Patients Taking Diuretics
Caution should be exercised in patients receiving diuretics due to the potential risk of dehydration and/or salt depletion. Renal function and serum potassium levels should be monitored in these patients.
Hepatic Impairment
This formulation is not recommended for patients with impaired liver function, as the ramipril component exceeds the maximum allowable dose acceptable for such patients.
Patients with Renal Impairment
To determine the optimal initial and maintenance dosage for patients with renal impairment, individual dose titration of ramipril, amlodipine, and hydrochlorothiazide should be performed (detailed information is provided in the individual product information leaflets for each component).
The daily dose of Sumilar N in patients with impaired renal function depends on creatinine clearance:
- If creatinine clearance is ≥ 60 mL/min, the maximum daily dose of Sumilar N is 10 mg/10 mg/25 mg.
- If creatinine clearance is between 30 and 60 mL/min, the maximum daily dose of Sumilar N is 5 mg/10 mg/25 mg.
- Sumilar N is contraindicated in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min/1.73 m²).
- For patients undergoing hemodialysis, the maximum daily dose is 5 mg/10 mg/25 mg; the medicinal product should be administered several hours after a hemodialysis session.
During treatment with Sumilar N, renal function and serum potassium levels should be monitored. If renal function worsens, Sumilar N should be discontinued and individual component doses adjusted accordingly.
Elderly Patients
Extreme caution is required in elderly patients, including more frequent monitoring of blood pressure, especially when administering the maximum dose of Sumilar N (10 mg/10 mg/25 mg), as clinical data in this patient group are limited. Elderly patients with arterial hypertension meeting eligibility criteria (see section "Indications") should be initiated on the lowest available doses of ramipril and amlodipine when switching to Sumilar N.
Method of Administration
Capsules should be taken once daily, at the same time each day, with or without food. Capsules must not be chewed or crushed. Concomitant use with grapefruit juice is not recommended. Capsules should be swallowed with sufficient liquid (e.g., drinking water).
Children
Sumilar N is contraindicated in children (under 18 years of age) due to lack of data on safety and efficacy.
Overdose
Regarding Ramipril
Symptoms associated with overdose of ACE inhibitors may include excessive peripheral vasodilation (with marked hypotension, shock), bradycardia, electrolyte imbalances, and renal failure. Close monitoring of the patient is required. Treatment should be symptomatic and supportive. Supportive measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore hemodynamic stability, including use of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is only minimally removed from systemic circulation by hemodialysis.
Regarding Amlodipine
Experience with intentional human overdose is limited. Available data suggest that significant overdose may lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of severe and potentially prolonged systemic hypotension have been reported, including fatal shock.
Regarding Hydrochlorothiazide
Overdose of hydrochlorothiazide may lead to acute urinary retention in susceptible patients (e.g., patients with benign prostatic hyperplasia).
Hydrochlorothiazide overdose is associated with depletion of electrolyte stores (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias, particularly in patients concurrently receiving digitalis glycosides or certain antiarrhythmic drugs.
Treatment is symptomatic and supportive. Recommended therapeutic measures include primary detoxification (administration of adsorbents). In case of hypotension, measures to restore hemodynamic stability should be implemented, and administration of alpha-1 adrenergic agonists (e.g., noradrenaline, dopamine) or angiotensin II (angiotensinamide) may be required.
A vasoconstrictor may be beneficial in restoring vascular tone and blood pressure, provided there are no contraindications to its use. Intravenous calcium gluconate may be helpful in reversing calcium channel blockade effects.
Regarding attempts to eliminate ramipril or ramiprilat, data on the effectiveness of forced diuresis, urine pH modification, hemofiltration, dialysis, or plasmapheresis are limited or lacking. If dialysis or hemofiltration is considered, the risk of anaphylactoid reactions with high-flux membranes should be taken into account.
In some cases, gastric lavage may be beneficial. Administration of activated charcoal to healthy volunteers within 2 hours after ingestion of 10 mg amlodipine significantly reduced its absorption.
Since amlodipine is highly protein-bound, dialysis is of minimal benefit. Removal of thiazide diuretics by dialysis is also minimal.
Treatment consists of restoration of fluid and electrolyte balance; correction of hyponatremia should be gradual. Active cardiovascular support should be provided, including continuous monitoring of cardiac and respiratory functions, placing the patient in a supine position with legs elevated, and monitoring circulating fluid volume and urine output.
Adverse reactions.
Regarding ramipril
The most common adverse reactions during ramipril treatment include hyperkalemia, headache, dizziness, hypotension, orthostatic hypotension, fainting, cough (non-productive cough), bronchitis, sinusitis, dyspnea, gastrointestinal inflammation, gastric discomfort, abdominal pain, dyspepsia, diarrhea, nausea, vomiting, skin rash (including maculopapular rash), muscle cramps, myalgia, chest pain, and fatigue. Serious adverse reactions include agranulocytosis, pancytopenia, hemolytic anemia, myocardial infarction, angioedema, vasculitis, bronchospasm, acute pancreatitis, hepatic failure, acute renal failure, hepatitis, exfoliative dermatitis, toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme.
Regarding amlodipine
The most common adverse reactions during amlodipine treatment include somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, edema, and fatigue. Serious adverse reactions include leukopenia, thrombocytopenia, myocardial infarction, atrial fibrillation, ventricular tachycardia, vasculitis, acute pancreatitis, hepatitis, angioedema, erythema multiforme, exfoliative dermatitis, and Stevens–Johnson syndrome.
Regarding hydrochlorothiazide
The active substance hydrochlorothiazide may lead to impaired glucose, lipid, and uric acid metabolism and has a reversible effect on plasma potassium levels.
The frequency of adverse reactions is defined according to the following conventional scale:
Very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1,000 and < 1/100); rare (≥ 1/10,000 and < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).
Table 3
Adverse reactions observed during treatment with each active substance separately
| Frequency |
Ramipril |
Amlodipine |
Hydrochlorothiazide |
|||||
| Disorders of the blood and lymphatic system |
||||||||
| Uncommon |
Eosinophilia |
|||||||
| Rare |
Decreased white blood cell count (including neutropenia or agranulocytosis), decreased red blood cell count, decreased hemoglobin levels, decreased platelet count |
Thrombocytopenia (sometimes with purpura) |
||||||
| Very rare |
Leukopenia, thrombocytopenia |
Bone marrow suppression, agranulocytosis, hemolytic anemia, leukopenia |
||||||
| Frequency unknown |
Bone marrow failure, pancytopenia, hemolytic anemia |
Aplastic anemia |
||||||
| Bone marrow suppression; neutropenia, including agranulocytosis; eosinophilia; hemoconcentration in case of fluid retention |
||||||||
| Immune system disorders |
||||||||
| Rare |
Hypersensitivity reactions |
|||||||
| Uncommon |
Allergic reactions |
|||||||
| Frequency unknown |
Anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies |
|||||||
| Endocrine system disorders |
||||||||
| Frequency unknown |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
|||||||
| Metabolism and nutrition disorders |
||||||||
| Very common |
Hypokalemia, hyperlipidemia |
|||||||
| Common |
Elevated blood potassium levels |
Hyperuricemia, hypomagnesemia, hyponatremia. Poor control of diabetes mellitus, reduced glucose tolerance, increased blood glucose levels, increased uric acid levels, gout exacerbation, increased cholesterol and/or triglycerides due to hydrochlorothiazide. |
||||||
| Uncommon |
Anorexia, altered taste sensation |
Decreased appetite, decreased plasma potassium levels, thirst sensation due to hydrochlorothiazide |
||||||
| Rare |
Elevated plasma potassium levels due to ramipril |
Hypercalcemia, hyperglycemia, glycosuria, worsening of metabolic diabetes |
||||||
| Very rare |
Hyperglycemia |
Hypochloremic alkalosis, which may induce hepatic encephalopathy or hepatic coma due to hydrochlorothiazide |
||||||
| Frequency unknown |
Decreased sodium levels in blood |
|||||||
| Psychiatric disorders |
||||||||
| Uncommon |
Depressed mood, anxiety, restlessness, agitation, sleep disturbances, including somnolence |
Mood changes (including anxiety), insomnia, depression |
||||||
| Rare |
Confusion |
Confusion |
Sleep disturbances, depression |
|||||
| Frequency unknown |
Attention disturbance |
|||||||
| Nervous system disorders |
||||||||
| Common |
Headache, dizziness |
Headache, dizziness, somnolence (especially at the beginning of treatment) |
||||||
| Uncommon |
Vertigo, paresthesia, ageusia, dysgeusia, burning sensation |
Tremor, dysgeusia, syncope, hypesthesia, paresthesia |
||||||
| Rare |
Tremor, imbalance |
Headache, dizziness, paresthesia |
||||||
| Very rare |
Increased muscle tone, peripheral neuropathy |
|||||||
| Frequency unknown |
Cerebral ischemia, including ischemic stroke and transient ischemic attack, psychomotor impairment, burning sensation, parosmia |
Extrapyramidal symptoms |
||||||
| Eye disorders |
||||||||
| Common |
Visual disturbances (including diplopia) |
|||||||
| Uncommon |
Visual disturbances, including blurred vision |
Visual disturbances |
||||||
| Rare |
Conjunctivitis |
|||||||
| Frequency unknown |
Choroidal effusion, xanthopsia, decreased lacrimation due to hydrochlorothiazide; secondary acute angle-closure glaucoma and/or acute myopia due to hydrochlorothiazide |
|||||||
| Ear and labyrinth disorders |
||||||||
| Uncommon |
Tinnitus |
|||||||
| Rare |
Hearing disturbances, tinnitus |
|||||||
| Cardiac disorders |
||||||||
| Common |
Palpitations |
|||||||
| Uncommon |
Myocardial ischemia, including angina or myocardial infarction; tachycardia; arrhythmia, palpitations, peripheral edema |
Arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation) |
||||||
| Rare |
Arrhythmias |
|||||||
| Very rare |
Myocardial infarction |
|||||||
| Unknown |
Orthostatic hypotension |
|||||||
| Vascular disorders |
||||||||
| Common |
Arterial hypotension, orthostatic drop in blood pressure, syncope |
Flushing, especially to the face and neck |
Orthostatic hypotension |
|||||
| Uncommon |
Flushing, especially to the face and neck |
Hypotension |
Necrotizing angiitis (vasculitis, cutaneous vasculitis) |
|||||
| Rare |
Vascular stenosis, hypoperfusion, vasculitis |
|||||||
| Very rare |
Vasculitis |
|||||||
| Frequency unknown |
Raynaud's syndrome |
|||||||
| Thrombosis due to significant reduction in circulating blood volume, vascular stenosis, hypoperfusion |
||||||||
| Respiratory, thoracic and mediastinal disorders |
||||||||
| Common |
Non-productive irritating cough, bronchitis, sinusitis, dyspnea |
Dyspnea |
||||||
| Uncommon |
Bronchospasm, including asthma exacerbation, nasal congestion |
Cough, rhinitis |
||||||
| Very rare |
Respiratory distress (including pneumonitis and pulmonary edema), acute respiratory distress syndrome (ARDS) |
|||||||
| Frequency unknown |
Bronchospasm, including bronchial asthma exacerbation; allergic alveolitis |
|||||||
| Gastrointestinal disorders |
||||||||
| Common |
Inflammatory gastrointestinal symptoms, digestive disturbances, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting |
Nausea, stomach pain, dyspepsia, intestinal peristalsis disorders (including diarrhea and constipation) |
Nausea, vomiting, diarrhea, cramps, loss of appetite |
|||||
| Uncommon |
Pancreatitis (in isolated cases fatal outcomes reported exclusively with ACE inhibitors), elevated pancreatic enzyme levels, angioneurotic edema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth |
Vomiting, dry mouth |
||||||
| Rare |
Glossitis, aphthous stomatitis |
Abdominal discomfort, constipation |
||||||
| Very rare |
Pancreatitis, gastritis, gingival hyperplasia |
Pancreatitis |
||||||
| Frequency unknown |
Pancreatitis (in isolated cases fatal outcomes reported with ACE inhibitors), elevated pancreatic enzyme levels |
Sialadenitis |
||||||
| Hepatobiliary disorders |
||||||||
| Uncommon |
Cholestatic or cytolytic hepatitis (in very rare cases with fatal outcome), elevated liver enzymes and/or conjugated bilirubin |
Calculous cholecystitis |
||||||
| Rare |
Cholestatic jaundice, hepatic cell injury |
Intrahepatic cholestasis, jaundice |
||||||
| Very rare |
Jaundice, hepatitis, elevated liver enzymes * |
|||||||
| Frequency unknown |
Acute liver failure |
|||||||
| Skin and subcutaneous tissue disorders |
||||||||
| Common |
Rash, including maculopapular |
Urticaria and other forms of rash |
||||||
| Uncommon |
Angioedema; in very rare cases airway obstruction due to angioedema, which may be fatal; pruritus, hyperhidrosis, rash, including maculopapular; pruritus; alopecia |
Alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, rash, exanthema, urticaria |
||||||
| Rare |
Exfoliative dermatitis, urticaria, onycholysis |
Photosensitivity reaction |
||||||
| Very rare |
Photosensitivity reaction |
Angioedema, Stevens-Johnson syndrome, exfoliative dermatitis, erythema multiforme, Quincke's edema, photosensitivity reaction |
Lupus-like reaction, lupus reactivation, necrotizing vasculitis, and toxic epidermal necrolysis |
|||||
| Frequency unknown |
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis exacerbation, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, photosensitivity, alopecia |
Toxic epidermal necrolysis |
Erythema multiforme, onycholysis, pemphigoid or lichenoid exanthema or enanthema, urticaria, systemic lupus erythematosus due to hydrochlorothiazide |
|||||
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
||||||||
| Frequency unknown |
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)** |
|||||||
| Musculoskeletal and connective tissue disorders |
||||||||
| Common |
Muscle cramps, myalgia |
Ankle swelling, muscle cramps |
||||||
| Uncommon |
Arthralgia |
Arthralgia, myalgia, back pain |
Muscle cramps |
|||||
| Frequency unknown |
Muscle weakness, musculoskeletal stiffness, tetanic cramps due to hydrochlorothiazide |
|||||||
| Renal and urinary disorders |
||||||||
| Uncommon |
Renal function impairment, including acute renal failure, increased urine production, worsening of background proteinuria, elevated blood urea levels, elevated blood creatinine levels |
Urination disorders, nocturia, increased frequency of urination |
Glycosuria, interstitial nephritis, renal function impairment, renal failure, worsening of background proteinuria |
|||||
| Reproductive system and breast disorders |
||||||||
| Common |
Impotence |
|||||||
| Uncommon |
Transient erectile impotence, decreased libido |
Impotence, gynecomastia |
||||||
| Frequency unknown |
Gynecomastia |
|||||||
| General disorders and administration site conditions |
||||||||
| Very common |
Edema |
|||||||
| Common |
Chest pain, fatigue |
Fatigue, asthenia |
||||||
| Uncommon |
Pyrexia |
Chest pain, pain, malaise |
Fever |
|||||
| Rare |
Asthenia |
|||||||
| Frequency unknown |
Weakness |
|||||||
| Endocrine system disorders |
||||||||
| Frequency unknown |
Syndrome of inappropriate antidiuretic hormone secretion |
|||||||
| Investigations |
||||||||
| Uncommon |
Increased or decreased body weight |
|||||||
| * In most cases associated with cholestasis. |
||||||||
** Non-melanoma skin cancer: Epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC (see also sections "Special precautions for use" and "Pharmacodynamics").
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.
Shelf life. 2 years.
Storage conditions. Store at temperatures not exceeding 30 ºC. Keep out of the reach and sight of children.
Packaging. 10 hard capsules per blister; 3 blisters or 10 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Lek Pharmaceuticals d.d.
Manufacturer's address and location of operations.
Verovskova 57, Ljubljana 1526, Slovenia.