Amlodipine-Perindopril-Richter (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter Poland, Co. Ltd. (Poland)

Or

Gedeon Richter-Rus, JSC (Russia)

Quality Control Release

GEDEON RICHTER, Plc. (Hungary)

Or

GEDEON RICHTER POLAND, Co. Ltd. (Poland)

Or

GEDEON RICHTER-RUS, JSC (Russia)

ATC Code

C09BB04 (Perindopril and Amlodipine)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Amlodipine-Perindopril-Richter	Tablets 5 mg+4 mg: 30 pcs.
		Tablets 5 mg+8 mg: 30 pcs.
		Tablets 10 mg+4 mg: 30 pcs.
		Tablets 10 mg+8 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat, with a bevel and engraving “CH3” on one side.

Excipients: microcrystalline cellulose (type 112), microcrystalline cellulose (type 14), polacrilin potassium, colloidal silicon dioxide, magnesium stearate.

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

Tablets white or almost white, round, flat, with a bevel and engraving “CH4” on one side.

Excipients: microcrystalline cellulose (type 112), microcrystalline cellulose (type 14), polacrilin potassium, colloidal silicon dioxide, magnesium stearate.

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

Tablets white or almost white, round, flat, with a bevel and engraving “CH5” on one side.

Excipients: microcrystalline cellulose (type 112), microcrystalline cellulose (type 14), polacrilin potassium, colloidal silicon dioxide, magnesium stearate.

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

Tablets white or almost white, round, flat, with a bevel and engraving “CH6” on one side.

Excipients: microcrystalline cellulose (type 112), microcrystalline cellulose (type 14), polacrilin potassium, colloidal silicon dioxide, magnesium stearate.

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

Clinical-Pharmacological Group

Combined antihypertensive drug (slow calcium channel blocker + ACE inhibitor)

Pharmacotherapeutic Group

Antihypertensive agent, combination (slow calcium channel blocker + ACE inhibitor)

Pharmacological Action

Mechanism of action

Amlodipine-Perindopril-Richter contains two antihypertensive components with complementary mechanisms of action aimed at controlling blood pressure in patients with arterial hypertension: Amlodipine belongs to the slow calcium channel blockers, and Perindopril belongs to the ACE inhibitors. The combination of these active substances enhances the antihypertensive effect of each of them.

Amlodipine

Amlodipine is an inhibitor of calcium ion influx, a dihydropyridine derivative (slow calcium channel blocker, or calcium ion antagonist). Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and vascular smooth muscle cells.

The antihypertensive effect of amlodipine is due to a direct effect on vascular smooth muscle cells. It is known that Amlodipine reduces total ischemic load through two actions:

• It causes dilation of peripheral arterioles, reducing total peripheral resistance (afterload). Since heart rate does not change, myocardial oxygen demand and energy consumption are reduced;
• It also probably causes dilation of the main coronary arteries and coronary arterioles in both normal and ischemic areas of the myocardium. Their dilation increases oxygen delivery to the myocardium in patients with coronary artery spasm (Prinzmetal’s angina, or variant angina).

Amlodipine has a long-term, dose-dependent antihypertensive effect. The antihypertensive effect is due to a direct vasodilatory effect on vascular smooth muscles. In arterial hypertension, a single dose provides a clinically significant reduction in blood pressure for 24 hours (in both the “lying” and “standing” positions).

Orthostatic hypotension is relatively rare with amlodipine use. Amlodipine does not cause a reduction in exercise tolerance or left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect.

In diabetic nephropathy, it does not increase the severity of microalbuminuria. It does not have any adverse effect on metabolism and plasma lipid concentrations and can be used in the treatment of patients with bronchial asthma, diabetes mellitus, and gout. A significant decrease in blood pressure is observed 6-10 hours after taking amlodipine, and the duration of the effect is 24 hours.

In patients with stable angina, a single daily dose of amlodipine increases exercise tolerance, delays the development of angina attacks and ischemic ST-segment depression by 1 mm, and reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

In patients with cardiovascular diseases (including coronary atherosclerosis with single-vessel disease and up to stenosis of 3 or more arteries, carotid artery atherosclerosis), who have had myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), or in patients with angina, the use of amlodipine prevents the development of intima-media thickening of the carotid arteries, reduces mortality from myocardial infarction, stroke, PTCA, coronary artery bypass grafting; leads to a reduction in the number of hospitalizations for unstable angina and progression of chronic heart failure (CHF); reduces the frequency of interventions aimed at restoring coronary blood flow.

It does not increase the risk of death or the development of complications and fatal outcomes in patients with CHF of functional class III-IV according to the NYHA classification while on therapy with digoxin, diuretics, and ACE inhibitors. In patients with CHF of functional class III-IV according to the NYHA classification of non-ischemic etiology, there is a possibility of pulmonary edema when using amlodipine.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE, or kininase II, is an exopeptidase that carries out both the conversion of angiotensin I to the vasoconstrictor substance angiotensin II and the breakdown of bradykinin, which has a vasodilatory effect, into an inactive heptapeptide. Inhibition of ACE leads to a decrease in the level of angiotensin II in plasma, which leads to an increase in plasma renin activity (due to suppression of negative feedback) and a decrease in aldosterone secretion.

Since ACE inactivates bradykinin, suppression of ACE is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin system, and the prostaglandin system is also activated. It is possible that this effect is part of the mechanism of the antihypertensive action of ACE inhibitors, as well as the mechanism of development of some side effects (such as cough).

Perindopril exerts its therapeutic effect through an active metabolite, perindoprilat. Other metabolites do not have an inhibitory effect on ACE in vitro.

Arterial hypertension

Perindopril is effective in the treatment of arterial hypertension of any severity. Against the background of perindopril use, a decrease in both systolic and diastolic blood pressure is noted in the “lying” and “standing” positions. Perindopril reduces total peripheral resistance, which leads to a decrease in blood pressure, while peripheral blood flow accelerates without a change in heart rate.

As a rule, Perindopril leads to an increase in renal blood flow, while the glomerular filtration rate (GFR) does not change.

The antihypertensive effect of perindopril reaches its maximum 4-6 hours after a single oral dose and persists for 24 hours. 24 hours after oral administration, a pronounced residual inhibition of ACE is observed (about 87-100%).

The decrease in blood pressure is achieved quite quickly. In patients with a positive response to treatment, normalization of blood pressure occurs within a month and is maintained without the development of tachyphylaxis. Discontinuation of treatment is not accompanied by the development of a “withdrawal” syndrome. Perindopril has a vasodilatory effect, promotes the restoration of elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

Stable CAD

It has been shown that against the background of taking perindopril tert-butylamine at a dose of 8 mg once/day in patients with stable CAD without clinical symptoms of CHF, there is a significant reduction in the absolute risk of complications, such as mortality from cardiovascular diseases, the frequency of non-fatal myocardial infarction and/or cardiac arrest with subsequent successful resuscitation by 1.9%. In patients who had previously had a myocardial infarction or coronary revascularization, the reduction in absolute risk was 2.2% compared to the placebo group.

Pharmacokinetics

The extent of absorption of amlodipine and perindopril when using the drug Amlodipine-Perindopril-Richter does not differ significantly from that when using the monodrugs.

Amlodipine

Absorption

After oral administration, Amlodipine is well absorbed from the gastrointestinal tract. The mean absolute bioavailability is 64-80%. The maximum plasma concentration is observed 6-12 hours after oral administration. Food intake does not affect the absorption of amlodipine.

Distribution

V_d is approximately 21 L/kg, indicating that most of the amlodipine is in the tissues and a smaller part is in the blood. Plasma protein binding is approximately 97.5%. Simultaneous food intake does not affect the bioavailability of amlodipine. Penetrates the BBB.

Steady-state concentrations are reached after 7-8 days of therapy.

Metabolism

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect. Metabolites do not have significant pharmacological activity.

Excretion

After a single dose of amlodipine, T_1/2 ranges from 35 h to 50 h, with repeated use T_1/2 is approximately 45 h. About 60% of the orally administered dose is excreted by the kidneys mainly as metabolites, 10% – unchanged, and 20-25% – through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg; 0.42 L/h/kg).

Perindopril

Absorption

After oral administration, Perindopril is rapidly absorbed from the gastrointestinal tract. C_max in plasma is reached within 1 h.

Distribution

V_d of unbound perindoprilat is about 0.2 L/kg. The binding of perindoprilat to plasma proteins, mainly to ACE, is dose-dependent and amounts to 20%.

Steady state is reached within 4 days.

Metabolism

Perindopril does not have pharmacological activity. Approximately 27% of the total amount of absorbed perindopril is converted into the active metabolite perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity.

C_max of perindoprilat in blood plasma is reached 3-4 hours after oral administration. Taking perindopril with food is accompanied by a decrease in the conversion of perindopril to perindoprilat, respectively reducing the bioavailability of the drug. Therefore, Perindopril should be taken once/day, in the morning, before meals.

There is a linear relationship between the plasma concentration of perindopril and the dose.

Excretion

T_1/2 of perindopril from blood plasma is 1 h. Perindoprilat is excreted by the kidneys, T_1/2 of the free fraction is 3-5 h. The terminal T_1/2 is approximately 17 h.

Pharmacokinetics in special patient groups

Patients with renal insufficiency

The change in amlodipine plasma concentration does not correlate with the severity of renal failure. Amlodipine is not removed from the body by dialysis.

The excretion of perindoprilat is slowed in patients with cardiac and renal insufficiency. When individually selecting the dose, the degree of renal function impairment (CC) should be taken into account. Routine monitoring of such patients should include monitoring of blood creatinine and potassium levels (see sections “Dosage Regimen” and “Special Instructions”).

Patients with hepatic insufficiency

The drug should be used with caution in patients with impaired liver function.

Data on the use of amlodipine in patients with hepatic insufficiency are limited. In patients with hepatic insufficiency, a decrease in the clearance of amlodipine is observed, leading to an increase in T_1/2 and AUC by approximately 40-60%. The dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril are impaired in patients with liver cirrhosis: hepatic clearance is reduced by 2 times. However, the amount of perindoprilat formed does not decrease, so dose adjustment is not required (see sections “Dosage Regimen” and “Special Instructions”).

Children and adolescents under 18 years of age

Currently, there are no data on the study of pharmacokinetic parameters of amlodipine and perindopril in children and adolescents under 18 years of age.

Elderly patients (over 65 years of age)

The time from drug administration to reaching C_max of amlodipine does not differ between elderly and younger patients. In elderly patients, a slowdown in the clearance of amlodipine is noted, leading to an increase in AUC and T_1/2.

The excretion of perindoprilat is slowed in the elderly. Renal function should be monitored before increasing the dose. Routine monitoring of such patients should include monitoring of blood creatinine and potassium levels (see sections “Dosage Regimen” and “Special Instructions”).

Indications

Arterial hypertension and/or CAD

• Stable exertional angina in patients who require therapy with perindopril and amlodipine.

ICD codes

Dosage Regimen

Amlodipine-Perindopril-Richter is recommended to be taken orally, 1 tablet once/day, preferably in the morning before meals, with a sufficient amount of water.

The dose of the drug Amlodipine-Perindopril-Richter is selected after previously conducted titration of the doses of the individual components of the drug: amlodipine and perindopril in patients with arterial hypertension and/or CAD.

If therapeutically necessary, the dose of the drug Amlodipine-Perindopril-Richter can be changed, or an individual selection of doses of the individual components can be preliminarily carried out: Amlodipine 5 mg + Perindopril 4 mg, or Amlodipine 5 mg + Perindopril 8 mg, or Amlodipine 10 mg + Perindopril 4 mg, or Amlodipine 10 mg + Perindopril 8 mg.

Maximum daily dose: Amlodipine 10 mg + Perindopril 8 mg.

Special patient groups

Patients with renal insufficiency. In patients with renal insufficiency, the excretion of perindoprilat is slowed. Therefore, in such patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood serum.

Amlodipine-Perindopril-Richter can be prescribed to patients with CC equal to or greater than 60 ml/min. The drug is contraindicated in patients with CC less than 60 ml/min. For such patients, individual selection of doses of the individual components is recommended.

Patients with hepatic insufficiency. For patients with mild or moderate hepatic insufficiency, dose selection should be carried out with caution. It is recommended to start taking the drug with low doses. The search for the optimal initial and maintenance dose for patients with hepatic insufficiency should be carried out individually, using amlodipine and perindopril preparations as monotherapy.

Children and adolescents under 18 years of age. The drug Amlodipine-Perindopril-Richter should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the efficacy and safety of the use of perindopril and amlodipine in this group of patients both as monotherapy and as part of combination therapy.

Elderly patients (over 65 years of age). In elderly patients, the excretion of perindoprilat is slowed. In patients 75 years of age and older, when prescribing the drug Amlodipine-Perindopril-Richter, the benefit/risk ratio should be assessed in each specific case due to limited safety data. Therapy should be carried out taking into account renal function. After starting treatment, renal function should be monitored before increasing the dose, especially in patients aged 75 years and older. Routine monitoring of such patients should include monitoring of serum creatinine and potassium levels.

Adverse Reactions

Clinical studies did not reveal any new significant adverse reactions for the combined drug Amlodipine + Perindopril compared to the existing data on the use of the individual drug components as monotherapy.

The most frequent adverse reactions reported in clinical studies are: dizziness, cough, edema.

Adverse reactions reported during clinical studies and/or in the post-marketing period for the components of the drug Amlodipine-Perindopril-Richter (Amlodipine and Perindopril) are listed below, as they may occur when taking the combined drug.

List of adverse reactions

The frequency of adverse reactions noted in therapy with the combined drug Amlodipine + Perindopril, and in monotherapy with amlodipine and perindopril, is presented using the following gradation: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), including isolated reports; frequency not known (frequency cannot be estimated from the available data).

*The assessment of the frequency of adverse reactions identified from spontaneous reports was based on data from clinical study results.

Development of syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported with concomitant use of other ACE inhibitors. SIADH is a very rare but possible complication associated with ACE inhibitor therapy, including Perindopril.

Additional information for the combination Amlodipine + Perindopril

Peripheral edema, known as an adverse effect of amlodipine, was observed with lower frequency in patients receiving the combination Amlodipine + Perindopril compared to patients receiving Amlodipine as monotherapy.

Contraindications

• Hypersensitivity to perindopril or other ACE inhibitors, amlodipine or other dihydropyridine derivatives, or to any of the excipients of the drug;
• Moderate and severe renal impairment (creatinine clearance less than 60 ml/min);
• History of angioedema (including with the use of other ACE inhibitors);
• Hereditary/idiopathic angioedema;
• Severe arterial hypotension (systolic BP less than 90 mm Hg);
• Shock (including cardiogenic);
• Left ventricular outflow tract obstruction (e.g., clinically significant aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Concomitant use with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy;
• Concomitant use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of angioedema;
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (efficacy and safety not established);
• Extracorporeal therapies leading to blood contact with negatively charged surfaces;
• Clinically significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney.

With caution

Unilateral renal artery stenosis, hepatic impairment, renal impairment, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis, thrombocytopenia, anemia), reduced blood volume (diuretic use, salt-free diet, hemodialysis, vomiting, diarrhea), coronary artery disease, acute myocardial infarction (and within 1 month after it), unstable angina, sick sinus syndrome (severe tachycardia, bradycardia), cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure, concomitant use of potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and lithium preparations, aliskiren and drugs containing aliskiren in patients without diabetes or renal impairment, angiotensin II receptor antagonists in patients without diabetic nephropathy, hyperkalemia, use during major surgery or general anesthesia, concomitant use with inhibitors or inducers of the CYP3A4 isoenzyme, use in patients after kidney transplantation, LDL apheresis, desensitization therapy, burdened allergic history, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, use in patients of Black race, elderly age.

Use in Pregnancy and Lactation

Considering the effects of the individual components of this combination, Amlodipine-Perindopril-Richter is contraindicated during pregnancy and breastfeeding.

Pregnancy

Amlodipine-Perindopril-Richter is contraindicated during pregnancy. Women planning pregnancy should be switched to an alternative antihypertensive agent with an established safety profile for use during pregnancy. If pregnancy is detected, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative antihypertensive therapy should be prescribed.

Amlodipine

The safety of amlodipine use during pregnancy and breastfeeding has not been established. In experimental animal studies, fetotoxic and embryotoxic effects of amlodipine were observed at high doses. The use of amlodipine during pregnancy is only possible if there is no safer alternative and when the benefit to the mother outweighs the risk to the fetus and newborn.

Perindopril

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy. Currently, there is no conclusive epidemiological data on the teratogenic risk of ACE inhibitor use in the first trimester of pregnancy. However, an increased risk of fetal development disorders cannot be excluded. When planning pregnancy, the drug should be discontinued and other antihypertensive agents approved for use during pregnancy should be prescribed. If pregnancy occurs, ACE inhibitor therapy should be discontinued immediately and, if necessary, other therapy should be prescribed.

It is known that exposure to ACE inhibitors during the second and third trimesters of pregnancy can lead to impaired fetal development (decreased renal function, oligohydramnios, delayed skull ossification) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

If a patient has taken ACE inhibitors during the second or third trimester of pregnancy, an ultrasound examination is recommended to assess the skull and renal function.

Newborns whose mothers took ACE inhibitors during pregnancy should be under close medical supervision due to the risk of arterial hypotension.

Breastfeeding period

Amlodipine

Amlodipine is excreted in breast milk in women. The average milk/plasma ratio for amlodipine concentration was 0.85 among 31 breastfeeding women who had pregnancy-induced hypertension and received Amlodipine at an initial dose of 5 mg/day. The dose was adjusted if necessary (depending on the mean daily dose and body weight: 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine received by the infant via breast milk is 4.17 mcg/kg.

Perindopril

Due to the lack of information regarding the use of perindopril during breastfeeding, perindopril intake is not recommended; it is preferable to adhere to alternative treatment with a more studied safety profile during breastfeeding, especially when feeding newborns or premature infants.

Fertility

Amlodipine

Biochemical changes in spermatozoa heads have been found in some patients treated with calcium channel blockers. However, there is currently insufficient clinical data regarding the potential effect of amlodipine on fertility. A study in rats revealed adverse effects on fertility in males.

Perindopril

No effect of perindopril on reproductive function or fertility has been identified.

Use in Hepatic Impairment

Use with caution in patients with hepatic impairment.

Use in Renal Impairment

Contraindications: moderate and severe renal impairment (creatinine clearance less than 60 ml/min); concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy; clinically significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney.

In patients with renal impairment, the elimination of perindoprilat is slowed. Therefore, in such patients, serum creatinine and potassium levels should be monitored regularly.

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Amlodipine

Hypertensive crisis

The efficacy and safety of amlodipine in hypertensive crisis have not been established. The medicinal product Amlodipine-Perindopril-Richter should not be used to relieve a hypertensive crisis.

Acute myocardial infarction

The use of Amlodipine-Perindopril-Richter in patients with acute myocardial infarction is not recommended due to insufficient clinical experience.

Chronic heart failure

Amlodipine-Perindopril-Richter should be used with caution in patients with CHF (NYHA functional class III and IV) due to the possibility of pulmonary edema.

Hepatic impairment

In patients with impaired liver function, the T_1/2 and AUC of amlodipine are increased.

Renal impairment

Patients with renal impairment can take Amlodipine at standard doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not removed from the body by dialysis.

Elderly patients (over 65 years)

In elderly patients, the T_1/2 of amlodipine may be prolonged and clearance may be reduced. Dose adjustment for elderly patients is not required; when increasing the dose, more careful monitoring of patients is necessary.

Withdrawal syndrome

Although calcium channel blockers do not have a withdrawal syndrome, it is advisable to discontinue amlodipine treatment by gradually reducing the dose. Amlodipine does not prevent the development of withdrawal syndrome upon abrupt discontinuation of beta-blockers.

Peripheral edema

Mild or moderate peripheral edema was the most frequent adverse event of amlodipine in clinical studies. The incidence of peripheral edema increases with increasing dose (when using amlodipine at doses of 2.5 mg, 5 mg, and 10 mg daily, edema occurred in 1.8%, 3%, and 10% of patients, respectively). Peripheral edema associated with the use of amlodipine should be carefully differentiated from symptoms of progressive left ventricular heart failure.

Other

Maintenance of dental hygiene and observation by a dentist is necessary (to prevent soreness, bleeding, and gingival hyperplasia).

It is necessary to control body weight and salt intake during therapy with amlodipine.

Perindopril

Hypersensitivity/Angioedema

In rare cases, angioedema of the face, upper and lower extremities, lips, mucous membranes, tongue, vocal folds, and/or larynx may occur in patients receiving ACE inhibitors, including Perindopril, at any time during therapy (see section “Adverse Reactions”). If symptoms appear, the drug should be discontinued immediately, and the patient should be observed until the symptoms of edema completely disappear. If the edema involves only the face and lips, its manifestations usually resolve on their own, although antihistamines may be used to treat the symptoms.

Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms occur, emergency therapy is required, including s.c. administration of epinephrine (adrenaline) and/or ensuring airway patency. The patient should be under medical supervision until the symptoms have completely and permanently resolved.
Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of its development when taking Amlodipine-Perindopril-Richter (see section “Contraindications”).

In rare cases, intestinal angioedema has occurred during therapy with ACE inhibitors. In such cases, patients experienced abdominal pain, as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was made using abdominal computed tomography, ultrasound, or during surgery. Symptoms resolved after discontinuation of the ACE inhibitor. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis (see section “Adverse Reactions”).

Anaphylactoid reactions during desensitization

There are isolated reports of anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy (e.g., with hymenoptera venom). In these patients, the anaphylactoid reaction was avoided by temporarily discontinuing the ACE inhibitor, and upon accidental or careless resumption of treatment, reactions could develop again.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Neutropenia, agranulocytosis, thrombocytopenia, and anemia may develop during therapy with ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia is rare. Amlodipine-Perindopril-Richter should be used with particular caution in patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, or with a combination of these risk factors, especially in patients with impaired renal function.

Some patients have developed severe infections, in some cases resistant to intensive antibiotic therapy. In such patients, it is recommended to periodically monitor the white blood cell count when using Amlodipine-Perindopril-Richter. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Dual blockade of the RAAS

The use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist (ARA II) in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus with confirmed target organ damage or with diabetic nephropathy, did not show a significant positive effect on the occurrence of renal and/or cardiovascular events and on mortality rates, while the risk of hyperkalemia, acute renal failure and/or arterial hypotension increased compared to monotherapy. Therefore, ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy.

Adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or a combination of these conditions, increases the risk of adverse events and serious adverse events such as hyperkalemia, arterial hypotension, impaired renal function, cardiovascular death and stroke.

Thus, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended. If therapy with dual blockade is considered absolutely necessary, it should be carried out only under strict medical supervision and with regular monitoring of renal function, blood electrolyte levels and blood pressure.

Concomitant use of Amlodipine-Perindopril-Richter with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients (see sections “Contraindications” and “Drug Interactions”).

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are generally not sensitive to antihypertensive drugs whose action is based on inhibition of the RAAS. Thus, the use of this drug in such patients is not recommended.

Renal impairment

The drug is contraindicated in patients with moderate and severe renal impairment (creatinine clearance less than 60 ml/min). In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), the initial dose of perindopril should be selected according to the creatinine clearance value, depending on the response to treatment. In such patients, serum creatinine and potassium levels should be monitored regularly.

In patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney (especially in the presence of renal impairment), an increase in serum urea and creatinine concentrations may occur during therapy with ACE inhibitors, which usually resolves upon discontinuation of therapy.

The use of ACE inhibitors in patients with renovascular hypertension is associated with an increased risk of severe arterial hypotension and renal failure.

In some patients with arterial hypertension without signs of renal vascular disease, an increase in serum urea and creatinine concentrations may occur, especially with the simultaneous use of perindopril and a diuretic, usually minor and transient. The likelihood of developing these disorders is higher in patients with pre-existing renal impairment.

Kidney transplantation

Since there are no data on the use of Amlodipine-Perindopril-Richter in patients after kidney transplantation, it is not recommended to prescribe Amlodipine-Perindopril-Richter to these patients.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, the risk of arterial hypotension and renal failure increases during therapy with ACE inhibitors (see section “Contraindications”). The use of diuretics may be an additional risk factor. Deterioration of renal function may be observed even with a slight change in serum creatinine concentration, even in patients with unilateral renal artery stenosis.

Hepatic impairment

In rare cases, the use of ACE inhibitors has been associated with a syndrome starting with the development of cholestatic jaundice, progressing to fulminant hepatic necrosis, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in liver enzyme activity occurs in patients receiving ACE inhibitors, Amlodipine-Perindopril-Richter should be discontinued, and the patient should be under appropriate medical supervision.

Elderly patients (over 65 years)

In elderly patients, therapy should be initiated and the dose increased with caution. Renal function should be assessed before increasing the dose. Therefore, in this group of patients, serum creatinine and plasma potassium levels should be monitored regularly.

Arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic arterial hypotension rarely develops in patients without concomitant diseases. The risk of excessive blood pressure reduction is increased in patients with reduced blood volume, which may occur during diuretic therapy, while following a strict salt-free diet, during hemodialysis, diarrhea and vomiting, as well as in patients with severe arterial hypertension with high renin activity (see section “Drug Interactions”). In patients with an increased risk of developing symptomatic arterial hypotension, blood pressure, renal function and serum potassium levels should be carefully monitored during therapy with Amlodipine-Perindopril-Richter.

A similar approach applies to patients with coronary artery disease and cerebrovascular diseases, in whom pronounced arterial hypotension can lead to the development of myocardial infarction or cerebrovascular complications.

In case of arterial hypotension, the patient should be placed in a supine position with legs elevated. If necessary, blood volume should be replenished by intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further use of the drug. After restoration of blood volume and blood pressure, treatment can be continued.

Mitral stenosis/aortic stenosis/hypertrophic obstructive cardiomyopathy

ACE inhibitors should be prescribed with caution to patients with mitral stenosis, as well as to patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy).

Ethnic differences

The higher risk of developing angioedema in Black patients should be taken into account. Like other ACE inhibitors, Perindopril may be less effective in reducing blood pressure in Black patients. This fact is likely due to the higher prevalence of low-renin status in the Black patient population with arterial hypertension.

Cough

A dry cough may occur during therapy with Amlodipine-Perindopril-Richter. The cough is non-productive, persists for a long time during the use of ACE inhibitors and disappears after their discontinuation. This should be taken into account when conducting a differential diagnosis of cough.

Surgery/general anesthesia

The use of ACE inhibitors in patients undergoing major surgery and/or general anesthesia may lead to a pronounced decrease in blood pressure if general anesthetics with antihypertensive effects are used. This is due to the blocking of angiotensin II formation by perindopril against the background of a compensatory increase in renin activity. Therapy with Amlodipine-Perindopril-Richter should be discontinued one day before surgery. If the development of arterial hypotension is associated with the described mechanism, blood pressure should be maintained by increasing the blood volume.

Hyperkalemia

During treatment with ACE inhibitors, including perindopril, hyperkalemia may develop. Risk factors for hyperkalemia are: renal failure, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride, or their combination), potassium supplements/potassium preparations or potassium-containing salt substitutes, as well as the use of other drugs that contribute to an increase in plasma potassium levels (e.g., heparin, ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid (3 g/day and more), COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim). The use of potassium supplements/potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in blood potassium levels, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If concomitant use of Amlodipine-Perindopril-Richter and the above drugs is necessary, treatment should be carried out with caution with regular monitoring of serum potassium levels (see section “Drug Interactions”).

Patients with diabetes mellitus

When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be carefully monitored during the first month of therapy (see section “Drug Interactions”).

Effect on ability to drive vehicles and operate machinery

No studies have been conducted on the effect of Amlodipine-Perindopril-Richter on the ability to drive vehicles and operate machinery.

Amlodipine and Perindopril may have a slight or moderate effect on the ability to drive vehicles and operate machinery. In cases where a patient experiences dizziness, headache, increased fatigue, weakness or nausea, the ability to drive a car or operate other machinery may be reduced. Caution should be exercised when taking Amlodipine-Perindopril-Richter, especially at the beginning of treatment.

Overdose

Information on overdose of Amlodipine-Perindopril-Richter is not available.

Amlodipine

Information on amlodipine overdose is limited.

Symptoms severe overdose may lead to excessive peripheral vasodilation with possible development of reflex tachycardia. Severe and possibly prolonged systemic arterial hypotension, including with the development of shock and fatal outcome, has been reported.

Treatment clinically significant arterial hypotension caused by amlodipine overdose requires maintenance of cardiovascular and respiratory function, elevation of the limbs, monitoring of blood volume and diuresis. Vasoconstrictors can be used to normalize vascular tone and blood pressure, provided there are no contraindications to their use. To eliminate the consequences of calcium channel blockade, intravenous administration of calcium gluconate is possible. In some cases, gastric lavage may be effective. The use of activated charcoal within 2 hours of taking 10 mg of amlodipine reduces the rate of absorption of amlodipine. Since Amlodipine is bound to proteins, hemodialysis is not effective.

Perindopril

Data on perindopril overdose are limited.

Symptoms significant decrease in blood pressure, shock, water-electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

Treatment intravenous infusion of 0.9% sodium chloride solution. The patient should be placed in a supine position with legs elevated. Intravenous administration of catecholamines is also possible. Perindopril can be removed from the systemic circulation by hemodialysis. For bradycardia resistant to therapy, placement of a pacemaker may be required. Dynamic monitoring of vital functions, plasma creatinine and electrolyte concentrations is necessary.

Drug Interactions

Amlodipine

Contraindicated drug combinations

Dantrolene (intravenous administration)

In laboratory animals, cases of fatal ventricular fibrillation and collapse have been observed with the use of verapamil and intravenous dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, concomitant use of Amlodipine-Perindopril-Richter, which contains Amlodipine, a calcium channel blocker, should be avoided in patients susceptible to malignant hyperthermia, as well as during the treatment of malignant hyperthermia.

Not recommended drug combinations

Grapefruit

Concomitant use of Amlodipine-Perindopril-Richter and consumption of grapefruit or grapefruit juice is not recommended due to a possible increase in the bioavailability of amlodipine in some patients, which, in turn, may lead to an enhancement of the blood pressure-lowering effects.

Drug combinations requiring special caution during use

Inducers of the cytochrome CYP3A4 isoenzyme

Data concerning the effect of the CYP3A4 isoenzyme on Amlodipine are absent.

Concomitant administration of inducers of the CYP3A4 isoenzyme (for example, rifampicin, preparations of St. John’s wort) may lead to a decrease in the plasma concentration of amlodipine.

Caution should be exercised when using the drug Amlodipine-Perindopril-Richter and inducers of the CYP3A4 isoenzyme concomitantly.

Inhibitors of the cytochrome CYP3A4 isoenzyme

Concomitant administration of amlodipine and potent or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in the concentration of amlodipine.

Clinical manifestations of these pharmacokinetic deviations may be more pronounced in elderly patients.

In this regard, monitoring of the clinical condition and adjustment of the dose of the drug Amlodipine-Perindopril-Richter may be required.

Drug combinations requiring caution during use

Tacrolimus

When used concomitantly with amlodipine, there is a risk of increased plasma concentration of tacrolimus.

To avoid tacrolimus toxicity when used concomitantly with amlodipine, the plasma concentration of tacrolimus should be monitored in patients and the dose of tacrolimus should be adjusted if necessary.

Cyclosporine

Interaction studies of cyclosporine and amlodipine in healthy volunteers and in special patient groups have not been conducted, except for patients after kidney transplantation.

Various studies of the interaction of amlodipine with cyclosporine in patients after kidney transplantation show that the use of this combination may either have no effect or increase the minimum concentration of cyclosporine to varying degrees up to 40%.

Control of cyclosporine concentration should be carried out in patients after kidney transplantation.

Simvastatin

When multiple doses of amlodipine 10 mg and simvastatin 80 mg were co-administered, a 77% increase in the systemic exposure of simvastatin was observed compared to simvastatin monotherapy.

In patients taking Amlodipine-Perindopril-Richter at a dosage of 10 mg + 4 mg and 10 mg + 8 mg, simvastatin intake should be limited to 20 mg/day.

mTOR inhibitors (mammalian Target of Rapamycin) (for example, sirolimus, everolimus, temsirolimus)

MTOR inhibitors, such as sirolimus, temsirolimus and everolimus, are substrates of the CYP3A isoenzyme.

Amlodipine is a weak inhibitor of the CYP3A isoenzyme.

When used concomitantly with mTOR inhibitors, Amlodipine may increase their exposure.

In patients simultaneously receiving therapy with mTOR inhibitors, the risk of developing angioedema may increase (see the “Special Instructions” section).

Antihypertensive agents (for example, beta-blockers) and vasodilators

Enhancement of the antihypertensive effect of the drug is possible.

Caution should be exercised when using concomitantly with nitroglycerin, other nitrates or other vasodilators, as this may lead to an additional decrease in blood pressure.

Sympathomimetics

Sympathomimetics may weaken the antihypertensive effect of the drug Amlodipine-Perindopril-Richter.

Amifostine

Enhancement of the antihypertensive effect of amlodipine is possible.

Atorvastatin

Concomitant multiple administration of amlodipine 10 mg and atorvastatin 80 mg led to a non-significant change in the pharmacokinetic parameters of atorvastatin at steady state.

Digoxin, warfarin

When amlodipine and digoxin are used concomitantly, the renal clearance and serum concentration of digoxin do not change.

When warfarin is used concomitantly with amlodipine, prothrombin time does not change.

Amlodipine does not affect the degree of binding of digoxin, phenytoin, warfarin and indomethacin to plasma proteins in vitro.

Cimetidine

When used concomitantly with cimetidine, the pharmacokinetics of amlodipine do not change.

Aluminum and magnesium-containing antacids

A single dose of such antacids together with amlodipine does not have a significant effect on the pharmacokinetics of amlodipine.

Other combinations of amlodipine

Calcium preparations may reduce the effect of CCBs.

Lithium preparations. When CCBs are used concomitantly with lithium preparations (data for amlodipine are absent), an increase in the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, or tinnitus) is possible.

Perindopril

Clinical trial data show that dual blockade of the RAAS as a result of simultaneous administration of ACE inhibitors, ARBs or aliskiren leads to an increased incidence of adverse reactions such as arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure), compared with situations where only one drug affecting the RAAS is used.

Drugs causing hyperkalemia

Some drugs may increase the risk of hyperkalemia: aliskiren and aliskiren-containing drugs, potassium salts, potassium-containing salt substitutes and dietary supplements, potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, drugs containing trimethoprim, including the fixed combination of trimethoprim and sulfamethoxazole (co-trimoxazole).

Concomitant use of the drug Amlodipine-Perindopril-Richter with these agents increases the risk of hyperkalemia.

Concomitant use is contraindicated

Aliskiren and drugs containing aliskiren

Contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and not recommended in other patients: the risk of hyperkalemia, deterioration of renal function and increased frequency of cardiovascular morbidity and mortality is increased.

The use of ACE inhibitors in combination with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see the “Contraindications” section).

Extracorporeal therapy

Extracorporeal treatments leading to contact of blood with negatively charged surfaces, such as hemodialysis using high-flux membranes (for example, polyacrylonitrile) and LDL apheresis using dextran sulfate, may lead to an increased risk of severe anaphylactoid reactions (see the “Contraindications” section).

Therefore, it is advisable to use a different type of membrane or use an antihypertensive agent of a different pharmacotherapeutic group.

Neutral endopeptidase inhibitors

An increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor used to treat acute diarrhea).

When ACE inhibitors are used concomitantly with drugs containing sacubitril (a neprilysin inhibitor), the risk of developing angioedema increases, which is why the concomitant use of these drugs is contraindicated.

ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril.

The administration of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Concomitant use is not recommended

Aliskiren and drugs containing aliskiren

In patients without diabetes mellitus or renal impairment, there may be an increased risk of hyperkalemia, deterioration of renal function and increased frequency of cardiovascular morbidity and mortality.

Dual blockade of the RAAS

The literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, simultaneous therapy with an ACE inhibitor and an ARB is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia and deterioration of renal function (including acute renal failure) compared with the use of only one drug affecting the RAAS.

Dual blockade (for example, when combining an ACE inhibitor with an ARB) should be limited to individual cases with careful monitoring of renal function, serum potassium levels and blood pressure.

Estramustine

Concomitant use of estramustine with ACE inhibitors is accompanied by an increased risk of angioedema.

Potassium-sparing diuretics (triamterene, amiloride), potassium preparations

Hyperkalemia (with possible fatal outcome) may develop, especially in case of impaired renal function (additional effects associated with hyperkalemia).

ACE inhibitors should not be used simultaneously with substances that increase plasma potassium levels, except in cases of hypokalemia.

The combination of the drug Amlodipine-Perindopril-Richter and the above-mentioned drugs is not recommended (see the “Special Instructions” section).

If, nevertheless, concomitant use is indicated, they should be used with precautions and regular monitoring of serum potassium levels.

The features of the use of spironolactone in heart failure are described further in the text.

Lithium preparations

When lithium preparations and ACE inhibitors are used concomitantly, a reversible increase in serum lithium concentration and associated toxic effects may be noted.

Concomitant use of the drug Amlodipine-Perindopril-Richter and lithium preparations is not recommended.

If such therapy is necessary, regular monitoring of serum lithium concentration should be carried out (see the “Special Instructions” section).

Concomitant use requiring special attention

Hypoglycemic agents (insulin, oral hypoglycemic agents)

The use of ACE inhibitors may enhance the hypoglycemic effect of insulin and oral hypoglycemic agents up to the development of hypoglycemia.

As a rule, this is observed in the first weeks of concomitant therapy and in patients with impaired renal function.

Baclofen

Enhances the antihypertensive effect of ACE inhibitors.

Blood pressure levels should be carefully monitored and, if necessary, the dosage of antihypertensive drugs should be adjusted.

Non-potassium-sparing diuretics

In patients receiving diuretics, especially those excreting fluid and/or salts, a significant decrease in blood pressure may be observed at the beginning of therapy with an ACE inhibitor, the risk of which can be reduced by discontinuing the diuretic, replenishing fluid or salt loss before starting therapy with the drug Amlodipine-Perindopril-Richter.

In arterial hypertension in patients with previous diuretic therapy, which could lead to excessive excretion of fluid and/or salts, diuretics should be discontinued before starting the use of the drug Amlodipine-Perindopril-Richter (in this case, a non-potassium-sparing diuretic can be prescribed again later).

Renal function (creatinine concentration) should be monitored during the first weeks of using the drug Amlodipine-Perindopril-Richter.

Potassium-sparing diuretics (eplerenone, spironolactone)

Use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day and low doses of ACE inhibitors

• In the therapy of heart failure of functional class II-IV according to the NYHA classification with left ventricular ejection fraction less than 40% and previously used ACE inhibitors and “loop” diuretics, there is a risk of hyperkalemia (with possible fatal outcome), especially if the recommendations regarding this drug combination are not followed.

Before using this combination of drugs, it is necessary to ensure the absence of hyperkalemia and renal failure.

It is recommended to regularly monitor serum creatinine and potassium levels: weekly during the first month of therapy and monthly thereafter.

NSAIDs, including high doses of acetylsalicylic acid (>3 g/day)

Concomitant use of ACE inhibitors with NSAIDs (acetylsalicylic acid in a dose that has an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors.

Concomitant use of the drug Amlodipine-Perindopril-Richter and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure and an increase in serum potassium levels, especially in patients with reduced renal function.

Caution should be exercised when prescribing this combination, especially in elderly patients.

Patients need to compensate for fluid loss and carefully monitor renal function, both at the beginning and during treatment.

Tissue plasminogen activators

Concomitant use with ACE inhibitors may increase the risk of angioedema (observational studies have revealed an increased incidence of angioedema in patients taking ACE inhibitors after using alteplase for thrombolytic therapy of ischemic stroke).

Concomitant use requiring attention

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

Concomitant use with ACE inhibitors may increase the risk of angioedema due to suppression of dipeptidyl peptidase IV (DPP-IV) activity by the gliptin.

Tricyclic antidepressants/antipsychotic agents (neuroleptics)/agents for general anesthesia

Concomitant use with ACE inhibitors may lead to an enhancement of the antihypertensive effect.

Corticosteroids (mineralo- and glucocorticoids), tetracosactide

Reduction of the antihypertensive effect (fluid and sodium ion retention as a result of the action of corticosteroids).

Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin)

Enhancement of the antihypertensive effect and increased risk of orthostatic hypotension.

Gold preparations

Rare cases of nitritoid reactions (a symptom complex including facial skin flushing, nausea, vomiting, arterial hypotension) have been described in patients receiving an intravenous gold preparation (sodium aurothiomalate) while taking ACE inhibitors, including perindopril.

Storage Conditions

The drug should be stored out of the reach of children, at a temperature not exceeding 30°C (86°F) in the original packaging to protect from light.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.