Perindopril 8/amlodipine 10 krka
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT
Perindopril 4/amlodipine 10 KRKA
Perindopril 4/amlodipine 5 KRKA
Perindopril 8/amlodipine 10 KRKA
Perindopril 8/amlodipine 5 KRKA
(Perindopril 4/amlodipine 10 KRKA
Perindopril 4/amlodipine 5 KRKA
Perindopril 8/amlodipine 10 KRKA
Perindopril 8/amlodipine 5 KRKA)
Composition:
Active substances: perindopril, amlodipine;
One tablet contains:
4 mg of perindopril tert-butylamine (corresponding to 3.34 mg of perindopril) and 10 mg of amlodipine (corresponding to 13.870 mg of amlodipine besylate), or
4 mg of perindopril tert-butylamine (corresponding to 3.34 mg of perindopril) and 5 mg of amlodipine (corresponding to 6.935 mg of amlodipine besylate), or
8 mg of perindopril tert-butylamine (corresponding to 6.68 mg of perindopril) and 10 mg of amlodipine (corresponding to 13.870 mg of amlodipine besylate), or
8 mg of perindopril tert-butylamine (corresponding to 6.68 mg of perindopril) and 5 mg of amlodipine (corresponding to 6.935 mg of amlodipine besylate);
Excipients: microcrystalline cellulose; pregelatinized starch; sodium starch glycolate; calcium chloride hexahydrate; sodium hydrocarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties:
4 mg/10 mg: white or almost white, capsule-shaped, biconvex tablets with a notch on one side; the notch is not intended for dividing the tablet into equal doses.
4 mg/5 mg: white or almost white, round, slightly biconvex tablets with beveled edges;
8 mg/10 mg: white or almost white, round, biconvex tablets with beveled edges and a score line on one side. The tablet can be divided into equal doses.
8 mg/5 mg: white or almost white, round, biconvex tablets with beveled edges;
Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme inhibitors. ACE inhibitors in combination with calcium antagonists. ATC code C09B B04.
Pharmacological Properties.
Pharmacodynamics.
The rate and extent of absorption of perindopril and amlodipine as individual agents contained in the medicinal product Perindopril/Amlodipine KRKA do not differ significantly.
Perindopril
Perindopril is an angiotensin-converting enzyme (ACE) inhibitor, which converts angiotensin I into angiotensin II. Angiotensin-converting enzyme, or kinase, is an exopeptidase that facilitates the conversion of angiotensin I into angiotensin II and also causes the breakdown of the vasodilatory agent bradykinin into an inactive heptapeptide. Inhibition of angiotensin-converting enzyme activity leads to a reduction in plasma angiotensin II concentration, increased plasma renin activity (due to suppression of negative feedback on renin release), and decreased aldosterone secretion. Since angiotensin-converting enzyme degrades bradykinin, inhibition of this enzyme results in increased activity of circulating and local kallikrein-kinin systems, and consequently, activation of the prostaglandin system. This mechanism contributes to the antihypertensive effect of ACE inhibitors and partially accounts for certain adverse effects (e.g., cough).
Perindopril is converted in the body into its active metabolite, perindoprilat. Other metabolites do not demonstrate ACE-inhibiting activity in vitro.
Arterial Hypertension
Perindopril is effective in mild, moderate, and severe arterial hypertension. It reduces both systolic and diastolic arterial pressure in both supine and standing positions.
Perindopril reduces total peripheral resistance, leading to a decrease in systemic arterial pressure. Peripheral blood flow increases with virtually no change in heart rate. Renal blood flow generally increases, while glomerular filtration rate remains practically unchanged.
The maximum antihypertensive effect develops within 4–6 hours after a single dose and lasts for at least 24 hours: the T/R ratio (maximum/minimum effectiveness over 24 hours) of perindopril ranges from 87% to 100%. Arterial pressure decreases rapidly. In patients who respond to treatment, normalization of arterial pressure occurs within a month and is maintained without tachyphylaxis.
Upon discontinuation of perindopril, no rebound effect occurs.
Perindopril reduces left ventricular hypertrophy.
Clinical studies have demonstrated that perindopril has vasodilatory properties. It improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries.
Combination therapy with a thiazide diuretic produces an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.
Heart Failure
In experimental studies, congestive heart failure was induced by coronary artery ligation, and it was demonstrated that perindopril reduces myocardial hypertrophy and excessive subendocardial collagen, restores the myosin and isoenzyme ratio, and reduces the incidence of reperfusion arrhythmias.
Perindopril reduces cardiac workload by decreasing both preload and afterload.
Studies in patients with heart failure have demonstrated:
- reduction in filling pressures of the right and left ventricles,
- reduction in systemic peripheral resistance,
- increase in cardiac index and improvement in cardiac output,
- increased regional myocardial blood flow.
In comparative studies, initial administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in arterial pressure compared to placebo.
Amlodipine
Amlodipine is a calcium ion antagonist that blocks calcium ion influx through the membranes into vascular and myocardial smooth muscle cells. The antihypertensive mechanism of amlodipine is due to its direct effect on vascular smooth muscle. The exact mechanism of amlodipine in angina is not fully established, but it is known that amlodipine reduces myocardial ischemia via two pathways.
- Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Reduced cardiac load leads to decreased energy consumption and myocardial oxygen demand.
- The mechanism of amlodipine may also involve dilation of major coronary arteries and arterioles. This dilation increases oxygen supply to the myocardium in patients with Prinzmetal’s angina. In patients with arterial hypertension, once-daily dosing provides clinically significant reduction in arterial pressure (both in supine and standing positions) throughout the 24-hour dosing interval.
In patients with angina, once-daily administration of amlodipine prolongs total exercise duration, time to onset of angina, and time to 1 mm ST-segment depression. Amlodipine reduces the frequency of angina attacks and decreases the need for nitroglycerin tablets.
Pharmacokinetics.
Perindopril
Absorption
After oral administration, perindopril is rapidly absorbed, with peak plasma concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.
Perindopril is a prodrug. 27% of the administered perindopril is detected in blood as the active metabolite, perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five inactive metabolites. Peak plasma concentration of perindoprilat is reached 3–4 hours after administration.
Food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability. Therefore, the daily dose of perindopril should be taken once daily in the morning before meals.
A linear relationship exists between perindopril dose and plasma concentration.
Distribution
The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding of perindoprilat to plasma proteins is 20%, primarily to angiotensin-converting enzyme, but this value is dose-dependent.
Elimination
Perindoprilat is excreted in urine. The terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady-state plasma concentration is achieved within 4 days of starting treatment.
Special Patient Populations
Elimination of perindoprilat is slowed in elderly patients and in patients with cardiac or renal insufficiency (see section "Dosage and Administration"). Dose adjustment is recommended for patients with renal impairment based on the degree of impairment (creatinine clearance).
Dialysis clearance of perindoprilat is 70 mL/min.
Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of perindopril is reduced by half. However, the amount of formed perindoprilat does not decrease. Therefore, dose adjustment is not required in such patients (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").
Amlodipine
After oral administration in therapeutic doses, amlodipine is well absorbed and reaches peak blood concentration 6–12 hours after intake. Absolute bioavailability ranges from 64% to 80%. The volume of distribution is approximately 21 L/kg. Food intake does not affect amlodipine bioavailability. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
The elimination half-life from plasma is approximately 35–50 hours, allowing once-daily dosing. Amlodipine is metabolized in the liver into inactive metabolites. 60% of the administered dose is excreted in urine, and 10% is excreted unchanged.
Use in Elderly Patients
The time required to reach peak plasma concentration of amlodipine is similar in elderly and younger patients. In elderly individuals, there is a tendency toward reduced amlodipine clearance, leading to increased AUC (area under the concentration-time curve) and prolonged elimination half-life. The recommended dosing regimen for elderly patients is similar, but dose escalation should be performed cautiously.
Use in Patients with Renal Impairment: see section "Dosage and Administration".
Use in Patients with Hepatic Impairment: The elimination half-life of amlodipine, as with all calcium antagonists, is prolonged in patients with hepatic dysfunction.
Clinical characteristics.
Indications.
Arterial hypertension and/or stable ischemic heart disease, for replacement therapy in patients whose condition is adequately controlled with perindopril and amlodipine taken concomitantly at the same doses.
Contraindications.
- Hypersensitivity to perindopril (or any other angiotensin-converting enzyme [ACE] inhibitors), to amlodipine (or other dihydropyridines), or to any excipients;
- History of angioedema after administration of any ACE inhibitors;
- Idiopathic or hereditary angioedema;
- Severe arterial hypotension;
- Shock, including cardiogenic shock;
- Left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
- Unstable angina (except Prinzmetal's angina);
- Heart failure following acute myocardial infarction (within the first 28 days) or with unstable hemodynamics;
- Concomitant administration with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
- Concomitant use with sacubitril/valsartan therapy – due to increased risk of angioedema. The medicinal product should not be administered within 36 hours after the last dose of sacubitril/valsartan or after switching from sacubitril/valsartan to another medicinal product containing a neprilysin inhibitor (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
- Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
- Significant bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney (see section "Special precautions for use");
- Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
Interaction with other medicinal products and other forms of interaction.
Related to perindopril
Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").
Medicinal products increasing the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications", "Special precautions for use"). Sacubitril/valsartan therapy should be initiated only 36 hours after the last dose of perindopril. Perindopril therapy should be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications", "Special precautions for use").
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (see section "Special precautions for use").
Medicinal products causing hyperkalemia
Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving Perindopril/amlodipine KRKA. Some drugs or therapeutic classes may increase the frequency of hyperkalemia: aliskiren, potassium salts,
potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors,
angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and cotrimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Combination of these drugs increases the risk of hyperkalemia. Therefore, combination of Perindopril/amlodipine KRKA with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and serum potassium levels should be monitored frequently.
Concomitant use is contraindicated (see section "Contraindications")
Aliskiren
In patients with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality is increased.
Extracorporeal treatments
Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) or low-density lipoprotein apheresis with 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.
Concomitant use is not recommended (see section "Special precautions for use")
Aliskiren
In any other patients, including those with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality is increased.
ACE inhibitors and angiotensin receptor blockers.
Published data show that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with RAAS-acting agents. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases under strict monitoring of renal function, potassium levels, and blood pressure.
Estramustine
Increased risk of adverse reactions such as angioedema.
Potassium-sparing diuretics, potassium-containing dietary supplements, or potassium-containing salt substitutes
Hyperkalemia (potentially fatal), especially in combination with renal impairment (additive hyperkalemic effect).
Combination of perindopril with the above-mentioned agents is not recommended (see "Special precautions for use"). If concomitant use is indicated, they should be used with caution and serum potassium levels should be monitored regularly. Information regarding spironolactone use in heart failure is provided below.
Lithium
Concomitant use of ACE inhibitors with lithium preparations may result in reversible increases in plasma lithium concentration and, consequently, increased risk of lithium toxicity (severe neurotoxicity). Concomitant use of perindopril with lithium preparations is not recommended. If such combination is necessary, plasma lithium levels must be closely monitored (see section "Special precautions for use").
Concomitant use requiring special attention
Antidiabetic agents (insulin, oral hypoglycemic agents)
Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combination therapy and in patients with renal impairment.
Diuretics not containing potassium
In patients taking diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake prior to starting perindopril therapy. Treatment should be initiated with low doses and gradually increased.
In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic therapy may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation.
In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.
In any case, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone is used concomitantly with low doses of ACE inhibitors at doses from 12.5 mg to 50 mg daily, the following should be considered:
-
Risk of hyperkalemia (potentially fatal) exists during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, if recommendations for use of this combination are not followed;
-
Before initiating such combination, absence of hyperkalemia and renal impairment should be confirmed;
-
Careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day
Reduced antihypertensive effect may occur with concomitant use of ACE inhibitors and NSAIDs such as: acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including the possibility of acute renal failure, and elevated plasma potassium levels, particularly in patients with a history of renal impairment. Such combination should be prescribed with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored promptly after initiation of combination therapy and periodically thereafter.
Concomitant use requiring attention
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Gold preparations
Nitritoid reactions (symptoms: facial flushing, nausea, vomiting, and arterial hypotension) rarely occur in patients receiving ACE inhibitors, including perindopril, concomitantly with injectable gold preparations (sodium aurothiomalate).
Related to amlodipine
Concomitant use not recommended
Dantrolene (infusion)
In animals, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, use of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.
Concomitant use requiring special attention
Inducers of CYP3A4
Plasma concentrations of amlodipine may be altered when used concomitantly with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustment considered both during and after concomitant use, especially with potent CYP3A4 inducers (e.g., rifampicin, St. John's wort).
Inhibitors of CYP3A4
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to significant increase in amlodipine exposure, potentially increasing the risk of arterial hypotension. The clinical significance of these changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.
Concomitant use of clarithromycin with amlodipine increases the risk of hypotension. Close monitoring of patients is recommended when amlodipine is used concomitantly with clarithromycin.
Concomitant use requiring monitoring.
Amlodipine may also enhance the blood pressure-lowering effect of other antihypertensive agents.
Tacrolimus
There is a risk of increased tacrolimus blood levels when used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully established. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels and, if necessary, dose adjustment are required when amlodipine is used concomitantly.
Inhibitors of mechanistic target of rapamycin (mTOR)
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. When used concomitantly with mTOR inhibitors, amlodipine may increase mTOR inhibitor concentrations.
Cyclosporine
Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other groups, except in kidney transplant recipients, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) were observed. For kidney transplant recipients receiving amlodipine, cyclosporine concentration monitoring should be considered and cyclosporine dose reduced if necessary.
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 receiving amlodipine, simvastatin dose should be limited to 20 mg daily.
Other combinations
Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients the bioavailability of amlodipine may increase, leading primarily to enhanced hypotensive effects.
Perindopril/amlodipine KRKA
Concomitant use requiring special monitoring
Baclofen
Enhanced antihypertensive effect. Blood pressure and renal function should be monitored and antihypertensive doses adjusted if necessary.
Concomitant use requiring monitoring:
- Antihypertensive agents (such as beta-blockers) and vasodilators:
Concomitant use of these agents may increase the hypotensive effect of perindopril and amlodipine.
Concomitant use with nitroglycerin and other nitrates or vasodilators may further reduce blood pressure and should therefore be administered with caution.
- Corticosteroids, tetracosactide reduce the antihypertensive effect of the drug (fluid and salt retention due to corticosteroid action).
- Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin) enhance hypotensive effects and increase the risk of orthostatic hypotension.
- Amifostine may enhance the hypotensive effect of amlodipine.
- Tricyclic antidepressants/neuroleptics/anesthetics enhance hypotensive effects and increase the risk of orthostatic hypotension.
Special precautions for use.
All warnings associated with each component of the medicinal product apply to Perindopril/amlodipine KRKA.
Special precautions for use of perindopril
Hypersensitivity/angioedema
Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors, including perindopril (see section "Adverse reactions"). This may occur at any time during treatment. In such cases, the medicinal product must be discontinued immediately and appropriate monitoring of the patient should be instituted until complete disappearance of symptoms. In isolated cases where swelling is confined to the face and lips, the condition usually resolves without treatment. Administration of antihistamines may be helpful in relieving symptoms.
Angioedema associated with laryngeal swelling may be fatal. If swelling involves the tongue, glottis or larynx, potentially causing airway obstruction, emergency therapy must be instituted immediately, which may include administration of adrenaline and/or securing airway patency. Patients should remain under close medical supervision until complete resolution of symptoms and stabilization of their condition.
Patients with a history of angioedema unrelated to ACE inhibitor therapy are at increased risk of angioedema while taking an ACE inhibitor (see section "Contraindications").
Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C-1 esterase levels were normal. The diagnosis of intestinal angioedema was established by abdominal computed tomography or ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor.
Intestinal angioedema should be considered in the differential diagnosis of patients presenting with abdominal pain who are taking ACE inhibitors.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Therapy with sacubitril/valsartan should be initiated no sooner than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").
Concomitant use of ACE inhibitors with neprilysin inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased 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"). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) or gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rare, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy prior to each apheresis session.
Anaphylactoid reactions during desensitization therapy
Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy with bee venom-containing products. These reactions can be avoided by temporarily discontinuing the ACE inhibitor, but may recur if provocation tests are performed carelessly.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Cases of neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases receiving immunosuppressants, allopurinol or procainamide, or in combination with these risk factors, especially in the presence of impaired renal function. Serious infections, occasionally unresponsive to intensive antibiotic therapy, may develop in such patients. If perindopril is administered to such patients, periodic monitoring of white blood cell counts is recommended, and patients should be advised to report any signs of infection (sore throat, fever).
Renovascular hypertension
In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of hypotension and renal impairment (see section "Contraindications"). Concomitant use of diuretics may be a contributing factor. Impaired renal function may be associated with only minor changes in serum creatinine levels even in patients with unilateral renal artery stenosis.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
If 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 blockers should not be used concomitantly in patients with diabetic nephropathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive therapy acting via inhibition of the RAAS. Therefore, this medicinal product is not recommended for use in such patients.
Pregnancy
Initiation of ACE inhibitor therapy during pregnancy is not recommended. Women planning pregnancy should be switched to alternative antihypertensive therapies with an established safety profile during pregnancy. If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use in pregnancy or lactation").
Precautions for use
Arterial hypotension
ACE inhibitors may cause a reduction in blood pressure. Symptomatic hypotension is less common in patients with uncomplicated hypertension and is more likely in patients with hypovolemia, those receiving diuretics, on a low-salt diet, undergoing dialysis, or with diarrhea or vomiting, or in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Symptomatic hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal impairment. The risk of symptomatic hypotension is greatest in patients with more severe heart failure who are receiving high doses of loop diuretics, have hyponatremia or functional renal impairment. To reduce the risk of symptomatic hypotension, patients should be closely monitored by a physician at the start of therapy and during dose titration. Similar precautions apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may precipitate myocardial infarction or stroke.
In case of hypotension, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication to further use of the medicinal product, which can usually be resumed without difficulty after restoration of blood volume and elevation of blood pressure.
Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy
As with other ACE inhibitors, perindopril should be administered with caution to patients with mitral valve stenosis or left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).
Renal impairment
In cases of renal impairment (creatinine clearance < 60 mL/min), individual dose adjustment of each component of the medicinal product is recommended (see section "Dosage and administration"). Routine monitoring of serum potassium and creatinine levels is part of standard medical practice in patients with impaired renal function (see section "Adverse reactions").
In some patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, increases in blood urea nitrogen and serum creatinine have been observed during ACE inhibitor therapy, which usually return to normal after discontinuation of treatment. This is particularly relevant in patients with pre-existing renal impairment. The risk of severe hypotension and renal impairment is increased in patients with concomitant renovascular hypertension. In some patients with hypertension who had no prior evidence of renovascular disease, increases in blood urea nitrogen and serum creatinine, usually mild and transient, have been observed, particularly when perindopril was administered concomitantly with a diuretic. However, this is more typical in patients with pre-existing renal impairment.
Hepatic impairment
Rare cases of a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal, have been reported in patients receiving ACE inhibitors. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes while receiving an ACE inhibitor should discontinue the drug and receive appropriate medical evaluation and treatment (see section "Adverse reactions").
Racial characteristics
ACE inhibitors are more likely to cause angioedema in patients of Black race than in patients of other races. As with other ACE inhibitors, perindopril is less effective in lowering blood pressure in patients of Black race compared to patients of other races, possibly due to lower plasma renin levels in this population with hypertension.
Cough
Cough has been reported during therapy with ACE inhibitors. The cough is non-productive, persistent and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/anesthesia
Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or anesthesia with hypotensive agents. The drug should be discontinued one day prior to surgery. If hypotension occurs and is considered to be due to this mechanism, the patient's condition can be corrected by increasing circulating blood volume.
Serum potassium
Elevations in serum potassium have been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. In patients with normal renal function, this effect is usually mild. Risk factors for hyperkalemia include renal impairment, worsening renal function, age ≥ 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium levels (e.g. heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and particularly aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to marked increases in serum potassium. Hyperkalemia may result in serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously, and serum potassium levels and renal function should be closely monitored. If concomitant use of perindopril and any of the above-mentioned drugs is considered necessary, they should be used with caution and serum potassium levels should be monitored frequently (see section "Interaction with other medicinal products and other forms of interaction").
Patients with diabetes mellitus
Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy.
Concerning amlodipine
Precautions for use
The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Heart failure
Patients with heart failure should be treated with caution.
In a long-term placebo-controlled trial involving patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher with amlodipine than with placebo (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular complications and future mortality.
Patients with hepatic impairment
In patients with hepatic impairment, amlodipine has a prolonged elimination half-life and increased AUC; dosing recommendations are not established. Therefore, amlodipine therapy should be initiated at the lowest dose, with caution at the beginning of treatment and during dose escalation. Patients with severe hepatic impairment may require gradual dose titration and careful monitoring.
Elderly patients
Dose increases in elderly patients should be made with caution (see sections "Pharmacokinetics" and "Dosage and administration").
Patients with renal impairment
Amlodipine may be used in patients with renal impairment at usual doses. Plasma concentration fluctuations of amlodipine are independent of the degree of renal impairment. Amlodipine is not removed by dialysis.
Perindopril/amlodipine KRKA
Precautions for use
All precautions applicable to each monocomponent, as stated above, also apply to the fixed combination Perindopril/amlodipine KRKA.
Interactions
Concomitant use of Perindopril/amlodipine KRKA with lithium, potassium-sparing diuretics or potassium-containing dietary supplements is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Use during pregnancy or breastfeeding
Considering the effects of the individual components of this combination medicinal product on pregnancy and lactation:
Perindopril/amlodipine KRKA is not recommended during the first trimester of pregnancy. Perindopril/amlodipine KRKA is contraindicated during the second and third trimesters of pregnancy.
Perindopril/amlodipine KRKA is not recommended during breastfeeding. A decision should therefore be made whether to discontinue breastfeeding or discontinue/abandon therapy, taking into account the importance of the therapy for the mother.
Pregnancy
Related to perindopril
ACE inhibitors are not recommended during the first trimester of pregnancy (see section "Special precautions for use"). ACE inhibitors are contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").
Epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy initiated.
It is known that use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
If ACE inhibitors were used during the second trimester of pregnancy, ultrasound evaluation of fetal renal function and skull ossification is recommended.
Infants whose mothers received ACE inhibitors should be closely monitored for hypotension, oliguria and hyperkalemia (see sections "Contraindications" and "Special precautions for use").
Related to amlodipine
The safety of amlodipine use during pregnancy in humans has not been established.
Reproductive toxicity was observed in animal studies at high doses.
Use during pregnancy is recommended only when safer alternatives are not available and the disease itself poses a greater risk to mother and fetus.
Period of breastfeeding
Related to perindopril
Due to lack of information on the use of perindopril during breastfeeding, use of Perindopril/amlodipine KRKA is not recommended. Alternative therapy with a better-established safety profile, especially for newborns or premature infants, is required during breastfeeding.
Related to amlodipine
Amlodipine passes into human breast milk. The fraction of the maternal dose received by the infant is estimated at 3–7%, maximum 15%. The effect of amlodipine on infants is unknown. The decision on whether to continue/stop breastfeeding or continue/stop amlodipine therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.
Fertility
Related to perindopril
No effect on reproductive parameters or fertility has been observed.
Related to amlodipine
Reversible biochemical changes in sperm head have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. An adverse effect on male fertility was observed in one rat study.
Ability to affect reaction speed when driving or operating machinery
When driving vehicles or operating machinery, the possibility of adverse reactions such as dizziness or weakness should be taken into account.
Dosage and Administration
Oral administration.
Initiate treatment with 1 tablet once daily, preferably taken in the morning before a meal.
Fixed-dose combination therapy is not suitable for initial treatment.
The dosage range of the medicinal product allows flexible adjustment of the component ratio according to clinical needs. The dose should be individually adjusted for each patient depending on the indication, disease course, and blood pressure levels.
Maximum daily dose: 1 tablet of Perindopril/amlodipine KRKA containing 8 mg/10 mg once daily.
Special Populations
Patients with Renal Impairment and Elderly Patients
Elimination of perindoprilat is reduced in elderly patients and in patients with renal insufficiency. Therefore, frequent monitoring of creatinine and potassium levels is required during treatment. Perindopril/amlodipine KRKA may be prescribed to patients with creatinine clearance ≥ 60 mL/min and is contraindicated in patients with creatinine clearance < 60 mL/min. For such patients, individual dose titration of perindopril and amlodipine as monotherapies is recommended.
Changes in plasma concentration of amlodipine do not correlate with the severity of renal impairment.
Patients with Hepatic Impairment (see sections “Pharmacodynamics” and “Special Warnings”)
Dosage regimen has not been established for patients with mild to moderate hepatic impairment; therefore, dose selection should be cautious, starting with the lowest available dose (see sections “Pharmacodynamics” and “Special Warnings”). For patients with hepatic impairment, individual dose titration of perindopril and amlodipine as monotherapies is recommended. The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with marked hepatic insufficiency, amlodipine therapy should be initiated at the lowest dose and titrated slowly.
Children
The medicinal product is contraindicated in children (under 18 years of age) due to lack of data from clinical studies in this patient group.
Overdose
There is no information available on overdose with Perindopril/amlodipine KRKA in humans.
Overdose (ingestion of large doses) of amlodipine may lead to excessive peripheral vasodilation and, consequently, to marked and possibly prolonged systemic hypotension, including shock, potentially resulting in fatal outcome. Clinically significant arterial hypotension caused by amlodipine overdose requires active measures to support cardiovascular function, including monitoring of cardiac and pulmonary parameters, positioning the patient supine with legs elevated, monitoring circulating blood volume and diuresis.
Vasoconstrictors are indicated to restore vascular tone and normal blood pressure levels. To counteract calcium channel blockade, intravenous calcium gluconate should be administered. In some cases, gastric lavage may be beneficial.
In healthy volunteers, administration of activated charcoal within 2 hours after 10 mg amlodipine intake has been shown to reduce the rate of amlodipine absorption. Since amlodipine is highly protein-bound, dialysis is unlikely to be effective.
Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid overload) to support perfusion and cardiac output may act as triggering factors.
Data on perindopril overdose in humans are limited. Symptoms of angiotensin-converting enzyme (ACE) inhibitor overdose include arterial hypotension, shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Treatment should include intravenous administration of physiological saline solution. If arterial hypotension occurs, the patient should be placed in a horizontal position with low head elevation. Angiotensin II and/or catecholamines may also be administered intravenously. Perindopril can be removed from systemic circulation by hemodialysis. For refractory bradycardia, pacemaker implantation should be considered. Continuous monitoring of vital signs, serum electrolytes, and creatinine levels is essential.
Adverse reactions.
The most commonly observed adverse reactions during treatment with perindopril and amlodipine administered separately include edema, somnolence, dizziness, headache (especially at the beginning of treatment), dysgeusia, paresthesia, visual disturbances (including diplopia), tinnitus, vertigo, palpitations, flushing, hypotension (and consequences associated with hypotension), dyspnea, cough, abdominal pain, nausea, vomiting, dyspepsia, changes in defecation rhythm, diarrhea, constipation, pruritus, rash, exanthema, joint swelling (ankle swelling), muscle spasms, fatigue, asthenia.
The adverse effects listed below were observed during treatment with perindopril or amlodipine administered separately and are classified according to MedDRA system organ classes and frequency of occurrence: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10000 to < 1/1000); very rare (< 1/10000); not known (frequency cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.
| System organ class |
Adverse reactions |
Frequency |
|
| Amlodipine |
Perindopril |
||
| Infections and infestations |
Rhinitis |
Occasionally |
Very rare |
| Blood and lymphatic system disorders |
Eosinophilia |
- |
Occasionally1) |
| Leukopenia/neutropenia2) |
Very rare |
Very rare |
|
| Agranulocytosis or pancytopenia2) |
- |
Very rare |
|
| Thrombocytopenia2) |
Very rare |
Very rare |
|
| Hemolytic anemia in patients with congenital deficiency of G-6PDH enzyme2) |
- |
Very rare |
|
| Decrease in hemoglobin and hematocrit levels |
- |
Very rare |
|
| Immune system disorders |
Hypersensitivity |
Very rare |
Occasionally |
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
- |
Uncommon |
| Metabolism and nutrition disorders |
Hypoglycemia3) |
- |
Occasionally1) |
| Hyperkalemia, reversible upon discontinuation2) |
- |
Occasionally1) |
|
| Hypernatremia |
- |
Occasionally1) |
|
| Hypoglycemia |
Very rare |
- |
|
| Psychiatric disorders |
Insomnia |
Occasionally |
- |
| Mood changes (including anxiety) |
Occasionally |
Occasionally |
|
| Depression |
Occasionally |
Occasionally |
|
| Sleep disorders |
- |
Occasionally |
|
| Nervous system disorders |
Somnolence (especially at the beginning of treatment) |
Common |
- |
| Dizziness (especially at the beginning of treatment) |
Common |
Common |
|
| Headache (especially at the beginning of treatment) |
Common |
Common |
|
| Dysgeusia |
Occasionally |
Common |
|
| Tremor |
Occasionally |
- |
|
| Hypoesthesia |
Occasionally |
- |
|
| Paraesthesia |
Occasionally |
Common |
|
| Syncope |
Occasionally |
Occasionally |
|
| Confusion |
Uncommon |
Very rare |
|
| Hypertonia |
Very rare |
- |
|
| Peripheral neuropathy |
Very rare |
- |
|
| Cerebrovascular events, possibly secondary to excessive hypotension in high-risk patients2) |
- |
Very rare |
|
| Extrapyramidal disorders |
Unknown |
- |
|
| Eye disorders |
Visual disturbance |
Common |
Common |
| Diplopia |
Common |
- |
|
| Ear and labyrinth disorders |
Tinnitus |
Occasionally |
Common |
| Vertigo |
- |
Common |
|
| Cardiac disorders |
Palpitations |
Common |
Occasionally1) |
| Tachycardia |
- |
Occasionally1) |
|
| Angina pain2) |
- |
Very rare |
|
| Myocardial infarction, possibly due to marked arterial hypotension in high-risk patients2) |
Very rare |
Very rare |
|
| Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) |
Occasionally |
Very rare |
|
| Vascular disorders |
Flushing |
Common |
Uncommon |
| Arterial hypotension (and related effects) |
Occasionally |
Common |
|
| Vasculitis |
Very rare |
Occasionally1) |
|
| Raynaud's phenomenon |
- |
Unknown |
|
| Respiratory, thoracic and mediastinal disorders |
Dyspnea |
Common |
Common |
| Cough |
Occasionally |
Common |
|
| Bronchospasm |
- |
Occasionally |
|
| Eosinophilic pneumonia |
- |
Very rare |
|
| Gastrointestinal disorders |
Gingival hyperplasia |
Very rare |
- |
| Abdominal pain |
Common |
Common |
|
| Nausea |
Common |
Common |
|
| Vomiting |
Occasionally |
Common |
|
| Dyspepsia |
Common |
Common |
|
| Change in defecation rhythm |
Common |
- |
|
| Dry mouth |
Occasionally |
Occasionally |
|
| Diarrhea |
Common |
Common |
|
| Constipation |
Common |
Common |
|
| Pancreatitis |
Very rare |
Very rare |
|
| Gastritis |
Very rare |
- |
|
| Hepatobiliary disorders |
Hepatitis, cholestatic jaundice |
Very rare |
- |
| Cytolytic or cholestatic hepatitis2) |
- |
Very rare |
|
| Elevated liver enzymes (mainly with cholestasis) |
Very rare |
- |
|
| Skin and subcutaneous tissue disorders |
Quincke's edema |
Very rare |
- |
| Angioneurotic edema of the face, limbs, lips, mucous membranes, tongue, glottis and/or larynx2) |
Very rare |
Occasionally |
|
| Multiform erythema |
Very rare |
Very rare |
|
| Alopecia |
Occasionally |
- |
|
| Purpura |
Occasionally |
- |
|
| Skin color changes |
Occasionally |
- |
|
| Increased sweating |
Occasionally |
Occasionally |
|
| Pruritus |
Occasionally |
Common |
|
| Rash, exanthema |
Occasionally |
Common |
|
| Urticaria2) |
Occasionally |
Occasionally |
|
| Photosensitivity reactions |
Very rare |
Occasionally1) |
|
| Pemphigoid |
- |
Occasionally1) |
|
| Psoriasis exacerbation |
- |
Uncommon |
|
| Stevens-Johnson syndrome |
Very rare |
- |
|
| Exfoliative dermatitis |
Very rare |
- |
|
| Toxic epidermal necrolysis |
Unknown |
- |
|
| Musculoskeletal and connective tissue disorders |
Joint swelling (ankle edema) |
Common |
- |
| Arthralgia |
Occasionally |
Occasionally1) |
|
| Myalgia |
Occasionally |
Occasionally1) |
|
| Muscle cramps |
Common |
Common |
|
| Back pain |
Occasionally |
- |
|
| Renal and urinary disorders |
Urinary disorders, nocturia, polyuria |
Occasionally |
- |
| Renal failure |
- |
Occasionally |
|
| Acute renal failure |
- |
Uncommon |
|
| Anuria/Oliguria |
- |
Uncommon |
|
| Reproductive system and breast disorders |
Erectile dysfunction |
Occasionally |
Occasionally |
| Gynecomastia |
Occasionally |
- |
|
| General disorders and administration site conditions |
Edema |
Very common |
- |
| Peripheral edema |
- |
Occasionally1) |
|
| Malaise |
Common |
- |
|
| Chest pain |
Occasionally |
Occasionally1) |
|
| Asthenia |
Common |
Common |
|
| Pain |
Occasionally |
- |
|
| Restlessness |
Occasionally |
Occasionally1) |
|
| Hyperthermia |
- |
Occasionally1) |
|
| Investigations |
Increased body weight, decreased body weight |
Occasionally |
- |
| Increased blood urea concentration |
Occasionally1) |
||
| Elevated plasma creatinine concentration |
- |
Occasionally1) |
|
| Elevated blood bilirubin levels |
- |
Uncommon |
|
| Elevated liver enzymes |
- |
Uncommon |
|
| Decreased hemoglobin and hematocrit |
- |
Very rare |
|
| Injury, poisoning and procedural complications |
Weakness |
- |
Occasionally1) |
- Frequency of adverse reactions is based on spontaneous reports during clinical trials.
- See section "Special precautions for use".
- See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions.
Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture and light. Keep out of reach of children.
Packaging.
10 tablets in a blister; 3 or 9 blisters in a cardboard box.
Prescription category.
Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and location of operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.