buy equipoise

Pharmacological properties buy equipoise is a long-acting muscle relaxant nedepolyariziruyuschim. Due to the competition due to the n-cholinergic receptors, located on the endplate of the neuromuscular synapse of skeletal muscles, blocks the transmission of the signal from the nerve to the muscle fibers. It does not cause muscle fasciculations, has no hormonal action. Even at doses several times greater than its effective dose required for 90% reduction in muscle contractility . The dose equal to 0.05 mg / kg body weight, provides a 40-50 minute muscle relaxation during various operations . The maximum effect pipekuroniya buy equipoise dose-dependent and occurs within 1.5-5 min. The effect is faster at all doses of 0.07-0.08 mg / kg. A further increase in the dose reduces the time required for the development of the effect, and significantly prolongs the action of the drug.  When administered intravenously, the initial volume of distribution (the V dc ) is 110 ml / kg body weight, volume of distribution in the saturation phase (the V dss ) is 300 (± 78 ) ml / kg, the plasma clearance (Cl) is approximately equal to 2,4 (± 0.5) ml / min / kg, the mean elimination half-life (T 1/2 ) is 121 (± 45) minutes. the average residence time in the blood plasma (MRT) – 140 min. Repeated administration of maintenance doses cumulative effect is insignificant, if at the time of 25% recovery of the original muscle contractility used doses of 0.01-0.02 mg / kg. Write mainly by the kidneys, while 56% of the drug – the first 24 hours. One-third of output unchanged, and the remaining amount -. In the form of 3-desacetyl pipekuroniya buy equipoise According to preclinical studies liver is also involved in the elimination pipekuroniya buy equipoise. Penetrates through the placental barrier.

Indications for use of

endotracheal intubation and relaxation of skeletal muscles with a total benzocaine during various surgical procedures requiring more than a 20-30 minute muscle relaxation and in the conditions of ventilation.

Contraindications
– Hypersensitivity to pipekuroniya buy equipoise and / or bromine and.
– Children under the age of 3 months.
– Severe hepatic impairment.

Be wary
of biliary tract obstruction, edema syndrome, increased blood volume, or dehydration, diuretics, disturbance of acid-base balance (acidosis, hypercapnia) and water and electrolyte metabolism (gipokaliemiya. gipermagniemiya, hypocalcemia), hypothermia, digitalization, hypoproteinemia, cachexia, myasthenia gravis (including myasthenia gravis, Eaton-Lambert syndrome) due to the possible in cases such as amplification and attenuation of the drug. Small doses Arduana with severe myasthenia gravis or Lambert-Eaton syndrome can cause very pronounced effect. Such patients the drug is administered in very low doses, after careful assessment of the potential risk of respiratory depression, kidney failure (prolongs the action of the drug and time postanesthesia depression), decompensated chronic heart failure, children under the age of 14, malignant hyperthermia, anaphylactic reaction caused by any muscle relaxant to the patient’s history (because of possible cross-allergy).

Pregnancy and lactation
No clinical studies to prove the safety of Arduana in pregnant women and the fetus is not enough. Use of the drug during pregnancy is not recommended.
Clinical data on the safe use Arduana lactation is not enough. Use of the drug is not recommended during breast-feeding.

Dosing and Administration
As was the case with other non-depolarizing muscle relaxants, dose Arduana selected individually for each patient, taking into account the type of anesthesia, the proposed surgery duration, possible interactions with other drugs, used prior to or during anesthesia, comorbidities, and general condition of the patient .
It is recommended to use the stimulator peripheral nerve fibers to monitor neuromuscular block.
use only intravenously. Immediately before the administration of 4 mg of dry substance supplied diluted solvent.

The recommended dose for adults and children over 14 years:
– initial dose for intubation and subsequent surgery: 0.06-0.08 mg / kg body weight, provides a good / excellent conditions for tracheal intubation within 150-180 seconds, and the duration 60-90 minutes of muscle relaxation;
– miorelaxation initial dose for intubation using suxamethonium: 0.05 mg / kg. provides a 30-60-minute muscle relaxation;
– the maintenance dose: 0.01-0.02 mg / kg, provides a 30-60-minute muscle relaxation during surgery;
– chronic renal insufficiency is not recommended doses in excess of 0.04 mg / kg (in high doses may increase the duration of muscle relaxation);
– with overweight and obesity possible extension of Arduana, so you should use a dose designed for ideal weight.

Doses for children: from 3 to 12 months. – 0.04 mg / kg (which provides muscle relaxation lasting 10 to 44 min.). From 1 to 14 years – 0.05-0.06 mg / kg (muscle relaxation – from 18 to 52 min.).

Termination effect: when 80-85% blockade measured by stimulator peripheral nerve fibers, or partial blockade at the time determined by clinical signs, the application of atropine (0.5-1.25 mg) in combination with neostigmine methyl sulfate (1 -3 mg), or galantamine (10-30 mg) stops muscle relaxant action Arduana.

Side effect On the part of the nervous system: rare (less than 1%): depression of the central nervous system (CNS), somnolence, hypoesthesia. paralysis of skeletal muscles. From the musculoskeletal system: rarely (less than 1%): the weakness of the skeletal muscles after the cessation of muscle relaxation, muscle atrophy. The respiratory system: rarely (less than 1%): apnea, pulmonary atelectasis, respiratory depression, laryngospasm in a result of an allergic reaction, bronchospasm, cough. On the part of the cardiovascular system: rarely (less than 1%): myocardial ischemia (up to a myocardial infarction) and brain, arrhythmia, tachycardia, bradycardia, decreased or increased blood pressure, atrial fibrillation, ventricular premature beats , ventricular tachycardia. From the side of hematopoiesis and hemostasis system: rare (less than 1%): thrombosis, reduction of activated partial thromboplastin and prothrombin time. From the urinary system: rarely (less than 1%): anuria. Allergic reactions: rare (less than 1 %): skin rashes, allergic reactions, angioedema. Laboratory findings: rare (less than 1%): hypercreatininemia, hyperglycemia, hypokalemia, hypomagnesemia, hypocalcemia. Other: blepharitis, ptosis.

Overdose

Symptoms: prolonged paralysis of skeletal muscles, and sleep apnea, marked reduction of blood pressure (BP), a shock.
In case of overdose or prolonged neuromuscular block of mechanical ventilation was continued until recovery of spontaneous breathing. Early recovery of spontaneous breathing as an antidote is administered an acetylcholinesterase inhibitor (e.g., neostigmine methylsulfate, pyridostigmine buy equipoise, edrophonium chloride): 0.5-1.25 mg atropine in combination with neostigmine (1.3 mg), or galantamine (10-30 mg). Until a satisfactory recovery of spontaneous breathing should be close monitoring of respiratory function.

Interaction with other drugs
inhaled anesthetics (halothane, methoxyflurane, ether diethyl ether, enflurane, isoflurane, cyclopropane), anesthetics for intravenous administration (ketamine propanidid. Barbiturates, etomidate, in-hydroxy and butyric acid), depolarizing and non-depolarizing muscle relaxants, some antibiotics (aminoglycosides, nitroimidazole derivatives, including metronidazole, tetracyclines, bacitracin, capreomycin, clindamycin, polymyxins, including colistin, lincomycin, amphotericin B), nitrate, anticoagulants, mineralocorticoid and steroids, diuretics, including . bumetanide, carbonic anhydrase inhibitors, ethacrynic acid, corticotropin, .alpha.-and β-blockers, thiamine, monoamine oxidase inhibitors (MAOIs), guanidine, protamine sulfate, phenytoin, blockers “slow” calcium channels, magnesium salts, procainamide, quinidine, lidocaine and procaine for intravenous enhance and / or prolong the action.
Drugs that decrease blood levels of potassium, aggravate respiratory depression (until it stops).
Opioid analgesics increase respiratory depression. High doses of sufentanil reduces the need for high initial doses of non-depolarizing muscle relaxants. Non-depolarizing muscle relaxants to prevent or reduce muscle tension caused by high doses of analgesics opiondnyh (including alfentanilom, fentanyl, sufentanil). Do not reduce the risk of bradycardia and hypotension caused by opiondnymi analgesics (especially against the background of vasodilators and / or beta-blockers).
During intubation with suxamethonium Arduan introduced after the disappearance of clinical signs of suxamethonium action. As is the case with other nedepolyariziruyuschimi relaxants introduction Arduana can shorten the time required for the onset of muscle relaxation, and increase the duration of maximal effect;
Prolonged preliminary application of glucocorticosteroids, neostigmine, edrophonium chloride, pyridostigmine, norepinephrine, azathioprine, epinephrine, theophylline, potassium chloride chloride, sodium chloride may weaken the effect of calcium.
Depolyariziruyuschie relaxants can both strengthen and weaken the action pipekuroniya buy equipoise (depending on the dose, time of use and individual sensitivity).
Doxapram temporarily masks the residual effects of muscle relaxants.

Cautions
Use only in a specialized hospital with proper equipment for artificial respiration and in the presence of a specialist to conduct artificial respiration due to the impact of the drug on the respiratory muscles.
Close supervision is necessary during surgery and in the early postoperative period in order to maintain vital functions to the full recovery of muscle contractility.
The calculation should take into account the dose applied anesthetic technique, possible interactions with drugs administered before or during anesthesia, the patient’s condition and sensitivity to the drug.
cases anaphylactic and anaphylactoid reactions when used muscle relaxants are described in the medical literature. Despite the absence of such action messages Arduana, the drug can be used only under conditions that allow to proceed immediately to these states treatment.
Caution must be especially careful in applying Arduana with a history of the patient’s anaphylactic reaction caused by a muscle relaxant because of possible cross allergy .
Doses Arduana, causing muscle relaxation, does not have a significant cardiovascular effect and hardly cause bradycardia.
Application and dose m-holinoblokatorov sedation in order to be careful preliminary assessment; It should also take into account the stimulating effect by n. vagus other simultaneously used drugs and type of surgery.
In order to avoid relative overdosing and ensure proper control over the recovery of muscle activity is recommended to use the stimulator peripheral nerve fibers.
Patients with disorders of neuromuscular transmission, obesity, renal failure, liver disease and biliary tract under guidance of a history of myocardial polio, should be prescribed the drug in smaller doses.
in the case of liver disease Arduana application is possible only in cases where the risk is justified. This dose should be minimal.
Some states (hypokalemia, digitalization, gipermagniemiya, diuretics, hypocalcemia, hypoproteinemia, dehydration, acidosis, hypercapnia, cachexia, hypothermia) may contribute to lengthening or enhancing effect.
As is the case with other muscle relaxants, prior to use Arduana should normalize the electrolyte balance and acid-base status, eliminate dehydration.
Like other muscle relaxants Arduan can reduce the activated partial thromboplastin and prothrombin time.
Children aged 1 year to 14 years are less sensitive to pipekuroniya buy equipoise and duration miorelaksiruyushego effect they are shorter than in adults and children aged up to 1 year.
Efficacy and safety of use in the neonatal period have not been studied.
Myorelaxation effect in infants from 3 months. up to 1 year does not differ from that in adults.
Only use fresh solution.

The impact on the car and the working mechanisms of management capacity
in the first 24 hours after the termination of the action miorelaksiruyuschego Arduana advised not to drive and engage in potentially hazardous activities that require high concentration and psychomotor speed reactions.

Release form
. Lyophilisates for solution for intravenous administration of 4 mg / together with the solvent – sodium chloride solution 0.9%
10 mg of the freeze-dried in a vial of colorless glass (hydrolytic class 1) contain 4 mg pipekuroniya buy equipoise; 2 ml of solvent in a colorless glass ampoule (hydrolytic class 1) 5 5 vials and ampoules in a plastic tray, the plastic pallet 5 in the carton box with instructions for use. Buy injectable steroids online, Buy Steroids Online buy anabolic steroids online.

equipoise side effects

equipoise side effects – a synthetic nucleoside analogue with a pronounced antiviral effect. It has a broad spectrum of activity against various DNA and RNA viruses.

Pharmacodynamics:

equipoise side effects is readily penetrates into the affected cells and virus rapidly phosphorylated equipoise side effects in intracellular adenosine mono-, di- and triphosphate. These metabolites, especially equipoise side effects triphosphate, have pronounced antiviral activity.

The mechanism of action of equipoise side effects is not well understood. However, it is known that equipoise side effects inhibits inosine monophosphate dehydrogenase (IMP), this effect leads to a marked decrease in the level of intracellular guanosine triphosphate (GTP), which is in turn accompanied by suppression of the synthesis of viral RNA and virus-specific proteins. equipoise side effects inhibits the replication of new virions that reduces viral load. equipoise side effects selectively inhibits the synthesis of viral RNA without inhibiting RNA synthesis in the normally functioning cells.

equipoise side effects is effective against many RNA and DNA viruses. The most sensitive to equipoise side effects DNA viruses include: Simplex herpes virus, porks-virus, virus of Marek`s illness. Insensitive to equipoise side effects DNA viruses include: Varicella Zoster, pseudorabies, cow smallpox. The most sensitive to equipoise side effects RNA viruses are: influenza A, B, paramyxovirus (parainfluenza, epidemic paratotite, Nucasl`s illness), reoviruses, RNA tumoral viruses. Insensitive to equipoise side effects RNA viruses are: enteroviruses, rhinovirus, Semlicy Forest.

equipoise side effects has activity against hepatitis C virus (HCV). The mechanism of action of equipoise side effects against HCV have not been fully elucidated. It is assumed that accumulates as phosphorylation equipoise side effects triphosphate competitively inhibits the formation of guanosine triphosphate, thereby reducing the synthesis of viral RNA. It is also believed that the mechanism of the synergistic action of equipoise side effects and alpha interferon against HCV due to increased phosphorylation of equipoise side effects with interferon.

Pharmacokinetics:

Absorption: with oral equipoise side effects is rapidly absorbed in the gastrointestinal tract. Moreover, its bioavailability is greater than 45%.

Distribution: equipoise side effects is distributed in plasma, mucous secretions and airway erythrocytes. A large number of equipoise side effects triphosphate accumulates in red blood cells, reaching a plateau at Day 4 and continue for several weeks after administration. Poluraspredeleniya period of 3.7 hours, volume of distribution (Vd) -. 647 – 802 liters. In exchange reception equipoise side effects accumulates in plasma in large quantities. The ratio of the bioavailability (AUC – area under “concentration / time” curve) and by repeated single dose equal to 6. The high equipoise side effects concentrations (over 67%) can be detected in cerebrospinal fluid after prolonged use.

Protein binding: slightly bound to plasma proteins.

The time to reach maximum plasma concentration – from 1 to 1.5 hours.

The time to reach a therapeutic concentration in the plasma depends on the minute blood volume.

The average value of the maximum concentration (C max ) in the plasma of about 5 micromoles per liter at the end of 1 week of receiving 200 mg every 8 hours and about 11 micromoles per liter at the end of 1 week of receiving 400 mg every 8 hours.

Biotransformation: equipoise side effects phosphorylated in liver cells in active metabolites as mono-, di- and triphosphate, which is then metabolized into 1,2,4 – triazolkarboksamid (amide hydrolysis trikarboksilovuyu deribozilirovanie and acid to form a triazole carboxylic metabolite).

Excretion: equipoise side effects is excreted from the body slowly. Half-life (T 1/2 ) after receiving a single 200 mg dose of from 1 to 2 hours due to the plasma and erythrocytes of 40 days. Upon termination of a course of reception the T 1/2 is about 300 hours. equipoise side effects and its metabolites are primarily excreted in the urine. Only about 10% is excreted in the feces. In unmodified form about 7% of equipoise side effects is displayed for 24 hours and about 10% – for 48 hours.

Pharmacokinetics in special clinical conditions: When taking the drug in patients with renal insufficiency AUC and the C max of equipoise side effects increased, due to a decrease in the true clearance. Patients with liver failure (A, B and C degrees) pharmacokinetics equipoise side effects does not change. After receiving a single dose with food containing fat varies significantly equipoise side effects pharmacokinetics (AUC and C max is increased by 70%).

 

Indications for use:

 

Chronic hepatitis C (treatment in combination with alpha-interferon).

 

Contraindications:

 

Hypersensitivity, pregnancy, lactation, chronic heart failure stages IIb-III, myocardial infarction, renal insufficiency (creatinine clearance – less than 50 ml / min), severe anemia, liver failure, decompensated cirrhosis, autoimmune diseases (including autoimmune hepatitis), not treatable thyroid disease, severe depression with suicidal intentions, children and Youth age (up to 18 years).

Carefully

 

Women of childbearing age (pregnancy is not desirable), decompensated diabetes (with bouts of ketoacidosis); chronic obstructive pulmonary disease, pulmonary embolism, chronic heart failure, thyroid disease (including hyperthyroidism), bleeding disorders, thrombophlebitis, mielodeprescia, hemoglobinopathies (including thalassemia, sickle-cell anemia), depression, suicidal (including history).

 

Dosage and administration:

 

The drug is taken by mouth without chewing and drinking water, along with the food intake.

Patients with hepatitis C is recommended to take arviron the rate of 15 mg per 1 kg of body weight, which corresponds to 800-1200 mg per day, ie, 2-3 capsules in the morning and 2-3 capsules in the evening. Typically, the recommended dosage for patients weighing less than 75 kg is 1000 mg per day (2 capsules 3 capsules in the morning and evening) patients with body weight more than 75 kg are advised to take 1200 mg per day (3 capsules in the morning and 3 capsules in the evening).

Duration arvironom combination therapy with interferon-alpha typically is 24 – 48 weeks. In addition, for treatment-naïve patients with duration of the course is at least 24 weeks and patients with genotype 1, the course duration is 48 weeks. In patients refractory to monotherapy with interferon alpha, as well as the duration of a relapse rate of the disease is not less than 6 months.

Side effects:

 

  • From the nervous system: headache, insomnia, asthenic syndrome, depression.
  • Cardio-vascular system: decrease in blood pressure, bradycardia, cardiac arrest.
  • From the side of hematopoiesis: hemolytic anemia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia.
  • From the digestive system: loss of appetite, nausea, hyperbilirubinemia.
  • Allergic reactions: skin rash, urticaria, angioedema, bronchoconstriction, anaphylaxis.
  • Other: hair loss.

 

Overdose:

Perhaps the increased severity of side effects.
Treatment: removal of the drug, symptomatic therapy.

Interaction with other drugs:

 

When combined equipoise side effects and interferon alfa-marked synergism of their actions.

In clinical use of different drugs at therapeutic doses in combination with equipoise side effects showed no significant interactions.

Purpose equipoise side effects zidovudine treatment during and / or simultaneously with stavudine existing HIV infection accompanied by a decrease in phosphorylation of these drugs, resulting in HIV viremia and treatment regimen requires a change. Not detected interaction equipoise side effects and nucleoside reverse transcriptase inhibitors or protease inhibitors. It is therefore possible joint use of these drugs and equipoise side effects for the treatment of patients co-infected with HIV and hepatitis C.

Medicaments containing compounds of magnesium and aluminum, simethicone reduces the bioavailability.

Special instructions:

Medical staff working with the preparation, one should consider its teratogenicity. Men and women of reproductive age during treatment and for 7 months after the end of treatment should use effective contraception.

Laboratory tests (complete blood count with leukocyte and platelet count, determination of electrolytes, creatinine, liver function tests) should be carried out before the start of therapy, at 2 and 4 weeks and then regularly.

During treatment with equipoise side effects maximum decrease in hemoglobin in the majority of cases it occurs after 4-8 weeks of starting treatment. By reducing the hemoglobin is less than 110 mg / mL should be temporarily reduce the dose of equipoise side effects at 400 mg per day, with a decrease in hemoglobin of less than 100 mg / ml dose should be reduced to 50% of the original. In most cases, the recommended dose modifications provide restoration of hemoglobin levels. By reducing the hemoglobin is less than 85 mg / ml should stop taking the drug.

In acute manifestations of hypersensitivity (urticaria, angioedema, bronchoconstriction, anaphylaxis) use of the drug should be discontinued immediately. Transient rashes do not serve as grounds for interruption of treatment.

During treatment, those experiencing fatigue, drowsiness or disorientation, should refrain from driving motor vehicles and activities potentially hazardous activities that require high concentration and psychomotor speed reactions.

In connection with a possible worsening of renal function in elderly patients prior to use of the drug is necessary to determine kidney function, in particular creatinine clearance.

 

Product form:

Capsules 200 mg. 10 capsules in blisters, 3, 6 or 14, the contour of cellular packaging with instructions for use in paper cartons.

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equipoise dosage

Arava belongs to a class of basic antirheumatic drugs and has antiproliferative, immunomodulatory, anti-inflammatory and immunosuppressive properties. The active metabolite of equipoise dosage inhibited A771726 degidroorotat dehydrogenase enzyme and possess antiproliferative activity. A771726 under in vitro inhibits mitogen-induced proliferation and DNA synthesis of T lymphocytes. A771726 manifests antiproliferative activity, apparently at the level of pyrimidine biosynthesis, since the addition of uridine in the cell culture inhibitory effect eliminates metabolite A771726. With the use of radioisotope ligand shown that A771726 selectively binds to the enzyme dehydrogenase degidroorotat than due to its property to inhibit this enzyme and lymphocyte proliferation in the G1 phase. The proliferation of lymphocytes is one of the key stages of rheumatoid arthritis.
Simultaneously A771726 inhibits expression of receptors for interleukin-2 (CB-25) and core antigens Ki-67 and PCNA, associated with the cell cycle.
The therapeutic effect of equipoise dosage was shown in several animal models of autoimmune diseases including rheumatoid arthritis.
equipoise dosage reduces the symptoms and slow the progression of joint damage in the form of active rheumatoid arthritis.
The therapeutic effect usually evident after 4-6 weeks and can grow further for 4-6 months.

Pharmacokinetics
equipoise dosage is rapidly converted to its active metabolite A771726 (primary metabolism in the intestinal wall and liver). In plasma, urine or feces were seen only trace amounts of unchanged equipoise dosage.
The only determined metabolite A771726 is responsible for the basic properties of the drug in vivo.
If ingestion is absorbed from 82 to 95% of the drug. The maximum plasma concentration of A771726 are determined from 1 to 24 hours after a single dose of the dose. equipoise dosage can be taken together with food.
Because of the very long half-life A771726 (approximately 2 weeks) was used loading dose of 100 mg daily for 3 days. This has allowed to quickly reach an equilibrium state plasma concentrations of A771726. Without a loading dose to achieve equilibrium concentration would require a 2-month drug. In studies with multiple assignment A771726 drug pharmacokinetic parameters were dose-dependent within the dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and a daily dose of equipoise dosage. At a dose of 20 mg per day, average plasma concentration of A771726 at equilibrium have the value of 35 ug / ml.
The plasma is rapid binding A771726 albumin. Unbound fraction of A771726 is about 0.62%. Binding of A771726 more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.
equipoise dosage is metabolised to one primary (A771726) and several secondary metabolites, including 4-triflyuorometilalanin.
The biotransformation of equipoise dosage to A771726 and subsequent metabolism of A771726 are controlled by several enzymes, and occur in microsomal and other cell fractions. Interaction studies with cimetidine (non-specific inhibitor of cytochrome P450) and rifampicin (non-specific inducer of cytochrome P450) showed that in vivo SYP-enzymes involved in the metabolism of equipoise dosage only to a small extent.
Excretion A771726 from the body and is characterized by a slow clearance of 31 ml / hr. equipoise dosage is excreted in the feces (probably due to biliary excretion) and in the urine. The half-life is about 2 weeks.
The pharmacokinetics of A771726 in patients on CAPD, is similar to that in healthy volunteers. A more rapid elimination of A771726 observed in patients on hemodialysis, which is not connected with the extraction of drug in the dialysate and displacing it from its association with the protein. Although A771726 clearance increased by approximately a factor of 2, terminal half-life is similar to that in healthy individuals, as at the same time increases the amount of the distribution.
The data on the pharmacokinetics of the drug in patients with hepatic impairment available.
Pharmacokinetic characteristics in patients younger than 18 years have not been studied.
Patients older age (65 or older) pharmacokinetic data correspond roughly to the middle age group.

Indications

As a basic means for the treatment of adult patients with active rheumatoid arthritis to reduce symptoms and the delay of progression of structural damage of the joints.
The active form of psoriatic arthritis.

Contraindications

 

The drug Arava should not be used in patients with hypersensitivity to equipoise dosage or to any other component of the drug.
The drug is contraindicated in:

  • in patients with impaired liver function;
  • in patients with severe immunodeficiency (e.g., AIDS);
  • in patients with significant disorders of bone marrow hematopoiesis, or with severe anemia, leukopenia or thrombocytopenia due to other reasons (other than rheumatoid arthritis);
  • in patients with severe, uncontrolled infections;
  • in patients with moderate or severe renal insufficiency (because of the small experience of clinical follow-up);
  • in patients with severe hypoproteinemia (e.g., nephrotic syndrome);
  • in pregnant women or women of childbearing age who are not using reliable contraception during treatment with equipoise dosage, and then as long as the plasma levels of the active metabolite remains above 0.02 mg / l (see. “Pregnancy and lactation”). Pregnancy must be excluded before starting treatment with equipoise dosage.

Contraindications receiving equipoise dosage during breastfeeding (see. “Pregnancy and breast-feeding”.)
Men receiving treatment with equipoise dosage should be warned about the possible foetotoxic effect of the drug (related to its possible impact on the father’s sperm) and the need to use reliable contraception.
Arava is not recommended for use in patients under 18 years since efficacy and safety data in this population are not available.

Pregnancy and breast-feeding

 

equipoise dosage should not be administered to pregnant women or women of childbearing age who are not using reliable contraception during treatment with equipoise dosage and for a while after this treatment (waiting period or abbreviated period of “laundering”; see below.). It must be ensured in the absence of pregnancy prior to treatment with equipoise dosage.
Patients should be informed that as soon as there comes a month or if the delay has another reason to assume pregnancy, they should immediately inform your doctor to do a pregnancy test; in the case of a positive pregnancy test physician should discuss with the patient the possible risk to this pregnancy. It is possible that the rapid decline in the level of the active metabolite in the blood with the help of the described below product launch procedures will help at the first delay of menses to reduce the risk to the fetus from equipoise dosage.
Women who take equipoise dosage and want to become pregnant, it is recommended to follow one of the following procedures to be sure that the fetus is not exposed to toxic concentrations of A771726 (control concentration below 0.02 mg / l).

The waiting period
can be expected that A771726 plasma concentration may be higher than 0.02 mg / l for a long period. It is believed that the concentration can be less than 0.02 mg / l in 2 years after stopping the treatment with equipoise dosage.
First time A771726 plasma concentration is measured after a two-year waiting period.
After that, you need to measure the concentration of A771726 in plasma, at least through 14 days. If the value of both measurements below 0.02 mg / l, is not expected any teratogenic risk.

The procedure of “laundering”
After stopping treatment with equipoise dosage:

  • 8 g of cholestyramine administered three times a day for 11 days;
  • Alternatively 50 g of charcoal, pulverized, administered 4 times a day for 11 days.

Regardless of the procedure “laundering” is necessary to inspect two separate tests at intervals of at least 14 days and to wait six weeks from the moment when the concentration of drug in plasma is first recorded below 0.02 mg / l, up to the moment of fertilization.
it is necessary to inform women of childbearing period that must elapse 2 years after stopping treatment with equipoise dosage, before they can try to get pregnant. If a 2-year waiting period under reliable contraception seems unreasonable, it may be advisable to conduct a “laundering” the procedure as a preventive measure.
And cholestyramine and activated charcoal may influence the absorption of oestrogens and progestogens, so reliable oral contraceptives do not provide an absolute guarantee in the period of “laundering “using cholestyramine or activated charcoal.
it is recommended to use alternative methods of contraception.
animal studies indicate that equipoise dosage or its metabolites pass into breast milk. Therefore, women who are breastfeeding should not take equipoise dosage.

Dosing and Administration

equipoise dosage treatment should start under the supervision of a physician who is experienced in the treatment of rheumatoid arthritis and psoriatic arthritis.
With regard to recommendations for treatment for the control, see the section “Special instructions”.
equipoise dosage treatment begins with a single oral loading dose of 100 mg for 3 days. As maintenance dose for rheumatoid arthritis recommended intake of 10 mg to 20 mg of equipoise dosage once daily, psoriatic arthritis – 20 mg 1 time per day.
The therapeutic effect usually appears after 4 – 6 weeks, and can grow further to 4 – 6 months.
There are no recommendations regarding the dosage of the drug for patients suffering from renal insufficiency mild.
Do not require any dose adjustment for patients older than 65 years.
The drug should be administered by experts with the necessary experience in the treatment of rheumatoid arthritis.
The tablets must be swallowed whole, drinking plenty of fluids. Food intake has no effect on the absorption of equipoise dosage.

Side effect

 

The classification of the intended frequency of side effects:
common = 1 – 10% of patients; atypical = 0.1 – 1% of patients; Rare = 0.01 – 0.1% of patients; very rare = 0.01% of patients or less.

The cardiovascular system
Common: mild increase in blood pressure.
Rare: marked increase in blood pressure
Very rare: vasculitis (due to the presence of underlying disease causal relationship to equipoise dosage intake could not be established).
The gastrointestinal tract, liver,
Common: diarrhea, nausea, vomiting, anorexia, oral mucosal disorders (eg, aphthous stomatitis, ulceration of the mouth), abdominal pain, increased activity of “liver” transaminases (especially ALT), less often – GGT and alkaline phosphatase, hyperbilirubinemia.
Rare: . hepatitis, jaundice / cholestasis
Very rare: severe liver injury such as liver failure, acute hepatic necrosis that may be fatal; pancreatitis.
Respiratory system and mediastinal disorders
Very rare: interstitial pulmonary process (including interstitial pneumonitis), which can be fatal.
Metabolism and nutrition
Common: weight loss, fatigue
Atypical: hypokalemia.
Nervous system
Common: headache, dizziness, fatigue, paresthesia.
Atypical: taste disturbance, anxiety.
Very rare: peripheral neuropathy
Locomotor apparatus
Typical:. Tenosynovitis
Atypical: tendon rupture
Leather and derivatives
Common: increased hair loss, eczema, dry skin.
Very rare: erythema multiforme.
Allergy
Common: mild allergic reactions, rash (including maculopapular rash), pruritus.
Atypical: urticaria.
Very rare: severe anaphylactic / anaphylactoid reactions, Stevens – Johnson syndrome, Lyell’s syndrome.
infection
Rare:. The development of serious infections, including opportunistic and sepsis, which can be fatal
may increase the number of possible infections (in particular, rhinitis, bronchitis and pneumonia).
hematopoietic system and lymphatic system
Typical:. Leukopenia (leukocytes> 2000 cells / mm)
Atypical: anemia, slight thrombocytopenia (platelets <100,000 / microliter).
Rare: eosinophilia, leukopenia (leukocytes <2000 / L), pancytopenia (presumably due to the antiproliferative effect)
Very rare : agranulocytosis.

Recent, concomitant or subsequent use of potentially myelotoxic agents may be associated with greater risk of hematological effects.
The risk of cancer, especially lymphoproliferative diseases increases with the use of certain immunosuppressive agents.
There may be a slight hyperlipidemia. Uric acid levels usually decrease.
Laboratory data, the clinical significance of which is not established, are not clinically proven, include a small increase in the levels of lactate dehydrogenase and creatine kinase in the blood plasma. Atypical manifestation of hypophosphatemia is easy.
We can not exclude the possibility of a reversible decrease in sperm concentration, total sperm count and motility.

Overdose

Symptoms. There have been reports of chronic overdose in patients treated with equipoise dosage at a dose up to 5 times the recommended daily dose, and reports of acute overdose in adults and children.
In most cases of overdose have been reported on the development of adverse events. Emerging adverse events were comparable to the safety profile of equipoise dosage. The most commonly observed adverse events were diarrhea, abdominal pain, leukopenia, anemia, and increase performance tests of functional liver condition. Treatment. In case of overdose or toxicity is recommended to take cholestyramine or activated charcoal, to accelerate the cleansing of the body. Kolestiramin received three healthy volunteers orally 8 g three times a day for 24 hours decreased the level of A771726 in plasma by about 40% at 24 hours and 49 – 65% after 48 hours. it was shown that the introduction of activated carbon (powder converted into a slurry) orally or gavage (50 g every 6 hours during the day) to reduce the concentration of the active metabolite A771726 in plasma by 37% after 24 hours and 48% after 48 hours. These procedures are “laundering” can be repeated as clinically indicated. Studies with hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the main metabolite of equipoise dosage, is not able to be displayed by dialysis.

Interaction with other drugs, laboratory and diagnostic tests

Increased side effects may occur in case of recent or concomitant use of hepatotoxic (including alcohol) or gematotoksichnosti and immunosuppressive drugs or when taking these drugs is started after equipoise dosage treatment without a “laundering” procedure (see. “Special Instructions”).
In patients with rheumatoid arthritis do not was found no pharmacokinetic interaction between equipoise dosage (10 – 20 mg per day) and methotrexate. (10 – 25 mg per week)
Patients receiving equipoise dosage, it is recommended not to give colestyramine or active carbon, because it leads to rapid and substantial reduction A771726 concentration ( active metabolite of equipoise dosage) in the blood plasma. It is believed that this is due A771726 recirculation breach in the liver and small intestine and / or violation of its gastrointestinal dialysis.
If the patient is already taking non-steroidal antiinflammatory drugs (NSAIDs) and / or corticosteroids, they can continue to take after starting treatment with equipoise dosage.
Enzymes involved in the metabolism of equipoise dosage and its metabolites are not exactly known. In vivo studies of its interaction with cimetidine (non-specific inhibitor of cytochrome P450) showed no significant interaction. After concomitant administration of a single dose of equipoise dosage subjects who received multiple doses of rifampicin (non-specific inducer of cytochrome P450), A771726 peak levels increased by approximately 40%, whereas the area under the concentration-time curve is not significantly changed. The mechanism of this effect is not clear.
Studies in vitro have shown that A771726 inhibits cytochrome R4502S9 (CYP2C9). In clinical trials, there was not any problems with the co-administration of equipoise dosage and NSAIDs metabolized CYP2C9.Special care should be given equipoise dosage with other medications, non-NSAIDs metabolized by means of CYP2C9, such as phenytoin, warfarin and tolbutamide. Reported an increase in prothrombin time, while the appointment of equipoise dosage and warfarin.
In a study in which equipoise dosage was given to healthy volunteers female together with three-phase oral contraceptive containing 30 mcg ethinyl estradiol, no decrease of contraceptive effect of the tablets were found, and pharmacokinetics of A771726 completely fits within the specified range.
at the moment there is no information on the joint use of equipoise dosage with antimalarials used in rheumatology (eg chloroquine and gidroksihlorina), preparations of Au (V / m or orally), the D-penicillamine, azathioprine and other. immunosuppressive drugs ( except methotrexate). Unknown risks associated with carrying out a comprehensive therapy, particularly after prolonged treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (eg hepato- or gematoksichnosti), the combination of this drug with other DMARDs (eg methotrexate) are undesirable. A recent concomitant or subsequent use of potentially myelotoxic agents may be associated with greater risk of haematological effects. Immunosuppressive drugs increase the risk of infections and malignancies, especially lymphoproliferative disorders.

Vaccination
There are no clinical data on the efficacy and safety of vaccinations under equipoise dosage treatment. However, it is not recommended to be vaccinated with live vaccines. It is necessary to take into account the long half-life of the drug Arava when planning vaccination with live vaccine after the abolition of the drug Arava.

special instructions

Arava can be administered to patients only after careful medical examination.
Before you start treatment with Arava should be aware of a possible increase in the number of side effects in patients previously treated with other basic facilities for the treatment of rheumatoid arthritis, which have a hepato-and haematological effects.
The active metabolite of equipoise dosage, A771726, It characterized by a long half-life, usually from 1 st to 4 weeks.
Because of the long half-life of the active metabolite of equipoise dosage, A771726, even when stopping treatment with equipoise dosage may arise or persist serious adverse effects (eg, hepatotoxicity, gematoksichnost or allergic reactions, see . below). In this case, carry out the procedure “laundering” .Protseduru can be repeated as clinically indicated. For suspected severe immunological / allergic reactions such as the syndrome of Stevens -. Johnson and toxic epidermal necrolysis holding full procedure “laundering” necessarily
So when similar cases, toxicity, or the transition to receiving another reference drug (eg, methotrexate) after treatment with equipoise dosage is necessary to carry out the procedure ” money “(see. below).

Liver Reactions
Since the active metabolite of equipoise dosage, A771726, bound to proteins and excreted by hepatic metabolism and secretion of bile, it is assumed that the level of A771726 in plasma may be increased in patients with hypoproteinemia. The drug Arava is contraindicated in patients with severe hypoproteinaemia or impairment of liver function. (see. section “Contraindications”.).
It was reported about rare cases of severe liver injury, in some cases fatal, in the treatment with equipoise dosage.
Most of these cases were observed within the first six months of treatment. Although not established a causal relationship between these adverse events with equipoise dosage, and in most cases there are several other suspicious factors, the exact implementation of the recommendations on the treatment for control is considered necessary.
The level of ALT should be checked before starting treatment with equipoise dosage, and then every 2 weeks for the first 6 months treatment, followed by a test once every 6-8nedel.
The following recommendations for the correction of a regimen of dosage or discontinuation of the drug, depending on the severity and persistence increased ALT.
When confirmed by 2-3 fold excess of the upper limit of normal ALT dose reduction from 20 mg to 10 mg per day can afford to continue receiving equipoise dosage with careful monitoring of this indicator.
If a 2-3 fold excess of the upper limit of normal ALT persists, or if there is a confirmed rise in ALT levels above the upper limit of normal in more than 3 times, taking equipoise dosage should be discontinued and should begin the process of “laundering”.
due to the possible additional hepatotoxic effects, it is recommended to abstain from alcohol during treatment with equipoise dosage.

Hematologic Reactions
Full blood count, including the determination of leukocyte and platelet counts should be performed prior to initiating treatment with equipoise dosage and every 2 weeks during the first 6 months of treatment and then every 6-8 weeks.
In patients with previously took place anemia , leukopenia and / or thrombocytopenia and patients with impaired bone marrow function or at risk of developing such disorders increases the risk of hematological disorders. If you have this kind of phenomena should be used “laundering” the procedure for reducing the level of A771726 in plasma.
In the case of severe haematological reactions, including pancytopenia, you must stop taking Arava medication and any other concomitant medication that suppresses bone marrow blood, and begin the process of “laundering” .

The combined use with other treatments
Currently, There are no data regarding the joint use of equipoise dosage with antimalarials used in rheumatology (eg chloroquine and hydroxychloroquine), administered by intramuscular injection or oral preparations of gold, D-penicillamine, azathioprine and other immunosuppressive agents (with the exception of methotrexate). Not known risk associated with the appointment of combination therapy, particularly after prolonged treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (eg hepato- or gematotoksichnosti), the combination of this drug with other DMARDs (eg methotrexate) is not advisable.

Switching to other treatments
As equipoise dosage long stored in the body, the transition to receiving another reference drug (eg, methotrexate) without sootvetstvuyuschegoprovedeniya “laundering” the procedure may increase the possibility of additional risk, even long after the transition (for example, the kinetic interaction organotoksichnost).
Similarly, recent treatment of hepatotoxic or gematoksichnymi drugs (eg methotrexate) may result in an increase in the number of side effects, so starting equipoise dosage treatment, it is necessary to carefully consider all the positive and negative aspects associated with the intake of this drug.

Skin reactions
In case of ulcerative stomatitis should stop taking equipoise dosage.
It was reported about rare cases of Syndrome Stevens – Johnson and toxic epidermal necrolysis in patients treated with equipoise dosage. In case of skin reactions and / or reactions on the part of the mucous membranes need to stop taking the drug Arava and any other associated preparation and immediately begin the process of “laundering”. It is necessary to achieve complete excretion of the drug. In such cases, the re-appointment of the drug is contraindicated.

Infection
is known that drugs like equipoise dosage and having immunosuppressive properties, making patients more susceptible to various infections, including opportunistic infections (infections caused by fungi and microorganisms capable of causing infection only in reducing immune). Arisen infections occur, usually hard and require early and intensive treatment. In the event of severe infection may need to interrupt equipoise dosage treatment and begin the process of “laundering”.
It is necessary to carefully monitor patients with a positive reaction to the tuberculin due to the risk of reactivation of tuberculosis.

The reactions of the respiratory tract
In the treatment with equipoise dosage were marked by rare cases of interstitial pulmonary process. Symptoms such as cough and dyspnoea may cause discontinuation of equipoise dosage.

Blood pressure
before treatment with equipoise dosage and periodically after the start should be controlled blood pressure.

Interactions
should be careful in the appointment of drugs metabolized by the action of CYP2C9 (phenytoin, warfarin, tolbutamide), with the exception of NSAIDs (non-steroidal anti-inflammatory drugs).

Advice for men
There are no data on the risk of fetotoxicity (related to the toxic effects of the drug on the father’s sperm) when using equipoise dosage men. The experimental data in this area have been conducted. To minimize the potential risk men when planning a baby must stop taking the use of equipoise dosage and colestyramine 8 g 3 times a day for 11 days or 50 g of pulverized activated carbon 4 times a day for 11 days.

equipoise results

equipoise results is a potent, active when taken orally selective angiotensin II receptor antagonists (ATI type). It blocks all the physiologically relevant effects of angiotensin II of, realized through the ATI type receptors, regardless of the source or route of synthesis of angiotensin II. Specific antagonizing angiotensin receptor II (ATI) results in increased plasma concentrations of renin and angiotensin II and aldosterone plasma concentrations decrease. When using the recommended doses of the drug serum concentration of potassium ions does not change significantly. equipoise results does not inhibit kininase-II (angiotensin converting enzyme), by which the formation of angiotensin II and destruction of bradykinin to inactive metabolites. To detect the action of equipoise results is not required of its metabolic activation.

equipoise results lowers blood pressure (BP) with minimal change in heart rate. When taken at doses up to 300 mg once per day reduction in blood pressure is dose-dependent, however with higher doses of hypotensive effect equipoise results increase is insignificant.

The maximum reduction in blood pressure is achieved within 3-6 hours after ingestion of the drug and the antihypertensive effect persists for at least for 24 hours. At 24 hours after administration of the recommended doses of equipoise results blood pressure reduction is 60-70% compared to the maximum hypotensive response to the drug by the diastolic and systolic blood pressure. When taken once daily at a dose of 150-300 mg of lowering blood pressure value by the end of dosing interval (i.e., 24 hours after drug administration) in the position of a patient lying or sitting on average 8-13 / 5-8 mmHg .st. (Systolic / diastolic blood pressure) compared to that of placebo.

The drug at a dose of 150 mg once a day is the same hypotensive response (decrease in blood pressure before taking the next dose and mean blood pressure reduction over 24 hours) as the same dose divided into two stages.

The antihypertensive effect of Aprovel drug develops within 1-2 weeks, and the maximum therapeutic effect is achieved 4-6 weeks after the start of treatment. The antihypertensive effect on the background of long-term care is maintained. After cessation of treatment blood pressure gradually returns to the initial value. When you remove the drug withdrawal syndrome absent.

The effectiveness of the drug Aprovel does not depend on age and sex. Patients blacks less responsive to mototerapiyu Aprovelem (as well as all other drugs that affect the renin-angiotensin-aldosterone system).

equipoise results has no effect on uric acid in the serum or on the excretion of uric acid in urine.

Pharmacokinetics

After oral administration, equipoise results is well absorbed, its absolute bioavailability is approximately 60-80%. Simultaneous food intake does not significantly influence the bioavailability of equipoise results.

Communication to plasma proteins is approximately 96%. Binding to cellular components of blood is insignificant. The volume of distribution is 53-93 liters.

After oral or intravenous administration of 14 C-equipoise results 80-85% of circulating plasma radioactivity accounted for unmodified equipoise results. equipoise results is metabolized by the liver by oxidation and conjugation with glucuronic acid. Oxidation of equipoise results is carried out mainly through the cytochrome P450 CYP2C9, CYP3A4 isoenzyme participate in the metabolism of equipoise results is negligible. The major metabolite being in the systemic circulation is equipoise results glucuronide (approximately 6%).

equipoise results has linear pharmacokinetics and dose proportional in the dose range from 10 to 600 mg; at doses greater than 600 mg (dose, twice exceeding the maximum recommended dose) becomes nonlinear kinetics of equipoise results (decrease absorption). After oral administration the maximum plasma concentration achieved after 1.5-2 hours. Total clearance and renal clearance and 157-176 comprise 3-3.5 ml / min., Respectively. The final half-life of equipoise results is 11-15 hours. With daily single dose of the drug equilibrium plasma concentration (Css) is reached after 3 days. With a daily intake of equipoise results 1 time per day marked accumulation of its limited plasma (less than 20%). In women (compared to men) occur somewhat higher plasma concentrations of equipoise results. However, gender-related differences in half-life and accumulation of equipoise results is not detected. Correction doses of equipoise results in women is required. The values of AUC (area under the concentration-time concentration curve) and C max (maximum plasma concentration) of equipoise results in elderly patients (> 65 years) is slightly higher than that of younger patients, but the end half-lives they do not differ significantly. No dose adjustment in elderly patients is not required.

equipoise results and its metabolites are excreted as the bile and urine. After oral or intravenous administration of 14 C-20% equipoise results radioactivity detected in urine, and the rest – in the feces. Less than 2% of the administered dose is excreted in the urine as unchanged equipoise results.

Renal impairment: In patients with impaired renal function or patients kotorm hemodialysis, pharmacokinetics of equipoise results are not significantly altered. equipoise results is not removed from the body during hemodialysis.

Impaired Hepatic Function: In patients with cirrhosis of mild or medium severe course of the pharmacokinetic parameters of equipoise results are not significantly altered. Pharmacokinetic studies in patients with severe hepatic impairment have not been conducted.

Indications

– Essential hypertension

– Nephropathy with hypertension and type 2 diabetes (as part
of combination antihypertensive therapy).

Contraindications

– Hypersensitivity to any component of the drug.

– Pregnancy.

– Lactation.

– Age 18 years (effectiveness and safety have been established).

– Hereditary galactose intolerance, lactase deficiency or
malabsorption of glucose and galactose.

Use with caution in: stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy (GOKMP), dehydration, hyponatremia, diarrhea, vomiting, a diet with restriction of salt intake, diuretics, bilateral renal artery stenosis, unilateral stenosis of the artery only functioning kidney, chronic heart failure stage III-IV (classification NYHA), ischemic heart disease and / or atherosclerotic lesions of the brain vessels, hyperkalemia, renal failure, hemodialysis, a recent kidney transplantation (no clinical experience), severe hepatic insufficiency (lack of clinical experience) .

Pregnancy and lactation Pregnancy

Like any other drug that acts directly on the renin-angiotensin-aldosterone system, equipoise results can not be used during pregnancy (I, II, III trimesters).

Switching to the appropriate alternative therapy should be made before the start of pregnancy planning.

If pregnancy occurs during treatment with equipoise results, it should be abolished as soon as possible.

lactation

During lactation receiving equipoise results is contraindicated. It is not known whether equipoise results is excreted in breast milk.

Dosing and Administration

Inside, the tablet is swallowed whole with water.

Usually takes the original and maintenance dose is 150 mg 1 time per day regardless of the meal. Aprovel at a dose of 150 mg 1 once daily generally provides a better 24 hour blood pressure control than 75 mg. However, in some patients, especially in patients who are on hemodialysis or in patients over 75 years of age, shall receive an initial dose should be 75 mg (Aprovel is possible to use the drug in tablets of 75 mg).

Patients who have a therapeutic effect when receiving Aprovelya 150 mg 1 time per day is insufficient, Aprovelya dose may be increased to 300 mg, or can assign another antihypertensive agent. In particular it has been shown that administration of a diuretic such as hydrochlorothiazide, increases the effects of Aprovelya (see. “Interaction with other medicinal products”).

In patients with hypertension and type 2 diabetes, treatment should start with a dose of 150 mg! once a day, which should be gradually increased up to 300 mg – doses being preferred maintenance dose for the treatment of nephropathy.

Evidence of the beneficial effects of Aprovelya the kidneys in patients with hypertension and type 2 diabetes comes from studies in which it was used in combination with other antihypertensive drugs necessary to achieve target blood pressure levels.

Impaired renal function. In patients with impaired renal function correct dosing regimen is required. For patients on hemodialysis, initially accepted the dose should be 75 mg (Aprovel is possible to use the drug in tablets of 75 mg).

Violation of water and electrolyte balance. Before you start taking Aprovelya to restore blood volume and / or eliminate hyponatremia.

Abnormal liver function. Not required Aprovelya correction dosing regimen in patients with impaired hepatic function or mild to moderate severity. There is no clinical experience with the drug in patients with severe hepatic impairment.

Elderly patients. Although the recommended treatment for patients over the age of 75 years, starting with a dose of 75 mg (possible use of the drug Aprovel tablets of 75 mg), usually elderly patients correct dosing regimen is required.

Use in pediatric patients. Safety and efficacy of Aprovel in patients with the drug for children and youth has not been established.

Side effect

The following side effects are given in the following forward bringing gradations frequency ihvozniknoveniya :: very common (> 1/10), common (> 1/100, <1/10); sometimes (> 1/1000, <1/100); rare (> 1/10000, <1/1000); very rare (<1/10000), (including isolated reports).

Arterial hypertension

In placebo-controlled studies, the incidence of side effects while taking equipoise results was the same as in the placebo and not dependent on the dose (in the recommended dose range), gender, age, race, or duration of therapy.

In the placebo-controlled trials in patients with arterial gapertenziey where 1965 patients received equipoise results were observed following side reactions.

On the part of the central nervous system
Common: dizziness.

Cardio-vascular system
Sometimes: tachycardia.

Vascular disorders
Sometimes: flushing of the skin.

The respiratory system
sometimes coughing.

On the part of the gastrointestinal tract
Common: nausea / rvota.Inogda: diarrhea, indigestion / heartburn.

Reproductive system
Sometimes: sexual dysfunction.

General
Common: fatigue.

Sometimes:. Chest pain From the laboratory parameters

Often (1.7%): a significant increase in plasma creatine phosphokinase in patients receiving equipoise results; None of these increases are not accompanied by clinical manifestations on the part of the musculoskeletal system.

Hypertension and type 2 diabetes with renal disease

In addition to adverse reactions identified in patients with hypertension in patients with hypertension, type 2 diabetes with microalbuminuria without renal dysfunction while taking equipoise results orthostatic dizziness and orthostatic hypotension were observed in 0.5% of patients (compared to the frequency of occurrence of these adverse reactions placebo).

In patients with hypertension, type 2 diabetes with severe proteinuria and renal impairment following adverse reactions were observed at> 2% of patients (compared to the frequency of their occurrence in patients receiving placebo).

From the nervous system
Common: orthostatic dizziness.

Vascular disorders
Common: orthostatic hypotension.

On the part of the musculoskeletal system
often: pain in the muscles and bones.

From the laboratory parameters
Hyperkalemia when taking equipoise results patients with diabetes are more common than with placebo. Diabetic patients with high blood pressure and microalbuminuria with normal renal function, hyperkalemia (> 5.5% mmol / l) when taking 300 mg of equipoise results was observed in 29.4% of patients (often) in the placebo group – 22% of patients . Diabetic patients with high blood pressure, chronic renal failure and severe proteinuria, hyperkalemia (> 5.5% mmol / l) while taking equipoise results met in 46.3% of patients (often) in the placebo group – 26.3 % of patients. In patients with high blood pressure and diabetic nephropathy treated with equipoise results, from 1.7% of patients experienced a clinically insignificant decrease in hemoglobin concentration (often).

Furthermore, with the appearance on the market of equipoise results, the following adverse reactions were also identified:

On the part of the immune system

Rare: as with all receptor antagonists angiotensin II, marked

rare cases of allergic reactions such as rash, urticaria, angioedema.

On the part of metabolism and nutrition Very rare: hyperkalemia.

From the nervous system

Very rare: headache.

On the part of the organ of hearing and vestibular

Very rare: tinnitus.

From the gastrointestinal tract

Very rare: dysgeusia (taste perversion).

From the hepato-biliary system

Very rare: abnormal liver function, hepatitis.

On the part of the musculoskeletal system

Very rare: myalgia, arthralgia (sometimes in combination with an increase in creatine kinase levels), seizures.

On the part of the kidney and urinary system

Very rare: impaired renal function including isolated cases of renal failure in patients at risk (see section “Special instructions”).

Overdose

Experience with the drug in adult humans at doses up to 900 mg / day for 8 weeks did not reveal any toxicity. The most likely manifestations of overdose are pronounced reduction in blood pressure and tachycardia; manifestation of overdose may be bradycardia. No further specific information regarding the treatment of an overdose of the drug Aprovel. It is necessary to establish a permanent monitoring of the patient and symptomatic and supportive therapy if required. In case of overdose it is recommended to induce vomiting, and / or to gastric lavage. may be useful for reducing the activated carbon overdose. Hemodialysis is ineffective.

Interaction with other drugs

Diuretics and other antihypertensives. When equipoise results combination with other antihypertensive agents may increase the hypotensive action; equipoise results without any problem were used in combination with other antihypertensive drugs, such as beta-blockers, blockers “slow” long-acting calcium channel blockers and thiazide diuretics.

Antihypertensive effects of equipoise results and thiazide diuretics are additive in nature. Patients whose blood pressure can not be controlled with monotherapy equipoise results, hydrochlorothiazide purpose small doses (12.5 mg) leads to a further reduction (compared to placebo) in blood pressure 7-10 / 3-6 mm Hg. Art. (Systolic / diastolic blood pressure at the end mezhdozovogo period). When receiving equipoise results with small doses of hydrochlorothiazide (12.5 mg per day), the hypotensive effect of this combination in patients blacks closer to that of the patients of the European races. Previous treatment with diuretics in high doses can lead to dehydration and increase the risk of hypotension at the beginning of treatment with Aprovel.

Potassium supplements and potassium-sparing diuretics, heparin. On the basis of experience gained in the use of other drugs that affect the renin-angiotensin-aldosterone system, while the use of potassium preparations containing potassium electrolyte solutions, potassium-sparing diuretics or other can raise blood potassium levels preparations (heparin), may increase the level of potassium in serum.

Li. Reversible increasing concentrations of lithium in blood serum and its toxicity was observed while using lithium angiotensin-converting enzyme. To date, while taking equipoise results similar effects have been observed very rarely. If there is a need to use this combination, during the treatment should be carefully monitored the concentration of lithium in blood serum.

Nonsteroidal anti-inflammatory drugs (NSAIDs). With the simultaneous use of angiotensin II antagonists and NSAIDs (ie selective COX-2 inhibitors, acetylsalicylic acid (more than 3 g / day) and non-selective NSAIDs) may weaken the antihypertensive effect. As with the joint application of angiotensin-converting enzyme inhibitors and NSAIDs, when used together angiotensin II antagonists and NSAIDs may increase the risk of renal impairment, including the possibility of acute renal failure, and an increase in serum potassium, especially in patients with already impaired renal function . It should be used with caution in this combination, especially in elderly patients. Patients need to restore blood volume and throughout the combination therapy and periodically after the end monitor renal function.

Additional information on equipoise results interactions. When combined with equipoise results hydrochlorothiazide pharmacokinetics of equipoise results is not affected. equipoise results is mainly metabolised by CYP2C9 and to a lesser extent undergoes glucuronidation. There were no significant pharmacokinetic or pharmacodynamic interactions with the combination of equipoise results and warfarin, drugs metabolized via CYP2C9. Studies of the effect of inducers of CYP2C9 activity, such as rifampicin, the pharmacokinetics of equipoise results are not carried out, equipoise results does not change farmakrokinetiku digoxin.

special instructions

Violation of water and electrolyte balance. In patients with dehydration and / or hyponatremia (as a result of intensive diuretic therapy, diarrhea or vomiting, dieting limited reception salt, diuretics), as well as in patients on hemodialysis can develop clinically significant hypotension, especially after the receiving the first dose. Necessary to correct all violations of water-electrolyte balance before the beginning of application of the drug Aprovel.

Renovascular hypertension. Patients with bilateral renal artery stenosis or stenosis of the artery only functioning kidney, while taking drugs that affect the renin-angiotensin-aldosterone system are at high risk with regard to the development of severe arterial hypotension or renal failure. Although the documentary evidence of such effects while taking Aprovel no drug should still take into account the possibility of their occurrence using angiotensin II receptor blockers (ATI type) in these patients.

Renal impairment and kidney transplantation. In applying Aprovelya in patients with renal impairment is recommended periodic monitoring of potassium and creatinine serum. No clinical data on the use of Aprovelya in patients with recent kidney transplantation.

Patients with hypertension and type 2 diabetes with damage . Kidney marked in Aprovelya beneficial effect against progression of renal and cardiovascular lesions had varying degrees of severity in different groups of patients: less pronounced, it was women and persons not belonging to the European race.

Hyperkalemia. As with other agents that affect the renin-angiotensin-aldosterone system, treatment with Aprovelem may develop hyperkalemia, especially in the presence of renal insufficiency and / or heart disease. In these patients, it is recommended to monitor the level of potassium in the blood serum.

Stenosis of the aortic or mitral valve, hypertrophic obstructive cardiomyopathy. As with other vasodilators, when appointing Aprovelya patients with aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy must be careful.

Primary aldosteronizm. Patients with primary aldosteronism normally do not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore Aprovelya use in such cases not feasible.

Other. In the group of patients whose vascular tone and renal function in predominantly depend on the activity of the renin-angiotensin-aldosterone system (patients with chronic heart failure III and stage IV [on classification NYHA] or with underlying renal disease, including renal artery stenosis ), treatment with angiotensin-converting enzyme inhibitors was associated with hypotension, azotemia, oliguria and, in rare cases with acute renal failure. As with other antihypertensive drugs, a significant reduction in blood pressure in patients with ischemic heart disease and / or atherosclerosis of cerebral vessels can lead to myocardial infarction or stroke. Treatment of such patients should be under the strict control of blood pressure.

Effects on ability to drive vehicles

Aprovelya Effect on ability to drive and perform work requiring increased attention, have not been studied, but based on its pharmacodynamic properties, Aprovel should not affect this ability. In road management, please note that during the treatment of dizziness and increased fatigue.

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equipoise steroid

The pharmacodynamic properties of each of the active substances included in the formulation Aprovask ® , irbesartan and equipoise steroid, promote additive antihypertensive effect when used in combination as compared to those of the application of each of these drugs alone. As angiotensin II receptor antagonists (ARAII) and blockers “slow” calcium channels, reduce blood pressure (BP) by reducing peripheral vascular resistance, calcium entry blockade of the cell and a decrease due to the action of angiotensin II vasoconstrictor action are complementary mechanisms.

Irbesartan
Irbesartan is a selective, potent ARAII (subtype-AT1). Angiotensin II is an important component of the renin-angiotensin-aldosterone system (RAAS). involved in the pathophysiology of hypertension and sodium ion homeostasis. For irbesartan displays its action does not require metabolic activation.

Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective antagonism to angiotensin II (AT1 subtype-). cells are vascular smooth muscle and the adrenal cortex. Irbesartan has no agonistic activity with respect to the AT1-receptor. His affinity for the AT1 receptors in 8500 times greater than for the AT2 receptor (RECEP tori, who had not shown due to the maintenance of equilibrium [homeostasis] the cardiovascular system).

Irbesartan RAAS not inhibit enzymes (such as renin, angiotensin converting enzyme [ACE]), and no effect on other hormone receptors or ion channels in the cardiovascular system involved regulation of blood pressure homeostasis and sodium ions. Blockade of the AT1-receptor irbesartan breaks the feedback loop in the renin-angiotensin system, increasing plasma concentrations of renin and angiotensin II.In the application of irbesartan reduced plasma aldosterone concentration, but when using the drug in recommended doses no significant changes in the content of potassium in the blood serum (mean increase potassium in the blood serum is less than 0.1 mEq / L). Irbesartan has no significant effect on the concentration of triglycerides, cholesterol or glucose in the blood serum. Irbesartan does not affect na serum uric acid concentration and excretion of uric acid by the kidneys.

Antigipertsnzivny effect of irbesartan is observed after the first dose of the significant development of therapeutic action within 1-2 weeks of treatment with the maximum effect occurring by 4-6 weeks. The long-term observational studies of irbesartan effect was maintained over 1 year.

A single dose of irbesartan in doses up to 900 mg per day caused a dose-dependent blood pressure reduction. A single dose of irbesartan in doses of 150-300 mg per day resulted in a greater decrease in systolic (SBP) / diastolic (DBP) blood pressure (24 h after dosing) in the “lying” position or the “sitting” (an average of 8-13 / 5-8 mm Hg. Art.) than with placebo. The effect of the drug at 24 hours post-dose was 60-70% of the corresponding maximum lowering DBP and SBP. Optimal efficacy in reducing blood pressure during 24 h is achieved at a single dose of the drug per day.

AD is reduced to approximately the same extent in the “standing” and “lying down.” Orthostatic effects occur rarely, and as with the use of ACE inhibitors, its occurrence can be expected in patients is, hyponatremia or hypovolemia.

Antihypertensive effects of irbesartan and thiazide diuretics are additive. Patients who are unable to achieve the target values of blood pressure irbesartan monotherapy, the addition of irbesartan to receive 1 per day small doses of hydrochlorothiazide (12.5 mg) results in an additional (compared to placebo added effect) decrease SBP / DBP. determined at 24 hours after administration, 7-10 / 3-6 mm Hg. Art., respectively.

Age and sex do not affect the efficiency of irbesartan. As in the case of treatment with other drugs affecting RAAS. at Blacks patients have weaker antihypertensive effect when irbesartan monotherapy.When irbesartan is taken with low doses of hydrochlorothiazide (eg 12.5 mg daily), the antihypertensive effect in patients blacks closer to that of Caucasian patients.

After the abolition of irbesartan blood pressure gradually returns to its original level. Syndrome “cancel” when you stop receiving irbesartan were observed.

equipoise steroid
equipoise steroid is a blocker of the “slow” calcium channels from the group of digidropirndina that inhibits the transmembrane transport of calcium ions into myocardial cells and vascular smooth muscle. The mechanism of the antihypertensive action of equipoise steroid is connected with a direct relaxing effect on vascular smooth muscle.

The exact mechanism by which equipoise steroid decreases the frequency and severity of angina attacks are not fully established, but equipoise steroid reduces myocardial ischemia due to the following two effects.

1) equipoise steroid expands the peripheral arterioles and thus reduces the total peripheral vascular resistance (SVR), the so-called afterload. Since the heart rate at equipoise steroid practically does not increase, the decrease load on heart muscle reduces myocardial energy consumption and oxygen requirement.

2) The mechanism of action of equipoise steroid antianginal also apparently associated with the expansion of the main coronary arteries and arterioles in myocardium areas with normal blood flow and in ischemic areas of the myocardium. This expansion increases coronary oxygen delivery to the myocardium in patients with coronary artery spasm (Prinzmetal angina or variant angina).

In patients with hypertension receiving equipoise steroid once daily provides a clinically significant reduction in blood pressure in the position of “lying” and “standing” within 24 hours. Due to the slow onset of the action of equipoise steroid is not intended for relief of hypertensive crises.

In patients with angina, once during the day receiving equipoise steroid when performing tests with physical activity increases the total time of exercise, the time until an attack of angina and time to occurrence of ST-segment depression on electrocardiogram 1 mm. In addition, the drug reduces the number of angina attacks daily, and the daily requirement of receiving nitroglycerin tablets.

When equipoise steroid was not observed any undesirable metabolic effects or changes in blood lipid concentrations. equipoise steroid can be administered to patients with asthma, diabetes and gout.

The clinical evidence for the efficacy of irbesartan and equipoise steroid combination with fixed doses were obtained in two multicenter, prospective, open, parallel group study with blinded assessment of performance indicators: study I-ADD and I-COMBINE. Results of both studies showed significantly greater efficacy of fixed-dose combination of irbesartan and equipoise steroid compared to equipoise steroid monotherapy or irbesartan monotherapy.

Pharmacokinetics
Irbesartan
Irbesartan is a drug orally active, which does not require biotransformation to exhibit their activity. After oral administration, irbesartan is rapidly and completely absorbed. The maximum concentration (C | SH ) of irbesartan in plasma achieved through 1.5-2 h after ingestion. The absolute bioavailability of irbesartan ingestion of 60-80%. Admission write does not affect the bioavailability of irbesartan.

Irbesartan approximately 96% bound to plasma proteins, and practically does not bind to formed elements of blood. The volume of distribution of irbesartan is 53-93 l / kg.

After oral or intravenous administration of 14 C at a proportion unchanged irbesartan irbesartan plasma falls 80-85% of circulating radioactivity in the systemic circulation. Irbesartan is metabolized in the liver by conjugation with glucuronic acid and oxidation. The main metabolite, located in the systemic circulation is irbesartan glucuronide (approximately 6%). Irbesartan is oxidized mainly by the cytochrome P450 isoenzyme -CYP2C9; CYP3A4 isoenzyme plays a minor role in the metabolism of irbesartan. Irbesartan is not metabolized by most isozymes, usually involved in the metabolism of drugs such as isozymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP2E1, reliable and does not induce or inhibit these isoenzymes. Irbesartan does not induce or inhibit isoenzyme CYP3A4.

Irbesartan and its metabolites are excreted as by the liver (in bile) and kidneys. After oral or intravenous administration after 14 C irbesartan about 20% of the radioactivity found in the urine with a small residual amount in the feces. Less than 2% of the dose excreted by the kidneys as unchanged irbesartan.

The half-life (T1 / 2) of irbesartan is 11-15 hours. Total clearance after intravenous administration of irbesartan is 157-176 ml / min, of which 3.0-3.5 ml / min accounted for renal clearance.

Irbesartan when applied in therapeutic dose range has linear pharmacokinetics. The equilibrium concentration (the C ss ) is reached on the third day after the start of the drug 1 time per day. There is a limited accumulation of irbesartan in plasma (<20%) due to the exchange rate of the drug 1 time per day.

In women with hypertension compared with men with hypertension had higher (on 11-44%) plasma concentrations of irbesartan after a single dose, but in the background of course taking irbesartan in women and men were no differences in the accumulation of irbesartan or its T1 / 2. There were no sex-related differences in the clinical efficacy of irbesartan.

Elderly patients without arterial hypertension (men and women) (65-80 years) with clinically normal renal and hepatic function area under the curve “concentration-time» (AUC) and C ‘ m in plasma were approximately 20-50 % higher than in younger patients (18-40 years), but T 1/2 in young and elderly patients can be compared. There was no significant age-related, differences in the clinical efficacy of irbesartan

Patients blacks with normal blood pressure numbers AUC and T1 / 2 of irbesartan are approximately 20-25% higher than in Caucasian patients with normal blood pressure numbers. Stach irbesartan but they had almost the same,

In patients with renal impairment (regardless of its severity) and in patients on hemodialysis, the pharmacokinetics of irbesartan are not significantly altered. Irbesartan is not removed from the blood by hemodialysis.

In patients with hepatic insufficiency due to cirrhosis of mild or moderate severity pharmacokinetics of irbesartan are not significantly altered.

Research on the effectiveness and safety of irbesartan have not been conducted in children.

equipoise steroid
After ingestion of therapeutic doses of equipoise steroid is well absorbed with achievement C 1SHH blood between 6 and 12 hours after administration. The absolute bioavailability of 64-90%. Eating does not violate the absorption of equipoise steroid.

equipoise steroid volume of distribution is approximately 21 l / kg. In in vitro studies have shown that approximately 97.5% being in the systemic circulation equipoise steroid binds to plasma proteins.

equipoise steroid is extensively metabolized in the liver to inactive metabolites. After the kidney is derived 10% of unchanged equipoise steroid and 60% of its metabolites; T1 / 2 of approximately 35 hours at -50 dosing one time per day.

In the elderly and young age the time to reach C PN equipoise steroid in the blood is the same. Elderly patients equipoise steroid clearance tends to decrease, resulting in increased AUC and T1 / 2.

In children 6-12 years and adolescents 13-17 years of equipoise steroid clearance while taking the drug inside was 22.5 and 27.4 l / hr, respectively, in boys and 16.4 and 21.3 l / h. respectively, in girls. There was a large variability in systemic exposure of equipoise steroid in different children and adolescents. Data obtained on the use of the drug in children under 6 years are limited.

Like other blockers “slow” calcium channels. in hepatic impairment may increase the T1 / 2 of equipoise steroid (see section “Precautions” and “Cautions”).

In patients with chronic heart failure (in all age groups) was observed increase in AUC N T1 / 2.

Pharmacokinetics with the combination of irbesartan / equipoise steroid adult
Simultaneous reception of irbesartan and equipoise steroid in the tablets of fixed combinations or in the form of free combinations had no effect on the pharmacokinetics of each of the active ingredients of the combination.

Three fixed combination dose of irbesartan and equipoise steroid (150 mg / 10 mg. 300 mg / 5 mg and 300 mg / 10 mg) are bioequivalent to the free combination dose (150 mg / 10 mg, 300 mg / 5 mg and 300 mg / 10 mg) both in terms of speed and in the degree of absorption.

When taken separately or simultaneously in doses of 300 mg and 10 mg median time to reach C nux irbesartan and equipoise steroid plasma remains unchanged, that is, 0.75-1 h and 5 h after administration, respectively. Similarly, C || pa x and irbesartan and equipoise steroid AUC when receiving individually or simultaneously in doses of 300 mg and 10 mg are in the same range, resulting in simultaneous intake relative bioavailability is 95% irbesartan, equipoise steroid and – 98%.

The average value of T1 / 2 for irbesartan and equipoise steroid taken alone or in combination. It is almost the same: 17.6 hours versus 17.7 hours for irbesartan and 58.5 hours versus 52.1 hours for equipoise steroid.Irbesartan and equipoise steroid excretion is unchanged when administered alone or in combination.

Pharmacokinetics irbesartan and equipoise steroid was linear in the combined use of irbesartan in doses from 150 mg to 300 mg, and equipoise steroid doses ranging from 5 mg to 10 mg.

Pharmacokinetics with the combination of irbesartan / equipoise steroid in children
No further information on the application of the fixed combination of irbesartan and equipoise steroid in children.

Indications for use:

Arterial hypertension (monotherapy after failure of irbesartan or equipoise steroid).

Contraindications:

 

  • Hypersensitivity to irbesartan, equipoise steroid and other dihydropyridine derivatives and to the preparation auxiliary substances,
  • Cardiogenic shock.
  • Clinically significant aortic stenosis.
  • Unstable angina (except Prinzmetal’s angina).
  • Pregnancy.
  • The period of breastfeeding.
  • Age 18 years (effectiveness and safety have been established).
  • The simultaneous use of medicines containing aliskiren in patients with diabetes or with moderate to severe renal insufficiency (glomerular filtration rate [GFR] <60 ml / min / 1.73 m “body surface area) (see. Forums” Interaction with other drugs means “and” Cautions “).
  • The simultaneous use of angiotensin-converting enzyme (ACE) in patients with diabetic nephropathy (see section “Interaction with other medicinal products” and “Cautions”).

 

Carefully

 

  • In patients with hypovolemia and hyponatremia, arising, for example, intensive treatment with diuretics, dialysis, a diet with restriction of salt intake, diarrhea, vomiting (risk of excessive blood pressure lowering, see. “Special Instructions” section)
  • In patients whose renal function is dependent on the activity of the RAAS (such as patients with hypertension with renal artery stenosis of one or both kidneys, patients with chronic III-1V functional class of heart failure [on NYHA classification]), treatment drugs affecting RAAS, was associated with the development of oliguria and / or progressive azotemia and rarely – acute renal failure and / or death, the risk of which can not be excluded when taking APAII, including irbesartan) (see “Special instructions” section)..
  • Patients with chronic heart failure II-IV functional class classification NYHA nonischemic etiology (because of the content in the composition of the equipoise steroid drug, the use of which in these patients was associated with an increase in reports of the development of pulmonary edema as compared with placebo, despite the lack of differences in rate of progression of heart failure) (see. “Special instructions” section).
  • In patients with hepatic insufficiency (risk of increased t1 / 2 equipoise steroid – see “Special Instructions” section.).
  • In patients with kidney failure after kidney transplantation, and (because of irbesartan content in the preparation is recommended to control potassium, and creatinine concentration in blood); after a recent kidney transplantation (lack of clinical experience irbesartan).
  • In patients with stenosis of the aortic and mitral valves or hypertrophic obstructive cardiomyopathy (GOKMP).
  • In patients with coronary heart disease and / or clinically significant atherosclerosis of brain vessels (with excessive decrease in blood pressure is a risk of ischemic disorders gain, until the development of acute myocardial infarction and stroke).
  • In patients with sick sinus syndrome (due to content in the drug equipoise steroid).

 

Use during pregnancy and during breastfeeding

Pregnancy
When receiving irbesartan at doses ≥ 50 mg / kg body weight / day (which in terms of kg of body weight is approximately equivalent to a maximum recommended dose of irbesartan in humans [MRDICH] of 300 mg / day) of pregnant rats with 0 to day 20 of gestation in rat fetuses were observed transient effects (minor or moderate expansion of the renal pelvis, hydroureter and / or absence of renal papillae).When receiving irbesartan at doses ≥ 180 mg / kg body weight / day (equivalent to about 4 * MRDICH when converted per kg of body weight) 0 pregnant rats on day 20 of gestation in the development of rat fetuses subcutaneous edema was observed. Gak of these abnormalities were not observed in the reception restriction irbesartan inwards in doses of 50, 150 and 450 mg / kg body weight / day pregnant rats from 6 to day 15 of gestation, they apparently are late gestational effects irbesartan. In rabbits, the use of irbesartan in a dose of 30 mg / kg body weight / day was associated with maternal mortality and abortions. Surviving females who received this dose, equivalent to 1.5 * MRDICH when converted per kg body weight had slight increase of resorption of fetuses and thus reducing the number of live fetuses in the litter. It was found that irbesartan crosses the placental barrier in rats and rabbits. In rats and rabbits did not reveal teratogenicity equipoise steroid.

Lack of sufficient volume and well-controlled studies of the drug Aprovask ® in pregnant women. The impact on the fetus of ACE inhibitors, which are taken by pregnant women during the second and third trimesters of pregnancy, leading to damage and death of the developing fetus. Like any other drugs that act directly on the RAAS, drug Aprovask ® is contraindicated during pregnancy. Preparation Aprovask® should not be used in women with childbearing potential unless they use effective contraception methods. In case of pregnancy during treatment with Aprovask ® , should be how to stop taking it as soon as possible (see. “Contraindications”),

Breastfeeding Period
drug Aprovask ® is contraindicated during breast-feeding period (see. “Contraindications”).

Dosing and Administration

Adult
drug is intended for oral administration. The tablet is swallowed with water. Preparation Aprovask ® may be taken simultaneously with food intake and fasting (i.e., regardless of the meal time).

Typically, the initial and maintenance dose of the drug Aprovask ® – 1 tablet per day.

The drug Aprovask ® should be used in patients who can not achieve the target values of blood pressure as monotherapy with irbesartan or equipoise steroid alone, or to continue the treatment of patients already taking irbesartan and equipoise steroid as separate tablets. Doses must be individualized, first with individual drugs irbesartan and equipoise steroid. Doses are selected depending on the response to treatment of blood pressure and blood pressure target value. The maximum recommended dose of the drug Aprovask ® is 150 mg / 10 mg, or 300 mg / 10 mg per day (due to the fact that the maximum daily dose is 10 mg equipoise steroid).

Children
The safety and efficacy of the drug Aprovask ® have not been established.

Elderly patients and patients with impaired renal function
is not normally necessary to reduce the dose in elderly patients (see. “Pharmacodynamics” section) and in patients with impaired renal function.

Patients with impaired liver function
The drug Aprovask ® should be used with caution, due to the presence of the drug equipoise steroid (see. Forums “Precautions” and “Cautions”).

Side effect

The frequency of adverse events / reactions (AE / HP) reported in clinical studies for the use of a combination of fixed-dose irbesartan and equipoise steroid (Clinical Studies I-ADD, I-COMBINE and I-IWF), in clinical trials on the use of irbesartan and his post-marketing use, as well as in clinical studies on the use of equipoise steroid, was determined according to the classification (WHO), the World Organization as follows: very common ≥ 10%; often ≥ 1% and <10%; uncommon ≥ 0.1% and <1%; rarely ≥ 0.01% and <0.1%; very rare <0.01%. the frequency is unknown – according to available data it is impossible to estimate the frequency of occurrence of AEs / TS.

HP incidence reported during postmarketing use of the drug, defined as “frequency not known” because the information on these HP came from spontaneous reports, without specifying the number of patients. taking the drug.

In clinical studies, but compared combinations of fixed-dose irbesartan / equipoise steroid monotherapy with irbesartan or equipoise steroid types and frequency occurring during the treatment of adverse events possibly related to study treatment were similar to those observed in previous clinical trials or post-marketing reports in monotherapy, irbesartan and equipoise steroid. The most frequent adverse events were peripheral edema, mainly related to equipoise steroid.

Adverse events observed during treatment, and possibly related to study drug in a clinical trial of irbesartan / equipoise steroid (I-ADD, I-SOMBINE and I-COMBO)
A fixed combination of irbesartan / equipoise steroid

General disorders and administration site in
Common: peripheral edema, edema.
Uncommon: asthenia.

Violations of the organ of hearing and labyrinth disorders
Uncommon: vertigo.

Violations of the heart
often: palpitations.
Uncommon: sinus bradycardia.

Disorders of the nervous system
Common: dizziness, headache, somnolence.
Uncommon: paresthesia.

Violations of the genital organs and breast
Uncommon: erectile dysfunction.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders
Uncommon: cough.

Violations by vessels
Common: orthostatic hypotension.
Uncommon: excessive blood pressure reduction.

Disorders of the gastrointestinal tract
Common: swelling of the gums.
Uncommon: nausea, pain in the upper abdomen, constipation.

Violations of the kidney and urinary tract
Common: proteinuria.
Uncommon: azotemia, hypercreatininemia.

Violations of the Metabolic and nutritional
Uncommon: hyperkalemia.

Violations of the musculoskeletal and coedinitelnoy tissue
Uncommon: “stiffness” of the joints, arthralgia, myalgia.

Adverse events observed with the use of irbesartan in clinical studies (including clinical trials I-ADD, I-COMBINE and I-COMBO) and with his post-marketing application

Violations by the immune system
Frequency unknown: hypersensitivity reactions (allergic reactions).

Violations of the metabolism and power
frequency is unknown: hyperkalemia.

Violations of the organ of hearing and labyrinth disorders
Common:. Vertigo
unknown frequency: tinnitus.

Disorders of the nervous system
Common: dizziness, headache *.
Uncommon: orthostatic dizziness.

* Incidence of headache in studies I-ADD, and a COMBINE I-I-IWF was evaluated as “rare”.

Violations of the heart
Uncommon: Tachycardia.

Disorders of the skin and subcutaneous tissue disorders
Frequency not known: leukocytoclastic vasculitis.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders
Uncommon: cough.

Disorders of the gastrointestinal tract
Common: nausea / vomiting, pain in the upper abdomen, disorders of the language glossodiniya (burning sensation and pain in the language).
The frequency is not known: dysgeusia (taste perversion).
Uncommon: diarrhea, dyspepsia, heartburn .

Disorders of the liver and biliary tract
Frequency not known: jaundice, increasing functional “liver” trial, hepatitis.

Disorders of the skin and subcutaneous tissue disorders
Uncommon:. Alopecia
is unknown frequency: angioedema, urticaria.

Violations of the musculoskeletal system and connective tissue disorders
Frequency not known: myalgia.

Violations of the kidney and urinary tract
Frequency not known: impaired renal function including isolated cases of renal failure in patients with risk factors for its development.

Violations of the genital organs and breast
Uncommon: erectile dysfunction.

General disorders and administration site in
Common: fatigue *, edema.
Uncommon:. Chest pain
frequency is unknown: asthenia.

* – The incidence of fatigue in studies I-ADD, I-COMBINE and I-COMBO has been evaluated as “rare”.

Injury, poisoning and complications manipulation
Uncommon: fall.

Adverse events observed with the use of equipoise steroid in clinical trials (including the clinical studies I-ADD, I-COMBINE and I-COMBO)

Violations of the blood and lymphatic system
Very rare: thrombocytopenia.

Violations by the immune system
Very rare: allergic reactions.

Violations of the metabolism and nutrition
Very rare: hyperglycaemia.

Mental disorders
Uncommon: insomnia, mood lability.

Disorders of the nervous system
Common: dizziness, headache * drowsiness.
Uncommon: hypoesthesia, paraesthesia, tremor, taste perversion, syncope.
Very rare: peripheral neuropathy.

* – The incidence of headache in studies I-ADD, I-COMBINE I-IWF and was evaluated as “rare”.

Violations of the organ of vision
Uncommon: visual disturbances.

Violations of the organ of hearing and labyrinth disorders.
Uncommon: tinnitus, vertigo.

Violations of the heart
often:. Palpitations
Very rare: Myocardial infarction, cardiac arrhythmias, ventricular tachycardia and atrial fibrillation (atrial fibrillation).

Violations of the vessels
often, “tides” of blood to the skin with a feeling of heat, redness of the skin *.
Uncommon: excessive lowering of blood pressure.
Very rare: vasculitis.

* – The incidence of redness of the skin in the I-the ADD research, I-COMBINE and I-IWF has been appraised as “rare”.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders
Common: Cough.
Uncommon: dyspnea, rhinitis.
Very rare: cough.

Disorders of the digestive system
often: nausea, abdominal pain, glossodiniya, glossitis.
Infrequently; dyspepsia, vomiting, changes in the rhythm of defecation, dry oral mucous membranes.
Very rare: pancreatitis, gastritis, gingival hyperplasia.

Disorders of the liver and biliary tract
Very rare: hepatitis, jaundice, and increased activity of “liver” enzymes (primarily associated with cholestasis).

Disorders of the skin and subcutaneous tissue
Common: contact dermatitis.
Uncommon: skin rash, pruritus, purpura, sweating, change in skin pigmentation (the appearance of discoloration of the skin), alopecia.
Very rare: angioneurotic edema, erythema multiforme, urticaria.

Violations of the musculoskeletal and connective tissue disorders
Uncommon: arthralgia, muscle cramps, myalgia, back pain.

Violations of the kidney and urinary tract
Uncommon: increased frequency of urination, tenesmus, nocturia.

Violations of the genital organs and breast
Uncommon: impotence, gynecomastia.

General disorders and administration site in
Common: fatigue, edema *, peripheral edema.
Uncommon:. Chest pain, asthenia, malaise, pain
Rare: swelling of the face.

* – According to research l-ADD, I-COMBINE and I-COMBO incidence of edema, “infrequently.”

Laboratory and instrumental data
Uncommon: weight gain, weight loss.

Overdose

Symptoms
When receiving irbesartan adults in doses up to 900 mg per day in the absence of toxicity found.

Evidence for equipoise steroid suggest that a strong overdose may lead to severe peripheral vasodilatation and possibly to the development of reflex tachycardia. Reported on the development of the severity and duration of excessive blood pressure lowering, until the development of a fatal shock.

Treatment
The patient should be under close medical supervision. Treatment should be symptomatic and supporting basic vital functions of the body.

No specific information on the treatment of irbesartan overdose.

The proposed measures with an overdose of the drug Aprovask ® include gastric lavage. Acceptance of activated charcoal to healthy volunteers immediately after or 2 hours after ingestion of 10 mg of equipoise steroid showed a slight decrease equipoise steroid absorption.

Due to the fact that equipoise steroid is highly contact with blood proteins and irbesartan not excreted by hemodialysis, it is unlikely that an overdose can be useful for hemodialysis.

If there was a very large overdose, should begin active monitoring of cardiac activity and respiration. It should be part of the measurement of blood pressure. No clinically significant reductions in blood pressure due to equipoise steroid overdose calls for active maintenance of cardiovascular activities, including giving the sublime position of the limbs. It is necessary to monitor the volume of circulating blood and urine output. It may require the introduction of vasoconstrictor drugs to restore vascular tone and blood pressure (in the absence of contraindications to their introduction). Intravenous calcium gluconate may be beneficial in eliminating the effects of calcium channel blockade.

Interaction with other drugs

The combination of irbesartan and equipoise steroid
Based on pharmacokinetic studies in which the irbesartan and equipoise steroid taken separately or in combination, no pharmacokinetic interaction between the irbesartan and equipoise steroid.

There has been no research on drug interactions drug Aprovask ® with other drugs.

Irbesartan
Based on in vitro studies of data should not expect any occurrence of interactions with drugs whose metabolism is carried out through the following cytochrome P450 isoenzymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6 , CYP2D6, CYP2E1 , or CYP3A4.

Irbesartan is metabolised predominantly by means of CYP2C9 isoenzymes, but during the clinical studies on the interaction when irbesartan was taken simultaneously with warfarin, which is metabolized via isoenzyme CYP2C9. no significant pharmacokinetic interactions were observed.

The pharmacokinetic performance of irbesartan are not violated when it is applied simultaneously with nifedipine and hydrochlorothiazide.

Irbesartan does not alter the pharmacokinetics of simvastatin, which is metabolized via isoenzyme CYP3A4, or digoxin (P-glycoprotein substrate).

Combination drug Aprovask with medications containing aliskiren, is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR less than 60 mL / min / 1.73 m 2 of body surface area) and is not recommended in other patients. ACE inhibitors: The use of the drug Aprovask ® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended for other patients.

Based on the experience gained from the use of other drugs that affect the RAAS pas, the simultaneous use of irbesartan with potassium drugs: salt substitutes containing potassium; potassium-sparing diuretics or other, capable of promoting blood drug content of potassium in the plasma (heparin), sometimes can significantly increase the serum potassium level that requires careful monitoring of blood parameters in patients potassium plasma during treatment.

Elderly patients, patients with hypovolemia (due diuretics) or with impaired renal function, the simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors tsikloooksigenazy-2 (COX-2) together with ARAII including irbesartan, can lead to deterioration of the function kidneys, including the development of acute renal failure. These effects are usually reversible.Periodically monitor renal function in patients taking concomitant APAII and NSAIDs, including selective COX-2 inhibitors.

Li: on the background of the joint use of irbesartan with lithium therapy has been described an increase in plasma lithium concentrations and toxic effects of lithium. In patients taking irbesartan together with lithium preparations should monitor the concentration of lithium in blood plasma.

equipoise steroid
equipoise steroid safely combined with thiazide diuretics, beta-blockers, alpha-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin sublingual, NSAIDs, antibiotics and hypoglycemic agents for oral administration.

These in vitro studies with human blood plasma show that equipoise steroid does not affect digoxin binding protein. phenytoin, warfarin or indomethacin.

Cimetidine: concomitant use of equipoise steroid and cimetidine did not violate the pharmacokinetics of equipoise steroid.

Grapefruit Juice: simultaneous reception of 240 mg of grapefruit juice with a single dose of 10 mg equipoise steroid in 20 healthy volunteers had no significant effect on the pharmacokinetics of equipoise steroid.

Sildenafil: When equipoise steroid and concomitant use of sildenafil drugs each independently showed antihypertensive activity.

Atorvastatin: ESP simultaneous reception of equipoise steroid 10 mg atorvastatin and 80 mg resulted in misleading change pharmacokinetic parameters Atorvastatin achieve able C ss .

Digoxin: simultaneous reception of equipoise steroid with digoxin did not change the concentration in serum digoxin or digoxin renal clearance in normal volunteers.

Warfarin: concomitant use of equipoise steroid and prothrombin time did not change while taking warfarin.

Cyclosporine: Cyclosporine pharmacokinetic studies have demonstrated that equipoise steroid had no significant effect on the pharmacokinetics of cyclosporin.

Tacrolimus: In an application of tacrolimus and equipoise steroid may increase tacrolimus concentration in blood plasma. It is necessary to control the concentration of tacrolimus in the blood plasma, and carry out correction of the dose if necessary.

Simvastatin: the simultaneous use of equipoise steroid with simvastatin may increase the exposure of simvastatin compared with simvastatin monotherapy. With simultaneous use of simvastatin and equipoise steroid is necessary to limit the daily dose of simvastatin to 20 mg.

special instructions

Excessive decrease in blood pressure; patients with hypovolemia and hyponatremia
Irbesartan rarely cause an excessive fall in blood pressure in hypertensive patients without other comorbidities. As well as taking ACE inhibitors, may be expected to excessive reduction of blood pressure with the corresponding symptoms in patients with hypovolemia and hyponatremia, which include patients undergoing intensive diuretic therapy, and / or patients with limited consumption of salt or patients undergoing hemodialysis. Hyponatremia and hypovolemia should be corrected before treatment with Aprovask ® or should consider the use of lower initial doses.

Patients with chronic heart failure
in the long-term, placebo-controlled study (PRAISE-2) of equipoise steroid in patients with chronic heart failure III-IV functional class (classification NYHA) non-ischemic aetiology, equipoise steroid was associated with an increase in reports of pulmonary edema despite no significant difference in the rate of progression of heart failure as compared to placebo.

Hepatic insufficiency
As when taking other blockers “slow” calcium channels. T1 / 2 of equipoise steroid is increased in patients with impaired hepatic function and its recommendations on dosing regime with abnormal liver function have not been established. Therefore Aprovask drug ® should be used with caution in these patients.

Hypertensive crisis
The safety and efficacy of the drug Aprovask ® have not been established for hypertensive crisis.

Effects on renal function
Due RAAS inhibition can be expected changes in renal function in patients predisposed. Patients who (kidney function is dependent on the activity of the RAAS (patients with hypertension with renal artery stenosis of one or both kidneys or patients with chronic heart failure III-IV functional class (in NYHA classification), treatment with other drugs that affect the RAAS , associated with the development of oliguria and / or progressive azotemia and rarely with acute renal failure and / or death. We can not exclude the possibility of such an effect in the application ARAII, including irbesartan.

Use in elderly patients,
patients who received irbesartan in clinical studies, there were no any differences in efficacy or safety of irbesartan in patients older age (65 years and older) compared with the patient Tami younger.

Pediatric Use
Safety and effectiveness in children is not currently installed.

Dual blockade of the RAAS by combining the drug Aprovask ® with medicines containing aliskiren, and angiotensin-converting enzyme.
Dual blockade of the RAAS with the combination Aprovask drug ® with ACE inhibitors or aliskiren ne recommended, as there is an increased risk of a sharp decline in blood pressure, giierkaliemii and renal dysfunction.

In patients with diabetes mellitus or moderate to severe renal insufficiency (with

GFR <60 mL / min / 1.73 m 2 of body surface) use of the drug Aprovask ® in combination with aliskiren is contraindicated. Patients with diabetic nephropathy is contraindicated use of the drug Aprovask ® in combination with an ACE inhibitor.

Effects on ability to drive or engage in other potentially hazardous activities
Effect of drug Aprovask ® on the ability to drive or engage in other potentially hazardous activities that require attention, has not been studied. However, based on its pharmacodynamic properties, the influence of the drug Aprovask ® on this ability is unlikely. But, in case of dizziness, vertigo, weakness, driving vehicles, or engage in other potentially hazardous activities is not recommended. anazole