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Mechanism of action. Indapamide is a derivative of sulfonamides with an indole ring, pharmacologically related to thiazide diuretics, acts by inhibiting sodium reabsorption in the cortical segment of the kidneys. This increases the excretion of sodium and chloride with urine and, to a lesser extent, potassium and magnesium, thus increasing urination and providing an antihypertensive effect.
Amlodipine is an inhibitor of the intake of calcium ions of the dihydropyridine group (a blocker of slow calcium channels or an antagonist of calcium ions), which prevents the transmembrane entry of calcium ions into the smooth muscles of the myocardium and blood vessels.
The mechanism of the antihypertensive effect of amlodipine is its ability to relax the smooth muscles of blood vessels.
Pharmacodynamic effects. Clinical studies of phases II and III have demonstrated that when using indapamide in monotherapy, the antihypertensive effect lasts 24 hours. This effect is manifested in doses in which diuretic properties are minimal. The antihypertensive effect of indapamide is associated with improved arterial elasticity, decreased arteriole resistance and OPSS. Indapamide reduces left ventricular hypertrophy.
When a certain dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the number of side effects increases. If there is no effect of treatment, the dose should not be increased.
Also, in the course of short, medium and long-term studies involving patients with hypertension, it was demonstrated that indapamide:
- does not affect lipid metabolism (TG, LDL and HDL);
- does not affect the metabolism of carbohydrates, even in patients with diabetes with hypertension.
In patients with hypertension, taking amlodipine once a day provides a clinically significant decrease in blood pressure over 24 hours in the supine and standing position. Due to the slow onset of amlodipine, its use does not lead to acute hypotension. Amlodipine was not associated with the occurrence of any metabolic adverse reactions or changes in the level of lipids in the blood plasma, so it can be used in patients with AD, gout and diabetes mellitus.
Pharmacokinetics The simultaneous administration of indapamide and amlodipine does not change their pharmacokinetic properties compared with their separate use.
Indapamide. The uniform prolonged release of indapamide is ensured by the matrix system in which the active substance is distributed.
Absorption. Indapamide, which is released from the tablet, is rapidly and completely absorbed in the digestive tract. Eating slightly increases the rate of absorption, but does not affect the amount of absorbed active substance.
Cmax in blood plasma is reached approximately 12 hours after oral administration of a single dose, repeated use reduces fluctuations in the level of indapamide in blood plasma between two doses of the drug. There is intraindividual variability.
Distribution. The binding of indapamide to plasma proteins is 79%. T½ is 14-24 hours (on average - 18 hours). A stable concentration level is reached after 7 days. Repeated administration does not lead to cumulation.
It is excreted mainly with urine (70% of the dose) and feces (22%) in the form of inactive metabolites.
High risk patients. In patients with renal failure, the pharmacokinetic parameters do not change.
Amlodipine. Amlodipine is released immediately.
Absorption, distribution, binding to plasma proteins. After oral administration in therapeutic doses, amlodipine is well absorbed, Cmax in the blood is reached 6-12 hours after administration. Absolute bioavailability is 64–80%. The volume of distribution is about 21 l / kg. In vitro studies have shown that about 97.5% of circulating amlodipine binds to plasma proteins.Eating does not affect the bioavailability of amlodipine.
Biotransformation / excretion. T½ Amlodipine from blood plasma is about 35-50 hours, which corresponds to a single dose. Amlodipine is extensively metabolized by the liver to inactive metabolites. 60% of the administered dose is excreted in the urine, 10% of which is unchanged amlodipine.
Use in patients with impaired liver function. The amount of clinical data regarding the use of amlodipine in patients with impaired liver function is limited. In patients with hepatic insufficiency, amlodipine clearance decreases, which leads to an increase in T½ and AUC by about 40-60%.
Use in elderly patients. Time to reach Cmax amlodipine in blood plasma in the elderly and in young patients is the same. In elderly patients, there is a tendency to a decrease in clearance of amlodipine, which leads to an increase in AUC and T½. In people with congestive heart failure, an increase in AUC and T½ was expected for the studied age group of patients.
Treatment of ag in patients requiring indapamide and amlodipine treatment in doses available in fixed combinations.
For oral use.
1 tablet per day once, preferably in the morning before meals. The tablet is swallowed whole, without chewing, washed down with water. The maximum daily dose is 1 tablet (1.5 mg / 10 mg).
The use of a fixed combination is not intended to initiate therapy.
If necessary, dose changes should be individually titrated for each of the components of the combination.
Special patient groups
Patients with impaired renal function (see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS). In case of severe renal impairment (creatinine clearance 30 ml / min), drug treatment is contraindicated. For patients with impaired renal function of mild to moderate severity, the recommended dose adjustment is not required.
Elderly patients (see SPECIAL INSTRUCTIONS and PHARMACOLOGICAL PROPERTIES). Elderly patients Arifam should be used taking into account renal function.
Patients with impaired liver function (see CONTRAINDICATIONS and SPECIAL INDICATIONS). In severe violations of liver function, drug treatment is contraindicated.
For patients with impaired liver function of mild to moderate severity, recommendations regarding the dosage of amlodipine have not been established, therefore, the dose should be selected with caution and treatment should begin with the lowest dose (see SPECIAL INSTRUCTIONS and PHARMACOLOGICAL PROPERTIES).
Hypersensitivity to active substances, other sulfonamides, dihydropyridine derivatives or any auxiliary substances;
- severe renal failure (creatinine clearance 30 ml / min);
- hepatic encephalopathy or severe hepatic impairment;
- severe arterial hypotension;
- shock (including cardiogenic);
- obstruction of the exit from the left ventricle (for example, severe aortic stenosis);
- heart failure with unstable hemodynamics after acute myocardial infarction.
In most cases, when using indapamide and amlodipine separately, adverse reactions such as hypokalemia, drowsiness, dizziness, headache, visual impairment, diplopia, palpitations, flushing, shortness of breath, abdominal pain, nausea, dyspepsia, defecation rhythm change, diarrhea were reported. , constipation, maculopapular rash, ankle edema, muscle cramps, edema, fatigue and asthenia.
During treatment with indapamide and amlodipine, adverse reactions with the following frequency of occurrence were reported: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, ≤1 / 100); rarely (≥1 / 10,000, ≤1 / 1000); very rarely (≤1 / 10,000); the frequency is unknown (impossible to estimate from the available data).
Infections and infestations: rhinitis (infrequently - amlodipine).
On the part of the blood system and lymphatic system: leukopenia (very rarely - indapamide and amlodipine); thrombocytopenia (very rarely - indapamide and amlodipine); agranulocytosis (very rarely - indapamide); aplastic anemia (very rarely - indapamide); hemolytic anemia (very rarely - indapamide).
From the side of the immune system: hypersensitivity (very rarely - amlodipine).
From the side of metabolism and metabolism: hypokalemia (often; during clinical trials, hypokalemia (potassium level in the blood plasma of 3.4 mmol / L) was observed in 10% of patients, in 4% of patients the level of potassium in the blood plasma was 3.2 mmol / l after 4–6 weeks of treatment, after 12 weeks of therapy, the average decrease in the level of potassium in the blood plasma was 0.23 mmol / l (see SPECIAL INSTRUCTIONS - indapamide); hyperglycemia (very rarely - amlodipine); hypercalcemia (very rarely - indapamide); hyponatremia with hypovolemia * (frequency unknown - indapamide).
From the psyche: insomnia (infrequently - amlodipine); mood changes (including anxiety) (infrequently - amlodipine); depression (infrequently - amlodipine); confusion (rarely - amlodipine).
From the side of the nervous system: drowsiness (often (especially at the beginning of treatment) - amlodipine); dizziness (often (especially at the beginning of treatment) - amlodipine); headache (rarely - indapamide, often (especially at the beginning of treatment) - amlodipine); tremor (infrequently - amlodipine); dysgeusia (infrequently - amlodipine); fainting (frequency unknown - indapamide, infrequently - amlodipine); hypesthesia (infrequently - amlodipine); paresthesia (rarely - indapamide, infrequently - amlodipine); hypertonicity (very rarely - amlodipine); peripheral neuropathy (very rarely - amlodipine); extrapyramidal disorders (extrapyramidal syndrome) (frequency unknown - amlodipine); in case of liver failure, hepatic encephalopathy may occur (frequency unknown - indapamide) (see CONTRAINDICATIONS and SPECIAL INDICATIONS).
From the side of the organ of vision: visual impairment (frequency unknown - indapamide, often - amlodipine); diplopia (often - amlodipine); myopia (frequency unknown - indapamide); blurred vision (frequency unknown - indapamide).
On the part of the organ of hearing and the vestibular apparatus: ringing in the ears (infrequently - amlodipine); vertigo (rarely indapamide).
On the part of the heart: palpitations (often - amlodipine); myocardial infarction (very rarely - amlodipine); arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) (very rarely - indapamide, infrequently - amlodipine); paroxysmal ventricular tachycardia of the “pirouette” type (potentially lethal) (frequency unknown - indapamide) (see SPECIAL INSTRUCTIONS and INTERACTIONS).
From the side of blood vessels: flushing (often - amlodipine); arterial hypotension (very rarely - indapamide, infrequently - amlodipine); vasculitis (very rarely - amlodipine).
From the respiratory system, chest and mediastinal organs: shortness of breath (often - amlodipine); cough (infrequently - amlodipine).
From the gastrointestinal tract: pain in the abdominal region (often - amlodipine); nausea (rarely indapamide, often amlodipine); vomiting (infrequently - indapamide, infrequently - amlodipine); dyspepsia (often - amlodipine); change in the rhythm of bowel movements (often - amlodipine); dry mouth (rarely - indapamide, infrequently - amlodipine); pancreatitis (very rarely - indapamide and amlodipine); gastritis (very rarely - amlodipine); gingival hyperplasia (very rarely - amlodipine); diarrhea (often amlodipine); constipation (rarely - indapamide, often - amlodipine).
From the hepatobiliary system: hepatitis (frequency unknown - indapamide, very rarely - amlodipine); jaundice (very rarely - amlodipine); impaired liver function (very rarely - indapamide).
On the part of the skin and subcutaneous tissue: maculopapular rash (often indapamide); purpura (infrequently - indapamide,infrequently - amlodipine); alopecia (infrequently - amlodipine); discoloration of the skin (infrequently - amlodipine); hyperhidrosis (infrequently - amlodipine); itching (infrequently - amlodipine); rash (infrequently - amlodipine); exanthema (infrequently - amlodipine); angioedema (very rarely - indapamide, very rarely - amlodipine); urticaria (very rarely - indapamide, infrequently - amlodipine); toxic epidermal necrolysis (very rarely - indapamide); Stevens-Johnson syndrome (very rarely - indapamide, very rarely - amlodipine); erythema multiforme (very rarely - amlodipine); exfoliative dermatitis (very rarely - amlodipine); Quinckes edema (very rarely - amlodipine); photosensitivity reactions (reported cases of photosensitivity reactions - indapamide, very rarely - amlodipine) (see SPECIAL INSTRUCTIONS).
From the musculoskeletal system and connective tissue: ankle edema (often - amlodipine); arthralgia (infrequently - amlodipine); myalgia (infrequently - amlodipine); muscle cramps (often - amlodipine); back pain (infrequently - amlodipine); possible exacerbation of existing systemic lupus erythematosus (frequency unknown - indapamide).
From the urinary system: violation of urination (infrequently - amlodipine); nocturia (infrequently - amlodipine); pollakiuria (infrequently - amlodipine); renal failure (very rarely - indapamide).
From the reproductive system and mammary glands: erectile dysfunction (infrequently - amlodipine); gynecomastia (infrequently - amlodipine).
General disorders and reactions at the injection site: edema (very often - amlodipine); fatigue (rarely - indapamide, often - amlodipine); chest pain (infrequently - amlodipine); asthenia (often - amlodipine); pain (infrequently - amlodipine); malaise (infrequently - amlodipine).
Laboratory results: weight gain (infrequently - amlodipine); weight loss (infrequently - amlodipine); prolongation of the Q – T interval on the ECG (see SPECIAL INSTRUCTIONS and INTERACTIONS) (frequency unknown - indapamide); increase in blood glucose (frequency unknown - indapamide) (the appropriateness of prescribing these diuretics should be carefully weighed before prescribing to patients with gout or diabetes mellitus); increased levels of uric acid in the blood (frequency unknown - indapamide) (the appropriateness of prescribing these diuretics should be carefully weighed before prescribing to patients with gout or diabetes); increased levels of liver enzymes (frequency unknown - indapamide, very rarely ** - amlodipine).
* May lead to dehydration and orthostatic hypotension; concomitant loss of chlorine ions can cause secondary compensatory metabolic alkalosis (the frequency and severity of this phenomenon is low).
** Mainly due to cholestasis.
Reporting suspected adverse reactions in the post-registration period of the drug is very important. It allows continuous monitoring of the balance of the benefit / risk indicator of the drug. Health professionals are required to report any suspected adverse reactions through the national reporting system.
Hepatic encephalopathy. in patients with impaired liver function, the use of thiazide-like diuretics can cause hepatic encephalopathy, especially in the case of an imbalance of electrolytes. in this case, the use of arifam should be stopped immediately due to the presence of indapamide in its composition.
Photosensitivity. When using thiazide and thiazide-like diuretics, cases of photosensitivity reactions have been reported (see ADVERSE EFFECTS). If a photosensitivity reaction occurs during treatment, it is recommended to stop taking the drug. If there is a need to restore its use, it is recommended to protect vulnerable areas from the sun or sources of artificial ultraviolet radiation.
Precautions for use
Hypertensive crisis. Targeted studies on the safety and effectiveness of amlodipine in a state of hypertensive crisis have not been conducted.
The balance of water and electrolytes
- Plasma sodium level. Before starting treatment and then at regular intervals, you should determine the level of sodium in blood plasma. A decrease in plasma sodium levels may initially be asymptomatic, and monitoring is therefore necessary. In elderly patients and patients with cirrhosis, monitoring should be carried out more often (see ADVERSE EFFECTS and OVERDOSAGE). Any treatment with diuretics can lead to hyponatremia, sometimes with very serious consequences. Hyponatremia combined with hypovolemia can lead to dehydration and orthostatic hypotension. Concomitant loss of chlorine ions can lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect is negligible.
- Plasma potassium level. A decrease in the level of potassium in the blood plasma with the occurrence of hypokalemia is the main risk when using thiazide and thiazide-like diuretics. Hypokalemia (3.4 mmol / L) should be prevented in high-risk patients, such as elderly patients, patients who are undernourished and / or taking many drugs, patients with cirrhosis, which is accompanied by edema and ascites, patients with coronary artery disease and heart failure. In such cases, hypokalemia increases cardiotoxicity of cardiac glycosides and the risk of arrhythmias.
Patients with an extended Q – T interval of congenital or iatrogenic origin are also at risk. In such patients, hypokalemia and bradycardia can contribute to the development of severe arrhythmias, including paroxysmal ventricular tachycardia of the “pirouette” type, which can be fatal.
In all the above cases, more frequent monitoring of the level of potassium in the blood plasma is necessary. The first determination of the level of potassium in the blood plasma should be performed within the 1st week of treatment. If hypokalemia is detected, the level of potassium in the blood plasma should be adjusted.
- Plasma calcium level. Thiazide and thiazide-like diuretics can reduce urinary calcium excretion and lead to a slight and temporary increase in plasma calcium levels. The occurrence of hypercalcemia may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function examined.
Blood glucose Due to the presence of indapamide in the composition of the drug, control of blood glucose is important for patients with diabetes mellitus, especially in the presence of hypokalemia.
Heart failure. Patients with heart failure Arifam should be prescribed with caution. In a long-term, placebo-controlled study in patients with severe heart failure (NYHA grade III and IV), the incidence of pulmonary edema was higher with amlodipine than with placebo. Patients with congestive heart failure should be prescribed calcium antagonists, including amlodipine, with caution, since they increase the risk of cardiovascular events and death.
Kidney function. Thiazide and thiazide-like diuretics are most effective when kidney function is not impaired or insignificant (plasma creatinine level 25 mg / l, i.e. 220 μmol / l in adults). In elderly patients, plasma creatinine levels are adjusted based on age, body weight and gender.
Hypovolemia caused by the loss of water and sodium due to diuretics at the beginning of treatment is associated with a decrease in glomerular filtration. This can lead to increased levels of urea and creatinine in blood plasma.This transient functional renal failure has no consequences in patients with normal renal function, but may exacerbate existing renal failure.
In patients with renal failure, amlodipine can be used in usual doses. Fluctuations in the concentration of amlodipine in blood plasma do not depend on the severity of renal failure. Amlodipine is not dialyzed.
Studies on the effectiveness of the combination drug Arifam with the participation of patients with renal dysfunction have not been conducted. For persons with impaired renal function, the dose of the drug should be selected in accordance with the dosage of each component when used in monotherapy.
The level of uric acid in the blood. Due to the presence of indapamide in the composition of the drug in patients with elevated uric acid levels in the blood, an increase in the number of gout attacks is possible.
Liver function. In patients with impaired liver function, an extension of T is noted½ amlodipine and AUC; There are no recommendations regarding the dosage regimen. Therefore, treatment with amlodipine must begin with the lowest dose. The drug should be used with caution at the beginning of treatment and with increasing doses.
Targeted studies to study the effectiveness of the combined drug Arifam with the participation of patients with liver dysfunction have not been conducted. Due to the properties of indapamide and amlodipine, Arifam is contraindicated in patients with severe hepatic impairment. In patients with impaired liver function of mild to moderate degree, the drug should be used with caution.
Elderly patients. In elderly patients, Arifam should be used taking into account renal function (see APPLICATION and Pharmacokinetics).
Excipients. Ariths should not be prescribed to patients with rare hereditary galactose intolerance, Lapp lactase deficiency or malabsorption of glucose and galactose.
The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Arifam has a slight or moderate effect on the ability to drive vehicles and work with mechanisms:
- indapamide does not affect attentiveness, but in some cases, various reactions may occur associated with a decrease in blood pressure, especially at the beginning of treatment or when used simultaneously with other antihypertensive drugs. As a result, the ability to drive vehicles or work with other automated systems may be impaired;
- Amlodipine may have a slight or moderate effect on the ability to drive vehicles and operate machinery. If patients taking amlodipine experience adverse reactions such as dizziness, headache, fatigue, or nausea, their reaction may be reduced. Caution is recommended, especially at the beginning of treatment.
Use during pregnancy or lactation. Given the effect of the components of the combined drug Arifam on pregnancy and lactation:
- the use of the drug during pregnancy is not recommended;
- the drug is contraindicated during lactation.
Indapamide Cautions. Data on the use of indapamide in pregnant women are absent or limited (less than 300 cases). A consequence of the long-term use of a thiazide diuretic in the III trimester of pregnancy may be a decrease in the BCC of a pregnant woman and uteroplacental blood supply, which can cause fetoplacental ischemia and fetal growth retardation. In addition, in rare cases, a newborn noted hypoglycemia and thrombocytopenia. Animal studies have not revealed a direct or indirect toxic effect on reproduction.
Cautions associated with amlodipine.Studies on the safety of the use of amlodipine in pregnant women have not been conducted. In animal studies with high doses, toxic effects on reproduction have been identified.
Indapamide Cautions. The amount of data on the penetration of indapamide / metabolites into breast milk is insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. The risk for newborns / infants cannot be excluded. Indapamide refers to thiazide-like diuretics, the use of which during breastfeeding is associated with a decrease or even inhibition of lactation.
Cautions associated with amlodipine. There is no data on the penetration of amlodipine into breast milk.
Indapamide Cautions. Reproductive toxicity studies have shown no effect on male and female rat fertility. Effects on human fertility are not expected.
Cautions associated with amlodipine. In some patients, when using calcium channel blockers, reversible biochemical changes in the sperm head were noted. There is insufficient clinical evidence regarding the potential effects of amlodipine on fertility. In one animal study, adverse reactions to male fertility were identified.
Children. The safety and effectiveness of Arifam for children have not been studied. No data available.
Interactions related to indapamide
Not recommended combinations
Lithium. It is possible to increase the concentration of lithium in blood plasma with the occurrence of symptoms of an overdose, similar to the symptoms of a salt-free diet (excretion of lithium in the urine decreases). However, if the use of diuretics is really necessary, you should carefully monitor the level of lithium in the blood plasma and adjust the dose of the diuretic.
Combinations requiring caution in use
Drugs that can cause the development of paroxysmal ventricular tachycardia of the "pirouette" type:
- class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide);
- class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide);
- some antipsychotic drugs:
- phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazin);
- benzamides (amisulpride, sulpiride, sultopride, tiapride);
- butyrophenones (droperidol, haloperidol);
- other medicines: bepridil, cisapride, diphemanil, iv erythromycin, halofantrine, misolastine, pentamidine, sparfloxacin, moxifloxacin, ivinkin.
The risk of ventricular arrhythmias, in particular paroxysmal ventricular tachycardia of the “pirouette” type increases (hypokalemia is a risk factor).
Before the appointment of such a combination, the presence of hypokalemia is checked and, if necessary, the potassium level is adjusted. It is necessary to monitor the clinical condition of the patient, the level of electrolytes in blood plasma and conduct ECG monitoring.
In the presence of hypokalemia, drugs that do not cause paroxysmal ventricular tachycardia of the pirouette type should be used.
NSAIDs (systemic use), including selective COX-2 inhibitors and acetylsalicylic acid in high doses (≥3 g / day). With simultaneous use, it is possible to weaken the antihypertensive effect of indapamide. Dehydrated patients have an increased risk of acute renal failure (decreased glomerular filtration). Before starting treatment, water balance should be restored and kidney function checked.
ACE inhibitors. In the presence of sodium deficiency, treatment with ACE inhibitors can cause sudden arterial hypotension and / or acute renal failure (especially in patients with renal artery stenosis).
For patients with hypertension in whom prior diuretic therapy has led to sodium deficiency, it is necessary:
- 3 days before the start of treatment with ACE inhibitors, stop the use of diuretics and then, if necessary, resume their use;
- or start the use of an ACE inhibitor with a low initial dose with a gradual increase in it.
In patients with congestive heart failure, the use of an ACE inhibitor should be started with a minimum dose, possibly after reducing the dose of concomitant diuretic that removes potassium.
In all cases, it is necessary to monitor renal function (creatinine level in blood plasma) during the first weeks of treatment with ACE inhibitors.
Other compounds that can cause the occurrence of hypokalemia: iv amphotericin B, GCS and mineralocorticoid (systemic use), tetracosactide, laxatives that stimulate peristalsis. The risk of hypokalemia (additive effect) is increased. It is necessary to control the level of potassium in the blood plasma and adjust it if necessary. This is especially necessary to remember while treating with cardiac glycosides. It is recommended to use laxatives that do not stimulate peristalsis.
Digitalis preparations. A decrease in the level of potassium in the blood increases the severity of the toxic effects of digitalis preparations. It is necessary to control the level of potassium in the blood and ECG, and also, if necessary, revise therapy.
Baclofen. The antihypertensive effect increases. At the beginning of treatment, the patients water balance should be restored and kidney function monitored.
Allopurinol Concomitant use with indapamide can lead to an increase in the frequency of hypersensitivity reactions to allopurinol.
Combinations requiring attention
Potassium-sparing diuretics (amiloride, spironolactone, triamteren). Despite the rationality of prescribing this combination to some patients, hypokalemia or hyperkalemia may occur (especially in patients with renal failure or patients with diabetes mellitus). It is necessary to control the level of potassium in the blood plasma, conduct ECG monitoring and, if necessary, review the therapy.
Metformin. The risk of lactic acidosis caused by metformin is increased, due to the possible development of functional renal failure associated with the use of diuretics, especially loopback. Metformin should not be prescribed if the creatinine level in blood plasma exceeds 15 mg / l (135 μmol / l) in men and 12 mg / l (110 μmol / l) in women.
Iodine-contrast agents. In the presence of dehydration caused by the use of diuretics, the risk of developing acute renal failure increases, especially when taking high doses of iodine contrast agents. The water balance should be restored before the use of iodine contrast agents.
Imipramin-like antidepressants, antipsychotics. The antihypertensive effect and the risk of developing orthostatic hypotension increase (additive effect).
Calcium (salt). Hypercalcemia may occur due to a decrease in elimination of calcium in the urine.
Cyclosporin, tacrolimus. It is possible to increase creatinine levels in blood plasma without changing the level of circulating cyclosporin, even in the absence of water and sodium deficiency.
GCS, tetracosactide (systemic action). The likely decrease in the antihypertensive effect (water and sodium ion retention under the influence of GCS).
Dantrolene (infusion). In animal studies after the use of verapamil and iv dantrolene, fatal ventricular fibrillation and cardiovascular collapse in combination with hyperkalemia were noted. If the patient is prone to malignant hyperthermia and its treatment, it is recommended to avoid the simultaneous use of calcium channel blockers, such as amlodipine, due to the risk of hyperkalemia.
It is not recommended to use amlodipine together with grapefruit or grapefruit juice, since in some patients the bioavailability may increase, which will lead to an increase in the hypotensive effect.
CYP 3A4 Inhibitors. The concomitant use of amlodipine with highly active or moderate CYP 3A4 inhibitors (protease inhibitors, azole antifungal agents, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine. These pharmacokinetic changes are clinically more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be necessary. There is an increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Careful observation is recommended to such patients.
Inductors CYP 3A4. There are no data on the effect of CYP 3A4 inducers on amlodipine. The simultaneous use of amlodipine and CYP 3A4 inducers (e.g. rifampicin, St. Johns wort) can lead to a decrease in the concentration of amlodipine in blood plasma. Amlodipine in combination with CYP 3A4 inducers should be used with caution.
The effect of amlodipine on other drugs