Arifam pills 10 + 1.5mg №30

Tradename

Arifam^®
  

Dosage Form

Film-pills with a modified release of 1.5 mg / 5 mg and 1.5 mg / 10 mg
 

Composition

One pill contains
active substance:
1.5 mg / 5 mg tablets: Indapamide 1.5 mg and Amlodipine besylate 6.935 mg, (equivalent to 5 mg of amlodipine)
1.5 mg / 10 mg tablets: indapamide 1.5 mg and amlodipine besylate 13.87 mg, (equivalent to 10 mg amlodipine)
Excipients:hypromellose 4000, lactose monohydrate, Magnesium stearate, povidone K 30, anhydrous colloidal silicon dioxide, Calcium hydrogen phosphate dihydrate, microcrystalline cellulose, sodium croscarmellose, corn starch, pregelatinized
shell: gilcerin, hypermellose, iron oxide red (E 172), macrogol 6000, magnesium stearate, titanium dioxide (E 171), purified water
 

Description

Round-coated two-layer tablets, film-coated, white, with an engraved symbol on one side of the pill (for a dosage of 1.5 mg / 5 mg);
Round-coated, double-layered, pink-pills with an engraved symbol on one side of the pill (for a dosage of 1.5 mg / 10 mg).
 

Pharmacotherapeutic group

Slow calcium channel blockers. Slow calcium channel blockers in combination with diuretics. Amlodipine and diuretics.

Pharmacological properties

Pharmacokinetics
Indapamide:
Indapamide 1.5 mg is represented by sustained release, the basis of which is a special carrier matrix, providing a gradual controlled release of indapamide.
Absorption:
The released indapamide is rapidly and completely absorbed in the gastrointestinal tract.
Food intake slightly increases the time of absorption of the drug, without affecting the full absorption of the active substance.
The maximum plasma concentration is reached 12 hours after ingestion of a single dose. With repeated administrations, fluctuations in the concentration of the drug in the blood plasma in the interval between intakes of the drug are smoothed out. There is an individual variability of drug absorption.
Distribution:
About 79% of the drug is bound to plasma proteins.
The half-life is 14-24 hours (average, 18 hours).
Equilibrium concentration is achieved after 7 days of taking the drug.
When re-taking the drug is not observed its accumulation.
Excretion:
Indapamide is excreted in the form of inactive metabolites, mainly by the kidneys (70% of the administered dose) and through the intestines (22%).
Amlodipine:
Amlodipine is represented by rapid release.
Absorption, distribution, binding to plasma proteins:
After oral administration of therapeutic doses, amlodipine is well absorbed, reaching a maximum concentration in the blood 6-12 hours after taking the drug. Absolute bioavailability is 64-80%.The volume of distribution is approximately 21 l / kg. In researchin vitro It was shown that about 97.5% of circulating amlodipine is bound to plasma proteins.
Eating does not affect the bioavailability of amlodipine.
Biotransformation / elimination
The final half-life of blood plasma is approximately 35-50 hours, which allows you to take the drug 1 time per day. Amlodipine is actively metabolized in the liver to form inactive metabolites: 10% unchanged, 60% of metabolites excreted in the urine.

Pharmacodynamics
Indapamide is a derivative of a sulfonamide with an indole ring and, by its pharmacological properties, is close to thiazide diuretics, which inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop. At the same time, kidneys excrete sodium, chlorine and, to a lesser extent, potassium and magnesium ions, which is accompanied by an increase in diuresis and a hypotensive effect.
Amlodipine is an inhibitor of calcium ion flux of the dihydropyridine group (a blocker of slow calcium channels or an antagonist of calcium ions); it inhibits the transmembrane flux of calcium ions in cardiomyocytes and smooth muscle cells of the vascular wall.
The mechanism of the hypotensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall.
The antihypertensive activity of indapamide is associated with an improvement in the elastic properties of large arteries, a decrease in arteriolar and general peripheral vascular resistance.
Indapamide reduces left ventricular hypertrophy.
Thiazide and thiazide-like diuretics at a certain dose reach a plateau of therapeutic effect, while the frequency of side effects continues to increase. Therefore, you should not increase the dose of the drug, if the therapeutic effect is not achieved.
In clinical studies of phases II and III, when indapamide was used in monotherapy in doses that did not have a pronounced diuretic effect, a 24-hour hypotensive effect was demonstrated.
In short, medium and long-term studies involving hypertensive patients, it has been shown that indapamide:
· Does not affect lipid metabolism: on the level of triglycerides, cholesterol, low-density lipoprotein and high-density lipoprotein;
· Does not affect the indicators of carbohydrate metabolism, including in patients with diabetes mellitus, suffering from hypertension.
In patients with hypertension, taking a single dose of amlodipine 1 time per day provides a clinically significant reduction in blood pressure, both in the supine and standing position for 24 hours. Due to the slow development of the antihypertensive effect, acute hypotension is not typical for the administration of amlodipine.
Amlodipine does not cause any unwanted metabolic reactions, does not affect the lipid profile, and can be used in patients with concomitant asthma, diabetes mellitus and gout.

Indications for use

- in the treatment of essential hypertension in patients taking indapamide and amlodipine in the same doses as in a fixed combination.
 

Dosage and administration

The drug is recommended to be taken in the morning before meals, 1 time per day. The pill should be swallowed whole, without chewing, with water.
Fixed-dose combination drug is not suitable for initial therapy. If a change in dosage is required, the titration should be carried out with individual components.
The duration of the course of treatment is determined by the attending physician.
 

Side effects

Very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000, <1/1000), very rarely (> 1/10000), the frequency is not set (based on the available data, it is not possible to estimate the frequency of development).
Often
- sleepiness
- dizziness, headache
- hyperemia
- abdominal pain, nausea
- maculopapular rash
- swelling of the ankle joint
- swelling
Infrequently
- insomnia
- mood swings (including anxiety)
- depression, tremor, dysgeusia, hypesthesia
- visual impairment (including diplopia)
- tinnitus, rhinitis
- cardiopalmus
- shortness of breath
- vomiting, dyspepsia, changing the rhythm of bowel movements (including diarrhea and constipation)
- arthralgia, myalgia, muscle cramps, back pain
- violation of urination, night increased frequency of urination
- polyuria
- impotence
- gynecomastia
- chest pain, asthenia, discomfort, weight gain, weight loss
Seldom
- confusion
- paresthesia
- vertigo
- dry mouth, constipation
- Purpura, alopecia, discoloration of skin, itching, rash, rash
- hyperhidrosis
- tiredness
Very rarely
- leukocytopenia, tombocytopenia, aplastic anemia, hemolytic anemia
- agranulocytosis
- allergic reactions
- hypokalemia, hyperglycemia, hypercalcemia
- hypertension, hypotension
- peripheral neuropathy
- myocardial infarction
- arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)
- vasculitis
- cough
- gastritis, pancreatitis, hepatitis, jaundice, increased levels of liver enzymes
- abnormal liver function
- gingival hyperplasia
- angioedema, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, angioedema
- photosensitivity
- renal failure
Frequency not set
- hyponatremia with hypovolaemia
- syncope
- myopia, blurred vision, reduced visual acuity
- tachycardia
- Hepatitis, increased levels of liver enzymes
- hepatic encephalopathy on the background of liver failure
- possible exacerbation of existing disseminated lupus erythematosus
- the extended QT interval on the electrocardiogram
- increase in the level of glucose and uric acid in the blood during therapy
 

Contraindications

- hypersensitivity to active substances, to other sulfonamides, to dihydropyridine derivatives or to any of the excipients
- severe renal failure (creatinine clearance below 30 ml / min)
- hepatic encephalopathy or severe hepatic failure
- hypokalemia
- pregnancy and lactation
- severe hypotension
- shock (including cardiogenic shock)
- obstruction of the output path of the left ventricle (aortic stenosis)
- heart failure after acute myocardial infarction
- galactose intolerance, Lappa lactase deficiency or glucose syndrome
galactose malabsorption
 

Drug interactions

Lithium
Increased plasma lithium levels with symptoms of overdose, as in the case of a salt-free diet (reduced lithium excretion in the urine). However, if the use of diuretics is necessary, the dose should be adjusted and the plasma lithium levels should be carefully monitored.
Drugs causing bidirectional tachycardia:
- class Ia antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide),
- Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide),
- Some antipsychotic drugs:
phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, Sulpiride, sultopride, tiaprid),
butyrophenones (droperidol, haloperidol),
others: bepridil, cisapride, difemanil, Erythromycin i.v., halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine i.v.
Increased risk of ventricular arrhythmias, in particularbidirectional tachycardia (hypokalemia is a risk factor).
Before starting treatment with this combination, one should be convinced of the absence of hypokalemia and make an adjustment, if necessary. Clinical monitoring, monitoring of electrolyte levels in plasma and ECG monitoring.
Patients suffering from hypokalemia, should be prescribed drugs that do not cause bidirectional tachycardia.
NSAIDs (systemic route of administration), including selective COX-2 inhibitors, high doses of Aspirin (³ 3 g / day):
Possible reduction in the hypotensive effect of indapamide.
The risk of acute renal failure in patients suffering from dehydration (reduced glomerular filtration). Hydrate the patient; monitor kidney function at the start of therapy.
Inhibitors of the angiotensin-converting enzyme (ACE):
In the case when therapy with ACE inhibitors begins against the background of the existing sodium depletion (especially in patients with renal artery stenosis), there is a risk of sudden hypotension and / or acute renal failure.
With hypertensionIf previous diuretic therapy caused sodium depletion, it is necessary:
- either stop taking diuretic 3 days before the start of therapy with an ACE inhibitor, and then start taking hypokalemic diuretic again, if necessary;
- or prescribe a low initial dose of an ACE inhibitor, and then gradually increase it.
With congestive heart failure, Acceptance of an ACE inhibitor should begin with a very low dose, if possible after a preliminary dose reduction of the concomitant hypokalemic diuretic.
In all casesDuring the first weeks of therapy with an ACE inhibitor, renal function (plasma creatinine) should be monitored.
Other drugs that cause hypokalemia: amphotericin B (w / w), gluco-and mineralocorticoid, tetracosactide, stimulant laxatives:
Increased risk of hypokalemia (additive effect).
Monitor plasma potassium and adjust it, if necessary. It is especially important to remember this with concomitant therapy with digitalis-based drugs. Use non-stimulant laxatives.
Digitalis based preparations:
Hypokalemia is a predisposing factor to the toxic effect of digitalis.
To monitor the level of potassium in the plasma, ECG monitoring and, if necessary, adjust therapy.
Baclofen:
Increased hypotensive effect.
Hydrate the patient; monitor kidney function at the start of therapy.
Combinations of drugs that require attention:
Potassium-sparing diuretics (amiloride, spironolactone, triamteren):
While appropriate combinations are effective in some patients, the risk of hypokalemia (especially in patients with renal insufficiency or diabetes) or hyperkalemia still exists. Plasma potassium levels, ECG monitoring should be monitored and, if necessary, therapy should be reviewed.
Metformin:
Increased risk of developing metformin-induced lactic acidosis due to possible functional renal failure in patients receiving diuretics, and especially loop diuretics.Metformin should not be administered if plasma creatinine levels exceed 15 mg / l (135 μmol / l) in men and 12 mg / l (110 μmol / l) in women.
Iodinated contrast agents:
In the case of dehydration caused by diuretics, there is an increased risk of developing acute renal failure, in particular when high doses of iodinated contrast media are used.
It is necessary to provide the necessary rehydration of the patient before the introduction of iodized drug.
Imipramen-like antidepressants, antipsychotics:
Increased hypotensive effect and increased risk of orthostatic hypotension (additive effect).
Calcium (salt):
The risk of hypercalcemia as a result of decreased calcium excretion in the urine.
Cyclosporin, tacrolimus:
The risk of increasing creatinine levels in plasma without changing the level of cyclosporine in the systemic circulation, even in the absence of water / sodium depletion.
Corticosteroids, tetracosactide:
Reduced hypotensive effect (water / sodium retention associated with taking corticosteroids).
Amlodipine-related:
Dantrolene (infusion): against the background of the introduction of Verapamil and intravenous dantrolene, there have been cases of ventricular fibrillation and fatal cardiovascular insufficiency associated with hyperkalemia. Due to the risk of hyperkalemia, it is recommended to avoid the combined use of calcium channel blockers, such as amlodipine, in patients with malignant hyperpyrexia, and in the treatment of malignant hyperpyrexia.
Taking amlodipine with grapefruit or grapefruit juice is not recommended, since bioavailability may increase in some patients, leading to an increased effect of pressure reduction.
CYP3A4 inhibitors: co-administration of amlodipine with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole fungicides, macrolides, such as erythromycin or Clarithromycin, verapamil or diltiazem) can lead to a significant increase in plasma concentration of amlodipine. The clinical expression of these pharmacokinetic variations may be more pronounced in older patients. Thus, clinical observation and dose selection may be required.
Inducers of CYP3A4: there are no available data on the effect of inducers of CYP3A4 isoenzyme on amlodipine. Combined use of CYP3A4 isoenzyme inducers (for example, rifampicin, Hypericum perforatum) can cause a decrease in plasma amlodipine concentration. When using amlodipine with inducers of the CYP3A4 isoenzyme, caution should be exercised.
The effects of amlodipine on other drugs
The effect of reducing pressure from amlodipine complements the effect of lowering blood pressure, caused by other drugs with antihypertensive properties.
In clinical studies of drug interactions, amlodipine did not detect effects on the pharmacokinetics of Atorvastatin, Digoxin, Warfarin, or cyclosporine.
Simvastatin : the combined use of multiple doses of 10 mg of amlodipine and 80 mg of simvastatin resulted in a 77% increase in simvastatin exposure compared to using simvastatin alone. The daily dose of simvastatin in patients taking amlodipine should not exceed 20 mg.
 

special instructions

Hepatic encephalopathy
If hepatic function is impaired, thiazide and related diuretics can cause hepatic encephalopathy, especially in the case of electrolyte imbalance. Due to the presence of indapamide in the composition of the drug, taking Arifam should be immediately discontinued if such a condition occurs.
Light sensitivity
It was reported about the occurrence of photosensitivity reactions in patients receiving thiazides and related diuretics. If photosensitivity reactions occur during drug therapy, treatment is recommended to stop. If reappointment of a diuretic is considered necessary, it is recommended to avoid exposure to solar or artificial UV rays.
Hypertensive crisis
The safety and effectiveness of amlodipine in a hypertensive crisis have not been established.
Water and electrolyte balance
• Sodium level in blood plasma
It should be checked before starting therapy and regularly during the course of therapy. Any diuretic therapy can cause hyponatremia, sometimes with very serious consequences. A sharp decrease in plasma sodium at the initial stage may be asymptomatic,therefore, it is important to regularly monitor plasma sodium levels. In elderly patients and patients with cirrhosis, monitoring should be carried out even more often.
• Potassium level in blood plasma
Potassium deposition in hypokalemia is the main risk of using thiazides and related diuretics. In some populations of high-risk patients, such as elderly patients, patients who feed on inferior and / or taking multiple medications, patients with cirrhosis of the liver, edema and ascites, coronary heart disease and heart failure, the risk of hypokalemia should be prevented ( 3.4 mmol / l). In this case, hypokalemia increases the cardiotoxicity of drugs based on digitalis and the risk of arrhythmias.
Patients with an extended QT interval, both congenital and iatrogenic, are also at increased risk. So, hypokalemia, as well as bradycardia, are a predisposing factor to the occurrence of severe arrhythmias, in particular, potentially lethal bidirectional tachycardia.
In all of the above situations, more frequent monitoring of plasma potassium levels is required. The first measurement of potassium in the blood plasma should be carried out during the first week after the start of treatment.
Detection of hypokalemia requires corrective action.
• Level of calcium in blood plasma
Thiazides and related diuretics can reduce urinary calcium excretion and cause a slight and transient increase in plasma calcium levels. Severe hyperkalemia may result from a previously unidentified hyperparathyroidism.
Drug therapy should be stopped and a study of the function of the parathyroid gland.
Blood glucose level
Due to the presence of indapamide in the composition of the drug, in patients with diabetes, it is important to monitor the level of glucose in the blood, especially with concomitant hypokalemia.
Heart failure
When conducting therapy in patients with heart failure, special care should be taken. In a long-term placebo-controlled study in patients with acute heart failure (III and IV functional class according to the NYHA classification), the incidence of pulmonary edema was higher in the group of patients taking amlodipine than in the group of patients taking placebo. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they increase the risk of cardiovascular complications and death.
Kidney function
Thiazides and related diuretics are fully effective only for patients with normal liver function or minimal abnormalities (plasma creatinine levels are below 25 mg / l, ie 220 µmol / l in an adult patient).In elderly patients, plasma creatinine levels should be adjusted according to age, weight, and gender.
Hypovolemia caused by the loss of water and sodium as a result of taking a diuretic, at the beginning of treatment causes a decrease in glomerular filtration rate. This can lead to an increase in blood urea and plasma creatinine. This transient functional renal failure has no effect on patients with normal renal function, but may aggravate an already existing renal failure.
In patients with renal failure, amlodipine can be used in normal doses. Changes in the concentration of amlodipine in the blood plasma do not correlate with the severity of renal failure. Amlodipine is not excreted by dialysis.
In patients with renal insufficiency, the dose of Arifam^® must comply with the doses of its components taken separately.
Uric acid level
Due to the presence of indapamide in the composition of the drug, patients with an increased level of uric acid may experience a tendency to an increase in gout attacks.
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