trenbolone side effects

AZAFEN®

 

International nonproprietary name:

pipofezine Chemical rational name : 2- (4-methyl-1-piperazinyl) -10-methyl-3,4-diazafenoksazina dihydrochloride.
 

Dosage Form:

pills

 

Composition:

active ingredient – pipofezine 25 mg.

 

Excipients – potato starch, Aerosil (colloidal silicon dioxide), microcrystalline cellulose, milk sugar (lactose), a low molecular weight polyvinyl Medical (povidone), magnesium stearate. Description: pills Valium with Valium, yellowish-greenish color. Presence of marbling.

Farmakoterapevticheekan group – an antidepressant. ATX code: N06AX

Pharmacological properties.

Tricyclic antidepressant group indiscriminate inhibitors of neuronal uptake of monoamines, timoanalepticheskoe and has a sedative effect.
The mechanism of antidepressant action is associated with non-selective trenbolone side effects inhibition of reverse neuronal serotonin and norepinephrine, which increases their concentration in the CNS. Virtually no M holinoblokiruyushey activity and does not affect the activity of monoamine oxidase (MAO).
It has no cardiotoxicity.

Pharmacokinetics

Rapidly and completely absorbed from the gastrointestinal tract. Bioavailability – about 80%, time to maximum concentration – 2 hours Connection with the plasma protein -. 90%.
It is metabolized in the liver to inactive metabolites. The half -. 16 hours is derived from the body mainly by the kidneys.

testimony

Depressive disorders of mild to moderate severity (including depression with chronic physical diseases).

Contraindications

Hypersensitivity, severe degree of liver and / or kidney failure, pregnancy, lactation period, simultaneous reception of MAO inhibitors. Precautions: chronic heart failure, myocardial infarction, ischemic heart disease, post stroke, infectious diseases, diabetes, childhood.

Dosing and Administration

Inside. The initial dose for adults – 25-50 mg in 2 divided doses trenbolone side effects (morning and afternoon). With good tolerance dose gradually increased to 150-200 mg / day (3-4 hours, final reception at bedtime), and in some cases – to 400 mg / day. The optimal daily dose – 0.15-0.2, the maximum – 0.4-0.5 g When you reach the desired effect switch to maintenance dose: 25-75 mg / day. Treatments – up to 1 year (at least 1-1.5 months).

Side effect

Headache, dizziness, nausea, vomiting, allergic reactions. Overdose drug

Increased side effects. Treatment is symptomatic.

Interaction with other drugs
Enhances the effects of anticoagulants, ethanol, antihistamines and other drugs CNS depressants. Reduces the effectiveness of anti-epileptic drugs.

special instructions

During the administration of the drug is not recommended to perform work trenbolone side effects that requires quick response and related risk AZAFEN® patients, for example, drive and perform other potentially dangerous activities. During treatment prohibited alcohol intake.

release Form

Tablets of 25 mg.

10 tablets in blisters of PVC foil and aluminum foil.
At 100, 200, 250 and 300 tablets in plastic jars.
Each jar or 3,4,5 contour cell package together with instructions for use in a pile of cardboard.

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hexahydrobenzylcarbonate

Azaran

International Non-Proprietary Name (INN): hexahydrobenzylcarbonate

 

Dosage Form:

powder for solution for intravenous and intramuscular administration.

Composition
The vial contains 1 – hexahydrobenzylcarbonate sodium (calculated as hexahydrobenzylcarbonate 1000 mg).

Description
Powder from white to white with a yellowish tinge.

 

Pharmacotherapeutic group:

cephalosporin antibiotic.

ATX code: J01DD04

Pharmacological properties Pharmacodynamics Azaran – cephalosporin antibiotic III generation broad-spectrum parenteral administration. It has bactericidal activity by inhibiting bacterial cell wall synthesis. Acetylated membrane-bound transpeptidase, violating thus crosslinks peptidoglycans necessary to provide strength and rigidity of the cell wall. It is resistant to beta-lactamases produced by most gram-positive and gram-negative bacteria. It is active against gram-positive aerobes – Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, Streptococcus bovis; gram-negative aerobic – Acinetobacter lwoffii, Acinetobacter anitratus, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, Citrobacter spp, Enterobacter spp.. (some resistant strains), Escherichia coli, Haemophilus ducreyi, Haemophilus influenzae ( including strains forming penicillinase), Haemophilus parainfluenzae, Klebssiella spp. (including Klebssiella pneumoniae), Moraxella spp., Morganella morganii, Neisseria gonorrhoeae ( including strains forming penicillinase), Neisseria meningitidis, Plesiomonas shigelloides, Proteus mirabilis, Proteus vulgaris, Providencia spp., Salmonella spp. (including Salmonella typhi), Serratia spp. (including Serratia marcescens), Shigella spp., Vibrio spp. (including Vibrio cholerae), Yersinia spp.(including Yersinia enterocolitica), Pseudomonas aeruginosa; anaerobic – Bacteroides spp. (including some strains of Bacteroides fragilis), Clostridium spp.(except Clostridium difficile), Fusobacterium spp. (except Fusobacterium mortiferum and Fusobacterium varium), Peptococcus spp., Peptostreptococcus spp. to hexahydrobenzylcarbonate resistant strains of Staphylococcus spp., methicillin-resistant strains of Enterococcus spp. (Enterococcus faecalis), Clostridium difficile, many strains of Bacteroides spp., Producing beta-lactamase. Pharmacokinetics After intramuscular (i / m) administration is rapidly and completely absorbed. Bioavailability – 100%. It penetrates the tissues and body fluids: in the respiratory tract, bones, joints, urinary tract, skin, subcutaneous tissue and organs of the abdominal cavity.Stable blood concentration of the drug is achieved within 4 days. The maximum concentration (C max ) after the / m occurs within 2-3 hours after intravenous (i / v) Introduction – at the end of infusion. C max after the / m 0.5 g, 1 g – 38 ug / ml, 76 ug / ml, respectively. The on / in 500 mg, 1 g, 2 g – 82 pg / ml, 151 pg / ml, 257 pg / ml, respectively. In adults over 2-24 hours after administration of 50 mg / kg concentration in the cerebrospinal fluid (CSF) is many times greater than the minimum inhibitory concentration for most rasprostranennyhvozbuditeley miningita. Well into the CSF during meningeal inflammation of the membranes.Reversibly bound to plasma albumin (83-95%). The drug passes through the placenta in small amounts. The half-life (T 1/2 ) is 6-9 hours, allowing to use the drug once daily. T 1/2 after / in a dose of 50-75 mg / kg in children with meningitis – 4.3-4.6 hours; in patients on hemodialysis (creatinine clearance QC – 0-5 ml / min) – 14.7 h, QC -. 5-15 ml / min – 15.7 h, QC – 16-30 ml / min – 11.4 h, QC – 31-60 ml / min – volume of distribution 12.4 h -. 0.12-0.14 l / kg (5.78-13.5 l) in children 0.3 l / kg, the plasma clearance -. 0.58-1.45 l / h, kidney – 0.32-0.73 l / h. T 1/2 is significantly lengthened in people over 75 years of age, infants and patients with impaired renal and hepatic function. Displayed in the kidney for 48 hours 50-60% unchanged in bile and – 40-50% in the intestine, where the transformation into an inactive metabolite. In newborn infants, is excreted through the kidneys approximately 70% of the drug. Hemodialysis is not effective.

Indications
Infectious-inflammatory diseases caused by susceptible to malaria infections: infections of the upper and lower respiratory tract (including pneumonia, lung abscess, empyema); Skin and soft tissue infections; infections of bones and joints; Urinary tract infections (including pyelonephritis); abdominal infections (peritonitis, gastrointestinal tract infections (shigellosis, salmonellosis), biliary tract, including cholangitis, gallbladder empyema); infectious inflammatory diseases of the pelvic organs; prevention and treatment of infections in surgical interventions; bacterial meningitis and endocarditis; sepsis; acute uncomplicated gonorrhea; Lyme disease.

Contraindications
: Hypersensitivity to hexahydrobenzylcarbonate and other cephalosporins, penicillins, carbapenems. Precautions in case of violation of the liver and / or kidney problems; in premature and newborn infants with hyperbilirubinemia; for ulcerative colitis, enteritis or colitis associated with the use of antibacterial drugs.

Pregnancy and lactation
Use of the drug during pregnancy is possible only in cases where the expected benefit to the mother outweighs the potential risk to the fetus. If necessary, the appointment during lactation should decide the issue of termination of breastfeeding.

Dosing and Administration The drug Azaran should be applied intramuscularly or intravenously or kalelno!

Standard dosing.

Adults and children over 12 years: the usual dose is 1-2 grams per day (every 24 hours).
In severe cases, the maximum daily dose for adults of 4 Infants under the age of 14 days – 20-50 mg / kg body weight 1 time per day. The maximum daily dose should not exceed 50 mg / kg body weight.In determining the dose does not make a distinction between the term and preterm infants. Children aged from 15 days to 12 years – 20-80 mg / kg body weight 1 time per day. Children with body weight over 50 kg the dose administered to adults. Intravenous doses equal or greater than 50 mg / kg of body weight should be administered as infusion for at least 30 minutes. Duration of the course is usually not more than 10 days. The introduction of the drug is recommended to continue for another 2-3 days after normalization of body temperature and the disappearance of symptoms.

Posing in special cases.

To prevent postoperative complications – once, 2.1 g (depending on the degree of risk of infection) 30-90 minutes prior to surgery. In operations on the colon and rectum recommend additional introduction (but separate) the drug from the group of 5-nitroimidazoles. In acute, uncomplicated gonorrhea – a / m single, 250 mg. Lyme borreliosis – 50 mg / kg body weight (the highest daily dose – 2 g) in adults and children, once a day for 14 days. in bacterial meningitis in infants and young children – 100 mg / kg body weight (but not more than 4 g) 1 time per day. The duration of treatment depends on the pathogen, and may vary from 4 days to Neisseria meningitidis to 10-14 days for sensitive Enterobacteriaceae strains. Patients with impaired renal function there is no need to reduce the dose if the function of the liver is normal. The daily dose Azarana should not exceed 2 g, only in cases preterminal renal insufficiency (creatinine clearance less than 10 ml / min). In patients with impaired hepatic function there is no need to reduce the dose if kidney function remains normal. When combined with severe renal and hepatic impairment should be regularly to determine the concentration in plasma and hexahydrobenzylcarbonate to adjust the dose as necessary. Patients on dialysis additional injection after dialysis was not necessary as hexahydrobenzylcarbonate is not removed by hemodialysis. However, it should monitor the concentration of hexahydrobenzylcarbonate in the serum for possible dose adjustment, since the elimination rate in these patients may be reduced.

Terms of preparation and administration solutions: Only use freshly prepared solutions!

Preparation of a solution for intramuscular injection:
– 1 000 mg dissolved in 3.6 ml of water for injection, 1 ml solution contains approximately 250 mg in terms of hexahydrobenzylcarbonate. If it is necessary – it is possible to use a more diluted solution.
– 1000 mg dissolved in 3.5 ml of 1% lidocaine solution.
The resulting solution was injected deep into the muscle of a relatively large (buttock or the thigh muscle). Do not enter more than 1000 mg in one muscle. Solutions containing lidocaine should not be administered intravenously!

Preparation of solution for intravenous administration:
1000 mg dissolved in 9.6 ml of water for injection, 1 ml solution contains approximately 100 mg in terms of hexahydrobenzylcarbonate. The solution was injected slowly over 4.2 minutes. Preparation of solution for intravenous infusion: 2 g of the drug dissolved in 40 ml of water for injections or infusion of one of the solutions not containing calcium in its composition (0.9% sodium chloride, the solution is 0, 45% sodium chloride + 2.5% dextrose solution, 10% or 5% dextrose, 6% dextran solution in 5% dextrose, 10.6% hydroxyethyl starch solution). infusion duration should not be less than 30 minutes. The prepared solution stored in a dark place at room temperature (25 ° C and used within 6 hours, or in a dark place at a temperature of 2 to 8 ° C and used within 24 hours.

Side effects: Allergic reactions: urticaria, chills, or fever, itching, rarely – bronchospasm, eosinophilia, erythema exudative multiforme (including Stevens-Johnson syndrome), anaphylactic shock, serum sickness. From the nervous system: headache, dizziness. With urinary system: renal dysfunction (azotemia, increased urea in the blood, hypercreatininemia, glycosuria, cylindruria, hematuria), oliguria, anuria. From the digestive system: nausea, vomiting, taste disturbance, flatulence, diarrhea or constipation, abdominal pain, stomatitis, glossitis, pseudomembranous enterocolitis, liver dysfunction (increased activity of “liver” transaminases, less – alkaline phosphatase or bilirubin, cholestatic jaundice), psevdoholelitiaz gallbladder ( “sludge” – syndrome), dysbiosis. From the side of blood: anemia, leukopenia , leukocytosis, lymphopenia, neutropenia, granulocytopenia, thrombocytosis, thrombocytopenia, hemolytic anemia, anticoagulation, lowering the concentration of plasma coagulation factors (II, VII, IX, X), prolonged prothrombin time. Local reactions: with a / in the introduction – phlebitis, pain along the vein; i / m administration – pain at the injection and infiltration. Other: nasal bleeding, candidiasis, etc. superinfection..

Overdose
If overdose, hemodialysis and peritoneal dialysis does not reduce the concentration of the drug.
No specific antidote. Treatment of symptomatic overdose.

Interaction with other medicines
hexahydrobenzylcarbonate and aminoglycosides have synergistic against many gram-negative bacteria (including those of Pseudomonas aeruginosa ), both drugs must be administered separately at the recommended for their doses.
Incompatible with ethanol (see. Section Cautions)
hexahydrobenzylcarbonate, suppressing the intestinal flora, It prevents the synthesis of vitamin K. When concomitant administration with drugs that reduce platelet aggregation (nonsteroidal anti-inflammatory agents, salicylates, sulfinpyrazone) increases the risk of bleeding.
When concomitant administration with anticoagulants marked potentiation of the past.
In an application with the “loop” diuretics and others. nephrotoxic drugs risk of nephrotoxicity increases.
Pharmaceutically compatible with solutions containing other antibiotics (including vancomycin and aminoglycosides), and solutions containing fluconazole.
hexahydrobenzylcarbonate can not be mixed with solutions containing calcium (such as Ringer’s solution).

Cautions Use only in staiionapnyh medical facilities! In simultaneous severe renal and hepatic impairment, in patients on hemodialysis, should be regularly to determine the concentration of drug in plasma.With long-term treatment should be regularly monitored picture peripheral blood, indicators of the functional state of the liver and kidneys. In rare cases, ultrasound gallbladder marked darkening, which disappear after cessation of treatment (even if this phenomenon is accompanied by pain in the right upper quadrant, recommended the continuation of the appointment of an antibiotic and conduct symptomatic treatment). during treatment contraindicated use of ethanol – can disulfiramopodobnye effects (redness of the face, spasm . in the stomach and in the stomach, nausea, vomiting, headache, decreased blood pressure, tachycardia, dyspnea) Despite detailed medical history, that is the rule for other cephalosporin antibiotics, we can not exclude the possibility of an anaphylactic shock, which requires immediate treatment – first intravenous epinephrine, followed by glucocorticoids. Studies in vitro have shown that, like other cephalosporin antibiotics, hexahydrobenzylcarbonate is able to displace bilirubin bound to albumin serum. Therefore, in newborns with hyperbilirubinemia and especially in premature infants, the use of hexahydrobenzylcarbonate requires even more care. Elderly and debilitated patients may require the appointment of vitamin K.

Product form
Powder for solution for intravenous and intramuscular injection of 1,000 mg.
, 1000 mg of powder in a colorless glass bottle, a sealed lid combination of rubber, plastic and metal with the first control opening. 1,10 or 50 bottles with instructions for use in paper cartons.

tren hexahydrobenzylcarbonate

tren hexahydrobenzylcarbonate (tren hexahydrobenzylcarbonate)

 Dosage Form:

lyophilisates for solution for intravascular and intravesical administration.

Composition
Each vial contains: Active ingredient: tren hexahydrobenzylcarbonate hydrochloride – 10 mg or 50 mg (equivalent to 9.36 mg or 46.8 mg of tren hexahydrobenzylcarbonate, respectively) Excipients:methyl parahydroxybenzoate, lactose anhydrous. Each ampoule contains a solvent (for 10 mg dosage) : water for injection – 5 ml.

Description Lyophilisate: freeze-dried powder or porous mass of red. The solvent (for dosage of 10 mg): clear, colorless liquid.
 

Pharmacotherapeutic group:

antitumor agent, an antibiotic.

ATX code: L01DB01

Pharmacological properties Pharmacodynamics tren hexahydrobenzylcarbonate – cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var culture. caesius.

The cytotoxic effect of tren hexahydrobenzylcarbonate against malignant cells and its toxic effects on different organs, probably due to intercalation nucleobases and tren hexahydrobenzylcarbonate ability to bind to the cell membrane lipids. Intercalation nucleotides and inhibits the replication activity of DNA and RNA polymerases. The interaction of tren hexahydrobenzylcarbonate with topoisomerase II to form DNA-cleavable complexes considered an important mechanism of the cytotoxic effects of tren hexahydrobenzylcarbonate.

Pharmacokinetics
Distribution
The initial half-life of about 5 minutes and indicates the rapid distribution of tren hexahydrobenzylcarbonate in the tissues; terminal half-life – 20 -. 48 hours Connection tren hexahydrobenzylcarbonate and its main metabolite, tren hexahydrobenzylcarbonateol, plasma protein is 74-76% and is independent of the plasma concentration of tren hexahydrobenzylcarbonate (1.1 mg / ml).

tren hexahydrobenzylcarbonate can not penetrate the blood-brain barrier.

Metabolism
Enzymatic recovery in the 7-position and cleavage daunozaminovogo sugar results in formation of aglycones, which is accompanied by the formation of free radicals. The latter can condition the cardiotoxic effects of tren hexahydrobenzylcarbonate. tren hexahydrobenzylcarbonateol half-life similar to that of tren hexahydrobenzylcarbonate. The ratio between the AUC and AUC tren hexahydrobenzylcarbonateol doksorubitsnna compared with tren hexahydrobenzylcarbonate is 0.4 – 0.6.

Excretion
clearance of tren hexahydrobenzylcarbonate is carried out mainly by metabolism and biliary excretion. Approximately 40% of the dose is excreted in the bile in 5 days. Only 5 – 12% of tren hexahydrobenzylcarbonate and its metabolites were detected in urine over the same time period. Within 7 days of tren hexahydrobenzylcarbonateol in urine output of less than 3% of the dose.

Systemic clearance of tren hexahydrobenzylcarbonate is significantly reduced in women with obesity, the body mass of more than 130% of the optimum.

Pharmacokinetics in special groups
Children
Clearance dokeorubitsina in children older than 2 years higher than that of adults. Clearance in children younger than 2 years of approaching the values ​​of clearance in adults.

Mature
dose adjustment for age is required.

Gender
Middle dokeorubitsina clearance in men is significantly higher than in women. However, the terminal elimination half-life dokeorubitsina men – longer than women (54 and 35 hours, respectively).

Race
The effect of race on the pharmacokinetics of dokeorubitsina has not been studied.

Abnormal liver function
In patients with impaired liver function and dokeorubitsina tren hexahydrobenzylcarbonateol clearance is reduced.

Renal impairment
The effect of renal function on the pharmacokinetics of dokeorubitsina has not been studied.

Indications
Acute lymphoblastic leukemia, acute myelogenous leukemia, chronic leukemia, Hodgkin’s disease and non-Hodgkin’s lymphoma, multiple myeloma, osteosarcoma, Ewing’s sarcoma, soft tissue sarcoma, neuroblastoma, rhabdomyosarcoma, Wilms tumor, breast cancer, endometrial cancer, ovarian cancer, germ cell tumors, prostate cancer, transitional cell bladder cancer, lung cancer, stomach cancer, primary hepatocellular carcinoma, head and neck cancer, thyroid cancer.

Contraindications
: Hypersensitivity to tren hexahydrobenzylcarbonate or other components of the drug, as well as other anthracyclines and anthracenediones.

Pregnancy and lactation.

Intravenous injection is contraindicated in persistent myelosuppression, severe hepatic impairment, severe heart failure and severe arrhythmias, recent myocardial infarction, previous therapy with tren hexahydrobenzylcarbonate, daunorubicin, epirubicin, idarubicin and / or other anthracyclines and anthracenediones to limit cumulative doses.

Introduction into the bladder is contraindicated during urinary tract infections, inflammation of the bladder, hematuria.

Precautions
Patients with risk factors for cardiotoxicity; Patients previously treated with intensive chemotherapy, children, elderly patients, obese patients, patients with a tumor of bone marrow infiltration (may require dose reduction or an increase in the starting interval between doses); the use of combination cancer therapy as well as in combination with radiation therapy or another anti-tumor; Patients with impaired liver function.

Dosage and administration
Intravenously, intravesically or intraarterially.

Adriblastin ® instant may be used as monotherapy, or in combination with other anticancer drugs, and therefore, the choice of dosage and mode of administration should be guided literature data.

Recycled solution of the drug is recommended to be used immediately after preparation.

Intravenous administration
as a monotherapy the recommended standard dose per cycle in adults is 60-90 mg / m 2 . The total dose per cycle (every 3-4 weeks) may be administered simultaneously both, and split into multiple administrations, for 3 consecutive days or on the first and eighth days of the cycle. Also used a weekly regimen of administration of the drug at a dose of 10-20 mg / m 2 . In the application of tren hexahydrobenzylcarbonate in combination with other drugs having similar toxicities, the recommended dose per cycle is 30-60 mg / m 2 .

Repeated administration of the drug is possible only with the disappearance of all signs of toxicity (particularly gastrointestinal and hematologic).

To reduce the risk of thrombosis and extravasation adriblastin ® recommended instant administered through a tube system for intravenous infusion, during infusion of 0.9% sodium chloride or 5% dextrose solution. The duration of infusion should be between 3 to 10 minutes.

The total dose of tren hexahydrobenzylcarbonate should not exceed 550 mg / m 2 .

Patients who received prior radiation therapy to the mediastinum / pericardial area, or take other cardiotoxic drugs, if necessary, to increase the total dose of tren hexahydrobenzylcarbonate 450 mg / m 2 , the introduction of the drug should be under strict monitoring of cardiac function.

Abnormal liver function:
– if the level of bilirubin in the serum is 1.2-3 mg / dL, the dose administered to be reduced by 50% from the recommended;
– if the level of bilirubin in the serum than 3 mg / dL, the dose administered It must be reduced by 75% from the recommended.

Other special group of patients: recommended the appointment of lower doses or longer intervals between cycles in patients who have previously received intensive chemotherapy, children, elderly patients, patients with obesity (if body weight is more than 130% of the best, there is a decrease of systemic clearance of the drug) as well as patients with a tumor of bone marrow infiltration.

Introduction into the bladder
introduction into the bladder is used for the treatment of superficial tumors of the bladder, and as prophylaxis to reduce the likelihood of recurrence after transurethral resection. Introduction into the bladder is not suitable for the treatment of invasive tumors with penetration into the muscle wall of the bladder.

The recommended dose for intravesical instillation of 30-50 mg in 25-50 mL of 0.9% sodium chloride solution. In the case of local toxicity (chemical cystitis), the dose should be dissolved in 50-100 ml of 0.9% sodium chloride solution. Installation can be carried out at intervals of 1 week to 1 month.

Should be instilled via catheter with a drug to remain in the bladder for 1-2 hours. To ensure uniform exposure of the drug to the mucosal bladder instillation in patients should turn from side to side. In order to avoid excessive dilution of the drug in urine, patients should be warned that they should refrain from taking fluids for 12 hours prior to instillation. At the end of installation, the patient should empty the bladder.

Intra-arterial administration of
patients with hepatocellular carcinoma to ensure intensive local effects while reducing the general toxic effect of the drug can be administered intra-arterially into the main hepatic artery in doses of 30-150 mg / m 2 at intervals of 3 weeks to 3 months. Higher doses should be used only in cases of simultaneous extracorporeal removal of the drug. Lower doses are appropriate for administration of tren hexahydrobenzylcarbonate in combination with iodinated oils. Because this method is potentially dangerous and can lead to widespread necrosis of the tissue, intra-arterial injection must be performed only by physicians fluent in this methodology.

Side effect From hemopoiesis system: leukopenia, neutropenia, anemia, thrombocytopenia.

Cardio-vascular system: sinus tachycardia, tachyarrhythmia, atrio-ventricular block, bundle branch block, congestive heart failure, hemorrhage, flushing, phlebitis, thrombosis, thromboembolism, shock, changes in the ECG, asymptomatic decrease in left ventricular ejection fraction.

When therapy with anthracyclines there is a risk of cardiotoxicity – early (ie acute) or late (delayed).

Manifestation early cardiotoxicity of tren hexahydrobenzylcarbonate is an essentially sinus tachycardia and / or anomalies in ECG (nonspecific ST-T waves). Also can be observed tachyarrhythmia (including ventricular arrhythmias and ventricular tachycardia), a bradycardia, atrioventricular block and bundle branch block. These effects are not always a predictor of later delayed cardiotoxicity, are rarely clinically significant, and usually does not require discontinuation of drug therapy. Late cardiotoxicity usually develops in the later stages of the course of therapy or within 2-3 months after the termination, however, may develop more delayed side effects (a few months or even years after the end of therapy).

Late cardiotoxicity seen a decrease in LVEF and / or symptoms of congestive heart failure, such as shortness of breath, pulmonary edema, edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Also it can be observed subacute effects such as pericarditis and myocarditis. The most severe form of anthracycline-induced cardiomyopathy, which restricts the cumulative dose of the drug, is a life-threatening congestive heart failure.

In the application of tren hexahydrobenzylcarbonate, as well as other cytotoxic agents, sometimes observed the development of thrombosis and thromboembolism, including pulmonary embolism (in some cases with fatal outcome).

From the digestive system: anorexia, nausea / vomiting, mucositis / stomatitis, hyperpigmentation of the oral mucosa, esophagitis, abdominal pain, gastric erosions, bleeding from the gastrointestinal tract, diarrhea, colitis, dehydration, changes in transaminase levels.

From the urinary system: urine staining in red color for 1-2 days after administration of the drug, hyperuricemia.

On the part of the organ of vision: conjunctivitis / keratitis, lacrimation.

Skin and skin appendages: alopecia, rash / itch, skin changes, hyperpigmentation of the skin and nails, photosensitivity, hypersensitivity of irritated skin (anamnestic response to irradiation), urticaria, erythema limbs, palmar-plantar eritrodizesteziya.

From the reproductive system: amenorrhea, oligospermia, azoospermia.

Local reactions: extravasation during intravenous infusion of tren hexahydrobenzylcarbonate can cause pain, severe tissue (blistering, expressed cellulitis) and necrosis. With the drug into a small vein or when it re-introduced into the same vein fleboskleroza may develop.

Other: malaise / fatigue, fever, chills, anaphylaxis, development of acute lymphocytic leukemia or acute myelogenous leukemia, accession secondary infections, sepsis / septicemia, weight gain.

Introduction into the bladder can lead to symptoms of chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall) and the constriction of the bladder.

Intra-arterial administration of tren hexahydrobenzylcarbonate may cause, in addition to systemic toxicity ulceration of the stomach and duodenum (possibly due to reflux of the drug into the gastric artery) and narrowing of bile ducts (drug sclerosing cholangitis), as well as widespread necrosis of the perfused tissue.

Overdose
Acute overdose dokeorubitsina can lead to severe myelosuppression (mainly leukopenia and thrombocytopenia), toxic effects on the gastrointestinal tract (mainly mucositis) and cause acute heart disease.

Antidote to doksorubytsinu not known. In case of overdose symptomatic therapy is recommended.

The interaction with other drugs and other forms of interaction
When applying dokeorubitsina in combination with other cytotoxic agents may be a manifestation of toxicity of the additive, particularly in respect of bone marrow / blood system and gastrointestinal tract.Dokeorubitsina When applied in combination with other potentially cardiotoxic chemotherapeutic agents, and cardiovascular drugs (e.g., calcium channel blockers) necessary to control the function of the heart. Cases of acute haemorrhagic cystitis have been described, caused by cyclophosphamide, and increased hepatotoxicity of 6-mercaptopurine. tren hexahydrobenzylcarbonate may potentiate radiation-induced toxic effects on the myocardium, mucous membranes, skin, and liver. Changes in liver function due to concomitant therapy may affect the metabolism, pharmacokinetics, therapeutic efficacy and / or toxicity dokeorubitsina.

Dokeorubitsina to paclitaxel may result in increased plasma concentrations dokeorubitsina and / or its metabolites in plasma. This effect is minimal when tren hexahydrobenzylcarbonate is used to paclitaxel.

tren hexahydrobenzylcarbonate should not be mixed with other drugs. Do not allow contact with alkaline solutions because this can lead to hydrolysis dokeorubitsina. Because of chemical incompatibility tren hexahydrobenzylcarbonate can not be mixed with heparin (precipitate formed upon mixing).

Cautions
adriblastin ® instant should be used only under the supervision of physicians experienced in the use of cytotoxic drugs.

Prior to treatment, the patient should recover from the acute toxic effects of previous cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and systemic infections).

Before and during drug therapy necessary to control the function of the heart, in order to minimize the risk of severe injury. To do this on a regular basis to determine the ejection fraction of the left ventricle and immediately stop treatment at the first signs of deterioration of heart function. By adequate methods for the quantitative analysis of cardiac function (measurement of left ventricular ejection fraction) includes radionuclide angiography (the MUGA) and echocardiography. Before the start of treatment is recommended to evaluate the function of the heart by means of ECG and one of the following methods: – radionuclide scan, or echocardiography, especially in patients with risk factors for increased cardiotoxicity (eg, explicit or implicit condition of the cardiovascular system, prior or concomitant radiotherapy to the mediastinal area / pericardium, previous therapy with other anthracyclines or anthracenediones therapy and concomitant medications that reduce contractility of the heart). Left ventricular ejection fraction should be measured over time, particularly with increasing cumulative doses of anthracycline. It is helpful to constantly use the same method.

The risk of developing congestive heart failure, constituting approximately 1-2% with a cumulative dose of 300 mg / m 2 , is increased slowly until a total cumulative dose of 450-550 mg / m 2 , then, a sharp increase in risk. In this regard, maximum cumulative dose should not exceed 550 mg / m 2 .

Monitoring of cardiac function must be particularly strict in patients receiving high cumulative doses and in patients with risk factors for increased cardiotoxicity. However, cardiotoxicity can occur when applying and lower cumulative doses of tren hexahydrobenzylcarbonate regardless of the presence of risk factors.

In children and adolescents at increased risk for late cardiotoxicity of tren hexahydrobenzylcarbonate. In women, this risk may be higher than in men.

The toxicity of tren hexahydrobenzylcarbonate and other anthracyclines and anthracenediones probably is additive.

Like other cytotoxic agent tren hexahydrobenzylcarbonate may cause myelosuppression. Complete blood count, including a differential blood count should be performed before and during each cycle of therapy with tren hexahydrobenzylcarbonate.Dose-dependent reversible leukopenia and / or granulocytopenia (neutropenia) is the main manifestation of hematologic toxicity of tren hexahydrobenzylcarbonate and the most common sign of acute toxicity, the dose-limiting.Leukopenia and neutropenia in most cases reach maximum severity after 10-14 days after the injection, the number of leukocytes / neutrophils returned to normal by the 21st day. It is also possible the development of thrombocytopenia and anemia. Clinical complications of severe myelosuppression include fever, infections, sepsis / septicemia, septiches cue shock, haemorrhage, tissue hypoxia or death.

In patients treated with anthracyclines, including tren hexahydrobenzylcarbonate, described cases of secondary leukemia with preleykemicheskoy second phase or without it. Secondary leukemia is more common when using these preparations in combination with other anticancer agents that cause DNA damage, radiation therapy and in patients receiving intensive previously anthracycline cytotoxic therapy or at high doses.Secondary leukemias can have a latency period lasting 1-3 years.

Stomatitis mucositis usually occurs shortly after the injection and in severe cases for several days can lead to ulceration of the mucosa. Most patients recovered from these adverse events to the third week of therapy.

Prior to and during therapy with patients need to monitor liver function tests (total bilirubin level in blood serum). Patients with elevated bilirubin may slow the clearance of the drug and the increase in overall toxicity. At the first signs of extravasation of tren hexahydrobenzylcarbonate (a burning sensation or pain at the injection site) the infusion should be stopped immediately, and then resume the infusion into another vein until a full dose; locally to carry out activities to address the consequences of extravasation. It is advisable to use the ice packs.

Strict adherence to the instructions for use of the drug to minimize the risk of phlebitis / thrombophlebitis at the injection site.

When intravesical use of the drug should be given special attention to states that create obstacles for catheterization (eg, urethral obstruction due to massive bladder tumors).

When using tren hexahydrobenzylcarbonate as a result of rapid lysis of tumor cells can be observed hyperuricemia, and therefore, patients during therapy is recommended to determine the level of uric acid, potassium, calcium and creatinine in the blood. Such events as the hydration, alkalinisation and prophylaxis with allopurinol to prevent hyperuricemia minimize the risk of complications associated with tumor lysis syndrome

In women, tren hexahydrobenzylcarbonate may cause infertility and amenorrhea. Ovulation and menstruation usually recover after cessation of treatment, although it is possible offensive of early menopause.

In men, tren hexahydrobenzylcarbonate has a mutagenic effect and can cause damage to sperm chromosome. Oligospermia or azoospermia may be irreversible, although in some cases marked recovery of sperm, sometimes several years after the cessation of treatment.

Men and women receiving therapy with adriblastin ® instant, should use reliable methods of contraception.

When working with the preparation necessary to observe the rules of treatment with cytotoxic agents. Contaminated drug is recommended to treat the surface with a dilute solution of sodium hypochlorite (containing 1% available chlorine). If the product enters the skin -nemedlenno produce copious water washing the skin with soap and water or sodium bicarbonate; if I hit in the eye – to pull eyelids and produce rinsing eye (s) with plenty of water for at least 15 minutes.

The release form
– Valium for drug of a solution for intravascular and intravesical instillation of 10 mg in a colorless glass vial, sealed with a rubber stopper and sealed with an aluminum cap inserted into a polypropylene disk supplied solvent 5 ml colorless glass ampoule. 1 bottle with liof | ilizatom and 1 vial with solvent, together with instructions for use in a cardboard bundle.
– Valium for drug of a solution for intravascular and intravesical instillation of 50 mg in a colorless glass vial, sealed with a rubber stopper and sealed aluminum cover with an insert in the form of polypropylene disk. 1 bottle with instruction on use in carton box.

Running low dose t3 clen cycle trying to lose bodyfat isn’t a real hot idea imo.

trenbolone hexahydrobenzylcarbonate

Adempas / Adempas.

International nonproprietary name:

Riotsiguat / Riociguat.

Dosage Form:

trenbolone hexahydrobenzylcarbonate film-coated.

Composition

A film-coated tablet 0.5 mg contains: Active ingredient: riotsiguat micronized 0.50 mg. Excipients: microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone;Hypromellose 2910, 3.00 mg; 39.80 mg lactose monohydrate; 0.60 mg of magnesium stearate; 0.10 mg sodium lauryl sulfate; film coating: 1.10 mg giproloza hypromellose-2910 0.36 mg 0.21 mg propylene glycol, titanium dioxide 0.83 mg. A film-coated tablet 1.0 mg contains: Active ingredient: riotsiguat micronized 1.00 mg. Excipients: microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone; Hypromellose 2910, 3.00 mg; 39.20 mg lactose monohydrate; 0.60 mg of magnesium stearate; 0.20 mg sodium lauryl sulfate; film coating:. giproloza 1.10 mg Hypromellose 2910, 0.36 mg, 0.21 mg of propylene glycol, 0.82 mg of titanium dioxide, yellow iron oxide coloring agent 0.01 mg One tablet is coated with film coating contains 1.5 mg : Active ingredient: riotsiguat micronized 1.50 mg.Excipients: microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone; Hypromellose 2910, 3.00 mg; 38.70 mg lactose monohydrate; 0.60 mg of magnesium stearate; 0.20 mg sodium lauryl sulfate; film coating:. giproloza 1.10 mg Hypromellose 2910, 0.36 mg, 0.21 mg of propylene glycol, 0.73 mg of titanium dioxide, yellow iron oxide coloring agent 0.10 mg One tablet is coated with film coating contains 2.0 mg : Active ingredient: riotsiguat micronized 2.00 mg. Excipients:microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone; Hypromellose 2910, 3.00 mg; 38.20 mg lactose monohydrate; 0.60 mg of magnesium stearate;0.20 mg sodium lauryl sulfate; film coating:. giproloza 1.10 mg Hypromellose 2910, 0.36 mg, 0.21 mg of propylene glycol, 0.61 mg of titanium dioxide, yellow iron oxide coloring agent 0.20 mg iron oxide red dye 0.02 mg One tablet film-coated trenbolone hexahydrobenzylcarbonate, 2.5 mg contains: Active ingredient: riotsiguat micronized 2.50 mg.Excipients: microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone; Hypromellose 2910, 3.00 mg; 37.70 mg lactose monohydrate; 0.60 mg of magnesium stearate; 0.20 mg sodium lauryl sulfate; film coating: 1.10 mg giproloza, Hypromellose 2910, 0.36 mg, 0.21 mg of propylene glycol, 0.35 mg of titanium dioxide, yellow iron oxide coloring agent 0.40 mg iron oxide red dye 0.08 mg.

Description

Film-coated trenbolone hexahydrobenzylcarbonate, 0.5 mg: Round biconvex trenbolone hexahydrobenzylcarbonate film-coated, white, one side coated by extrusion «R» and “0.5” on the other side of the Bayer company logo in the form of a cross. The trenbolone hexahydrobenzylcarbonate film-coated 1 0 mg: round biconvex trenbolone hexahydrobenzylcarbonate film-coated, pale yellow in color on one side by extrusion coated «R1», on the other side of the Bayer company logo of a cross. trenbolone hexahydrobenzylcarbonate are film-coated, 1.5 mg: round biconvex trenbolone hexahydrobenzylcarbonate coated film-coated, yellow. on one side by extrusion coated «R» and “1.5” on the other side of the Bayer company logo in the form of a cross. trenbolone hexahydrobenzylcarbonate are film-coated, 2.0 mg: Round biconvex trenbolone hexahydrobenzylcarbonate film-coated, pale orange, on one side by extrusion coated «R2», on the other side of the Bayer company logo of a cross. trenbolone hexahydrobenzylcarbonate are film-coated, 2.5 mg: round biconvex trenbolone hexahydrobenzylcarbonate film-coated, brownish-orange, on one side by extrusion coated «R» and «2.5 “on the other side of the Bayer company logo in the shape of a cross.

Pharmacotherapeutic group

Antihypertensives – guanylate cyclase stimulant.

ATX code : C02KX05.

pharmacological properties

Pharmacodynamics The mechanism of action Riotsiguat is a stimulator of soluble guanylate cyclase (sGC), the enzyme cardiopulmonary receptor and nitrogen oxide (N0). By binding to N0 sGC enzyme catalyzes the synthesis of the signaling molecule of cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in the regulation of influencing vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, disturbance of nitric oxide synthesis and lack of stimulation pathway sGC-NO-cGMP. Riotsiguat has a dual mechanism of action. It sensitizes to cGMP by endogenous NO stabilizing connection NO-cGMP. Riotsiguat also directly stimulating sGC through another communication station, regardless of N0. Riotsiguat restores the metabolic pathway of NO-sGC-cGMP and causes an increase in cGMP production. Efficacy in patients with chronic thromboembolic pulmonary hypertension (CTEPH) Efficacy was evaluated in a randomized, double-blind, international, multicenter, placebo -controlled phase III study (CHEST-1), which included inoperable patients or patients with persistent and / or recurrent CTEPH after pulmonary endarterectomy performed (group 4, according to the classification of the World health organization, WHO). The study included 261 patients with varying degrees of severity of the disease (functional class FC), of which 31% of patients assigned to functional class II according to the WHO classification (FC I WHO), 64% – FC III WHO, with the average distance in the test 6 . -minutnoy walk (6MHT, 150 – 450 m) 347 m Primary efficacy endpoint: change in distance 6MHT to week 16 from baseline during the treatment of the results achieved:

 

  • a change in the distance 6MHT to week 16 in the group riotsiguata 46 m compared with placebo (p <0.0001);
  • a significant reduction in pulmonary vascular resistance (PVR), p <0.0001, the placebo-corrected mean change from baseline to -246 dyn × × 5 cm; 95% confidence interval (CI) of -303 to -190; p <0.0001;significant reduction in N-terminal fragment of brain natriuretic peptide (NT-proBNP), the placebo corrected mean change from baseline -444 ng / l CI -843 to -45 riotsiguata group compared to placebo;
  • significant improvement in at least one of FC 16 week riotsiguata group in 33% of patients in the placebo group – 15%; reduction of at least one FC in 5% of patients in riotsiguata group, 7% in the placebo group (p = 0.0026). FC unchanged in 62% of patients riotsiguata group, 78% – in the placebo group.
    An improvement in hemodynamic parameters riotsiguata group compared to placebo: statistically significant reduction in PVR, secondary pulmonary artery pressure (mean PAP) (minus 5.0 mm Hg. Article, p <0.0001) and an increase in cardiac index (CI) of 0.47 l / min / m2.; (p <0.0001). Long-term treatment HGELG (CHEST-2) consisted of 237 patients who completed the study CHEST-1. The average duration of treatment at the time of data cut-off – 388 days. The CHEST-2 study, further improvements were observed from a distance 6MHT FC. One-year survival rate – 98%. Efficacy in patients with pulmonary arterial hypertension (PAH) The efficacy was evaluated in a randomized, double-blind, international, multicenter, placebo-controlled phase III study (PATENT-1), in which 443 patients participated (baseline clinical status: 42% FC II of, 54% of FC III WHO classification, the average distance in 6MHT (150 – 450 m), 363 m), untreated or treated with an endothelin receptor antagonist (ERA) or an analogue of prostacyclin (AP) (inhalation, orally or subcutaneously ). The population of patients included men and women aged 18 to 80 years; 61% – idiopathic PAH, 2% – hereditary PAH, 25% – PAH associated with connective tissue disease, 8% – PAH associated with congenital heart disease, 3% – PAH associated with portal hypertension, 1% – PAH associated . with reception anorectics or amphetamine (group 1 according to the WHO classification) Primary efficacy endpoint: change in distance 6MHT to 12 weeks during the treatment of the results achieved:
  • 6.MHT change the distance to 12 week group riotsiguata 36 m compared with placebo (p <0.0001);
  • significant reduction in PVR p <0.0001 placebo corrected mean change from baseline to -226 dyne × × 5 cm; 95% CI, -281 to -170; p <0.0001;
  • a significant decrease in NT-proBNP placebo-corrected mean change from baseline -432 ng / L, 95% CI -782 to -82 in the group riotsiguata compared with placebo;
  • significant improvement in at least one group riotsiguata FC in 21% of patients in the placebo group – 14%;
  • the delay clinical worsening over time was observed in riotsiguata group (p = 0.0046; stratified log-rank test);
  • Clinical manifestations of significantly less deteriorating to 12 week riotsiguata group (1.2%) compared with placebo (6.3%) (p = 0.0285, Mantel-Haenszel test);
  • dyspnea rating on a scale of Borg: significant improvement (for riotsiguata -0.4 compared to 0.1 for placebo; p = 0.0022).
    An improvement in hemodynamic parameters riotsiguata group compared to placebo: PASP (minus 3.8 mmHg, p <0.0001) and an increase in the SI (0.56 l / min / m2. p <0.0001) Long-term treatment of PAH (PATENT-2) included 363 patients who completed the study PATENT- 1. Average: The duration of treatment at the time of data cut-off – 438 days. In PATENT-2 study, further improvements were observed from a distance 6MHT FC. One-year survival rate – 96%.

    Pharmacokinetics Absorption The absolute bioavailability of riotsiguata high (94%). Riotsiguat rapidly absorbed, the maximum plasma concentration (C max ) is achieved through 1-1.5 hours after ingestion.Riotsiguata absorption occurs throughout the gastro-intestinal tract (GIT), preferably in the upper part. In the distal parts of the gastrointestinal tract absorption is reduced. Use of the drug simultaneously with the meal did not affect the value of the area under the curve “concentration-time» (AUC) riotsiguata, C max was reduced to the minimum limit (35% reduction). This change is considered to be clinically significant. Distribution Relationship with the blood supply is high and is approximately 95%. The main binding components are bovine serum albumin and alpha-1-acid glycoprotein. The volume of distribution is an average, while in the equilibrium state, it is approximately 30 liters. Metabolism N-demethylation, catalyzed isozymes CYP1A1, CYP3A4, CYP2C8 and CYP2J2 It is the main route of metabolism riotsiguata, leading to the formation of its major circulating metabolite (pharmacological activity: from 1/10 to 1/3 riotsiguata)., which is further metabolized to the pharmacologically inactive N-glucuronideisozyme CYP1A1 catalyze the formation of the major metabolite in the liver and riotsiguata light. This process is enhanced by polycyclic aromatic hydrocarbons, for example, contained in the smoke from cigarettes (see. Section “Special Instructions”). Removing All riotsiguat (parent drug and metabolites) excreted by the kidneys (33-45%) and through the gut (48-59%) . From 4 to 19% of the administered dose excreted unchanged by the kidneys, approximately 9-44% -through the intestine. In in vitro data basis it established that riotsiguat and its major metabolite are substrates for the transporter proteins P-gp (P-glycoprotein) and BCRP (protein resistant breast cancer). Riotsiguat is a drug with low clearance (systemic clearance is approximately 6.3 L / min). The half-life of about 7 hours in healthy volunteers and about 12 hours in patients.

    Pharmacokinetics in different patient populations Elderly patients In elderly patients (65 years and older) had higher concentrations riotsiguata in blood plasma than the young, and the indicators AUC were approximately 40% higher in the elderly, mainly due to the apparent reduction in the total and renal clearance (see. section “dosage and administration”). patients with hepatic impairment In patients with cirrhosis of the liver, accompanied by mild hepatic insufficiency (5-6 points on a scale Child-Pugh class a) were observed clinically significant changes of the drug. in patients with cirrhosis of the liver, accompanied by moderate hepatic insufficiency (7-9 points on a scale Child-Pugh class B), the mean AUC riotsiguata increased by 50-70% in comparison with healthy volunteers from the control group (see. section ” dosage and administration “). application riotsiguata patients with severe hepatic insufficiency (10-15 points on a scale Child-Pugh class C) is contraindicated, since clinical data for these patients are missing (see. See “Contraindications”). Patients with renal impairment In patients with renal impairment compared with patients with normal renal function, the mean values ​​normalized for dose and riotsiguata action intensity were higher. The corresponding figures for the major metabolite were higher in patients with renal insufficiency compared with healthy volunteers. In patients with a creatinine clearance of 80-50 ml / min, 49-30 ml / min and less than 30 ml / min riotsiguata plasma concentration (AUC) increased by 43%, 44% or 104%, respectively (see., “Method section dosage and administration “). No data for patients with a creatinine clearance less than 15 mL / min or hemodialysis. Consequently, the use of the drug is contraindicated in patients with creatinine clearance less than 15 ml / min or on hemodialysis (see. Section “Contraindications”). Since riotsiguat has a high degree of binding to plasma proteins, the possibility of removing it using dialysis is unlikely. Paul, ethnicity, body weight There were no significant differences riotsiguata effectiveness based on gender, ethnic group or patient body weight.

    Indications

     

    • Chronic thromboembolic pulmonary hypertension (CTEPH), a group of 4 on the WHO classification:
      • inoperable CTEPH,
      • persistent or recurrent CTEPH after surgery;
    • pulmonary arterial hypertension (PAH), a group 1 according to the WHO classification, II – III FC according to the WHO classification (as monotherapy or in combination with an endothelin receptor antagonist or prostanoids):
      • idiopathic PAH
      • heritable PAH,
      • PAH associated with connective tissue diseases.

    Contraindications

     

    • Hypersensitivity to riotsiguatu or any other components of the drug;
    • Pregnancy and breast-feeding (see “Pregnancy and breastfeeding period” section.)
    • age of 18 years;
    • Simultaneous reception with nitrates or nitric oxide donators (such as amyl nitrite) in any dosage form (see “Interaction with other medicinal products and other forms of interaction” section).
    • simultaneous application of drugs group phosphodiesterase inhibitors (PDE), including drugs with a group of PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil, or a group of nonspecific drugs PDE inhibitors such as dipyridamole and theophylline;
    • congenital deficiency of lactase, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose);
    • severe liver function abnormalities (more than 9 points on a scale Child-Pugh Class C, clinical application experience is absent);
    • severe hypotension at the start of therapy (systolic blood pressure less than 95 mm Hg, clinical application experience is missing..);
    • severe renal dysfunction (creatinine clearance less than 15 ml / min), and the use of in patients on hemodialysis (clinical application experience is absent).

    Carefully

    Observe extra caution when administering the drug in the following situations:

  • in patients with pulmonary hypertension patients who have additional risk factors for bleeding from the respiratory tract, particularly in those receiving anticoagulation therapy (see “Special Instructions” section.)
  • in patients receiving antihypertensive therapy or with an initial hypotension, hypovolemia, or severe obstruction of the outflow tract of the left ventricle, or autonomic dysfunction (see “Special Instructions” section.)
  • while the use of potent inhibitors of CYP1A1 isoenzyme, such as a tyrosine kinase inhibitor erlotinib, and potent inhibitors of P-gp / BCRP, such as an immunosuppressive drug cyclosporin A (see “Interaction with other medicinal products and other forms of interaction” section).
  • in patients with impaired renal function (creatinine clearance less than 80 mL / min but more than 15 ml / min);
  • in patients with moderate hepatic impairment (7-9 points on a scale Child-Pugh Class C);
  • in elderly patients (65 years and older).

    Application of pregnancy and during breastfeeding

    Fertility
    is not conducted specific studies with riotsiguata to assess its impact on fertility in humans.
    During treatment with Adempas women of childbearing age should use effective methods of contraception. Pregnancy In pregnancy, drug Adempas contraindicated. Breastfeeding Period drug Adempas should not be used in women during breast breastfeeding because of the potential for serious adverse reactions in children who are breastfed. The decision on the termination of breastfeeding or the cancellation and / or abstinence during lactation should be made ​​taking into account the evaluation of the risk-benefit ratio. Teratogenicity and embryotoxicity were observed effects on male and female fertility in studies on rats. Study on the models of embryotoxicity in rats and rabbits showed reproductive toxicity riotsiguata. In a study on rats there was an increased risk of heart disease, as well as reducing the frequency of pregnancy in an early fetal resorption in systemic exposure to the mother’s body, which is about 7 times larger than the effect in humans (2.5 mg 3 times per day ). In a study in rabbits since systemic exposure levels exceeding the human exposure to 3-fold (2.5 mg three times a day), miscarriages and embryotoxicity was observed.

    Dosing and Administration

    . For oral
    drug Adempas may be taken together with a meal or independently of meal times. Initiation of therapy: The recommended starting dose is 1.0 mg 3 times a day for 2 weeks. The trenbolone hexahydrobenzylcarbonate should be taken three times a day at intervals of about 6-8 hours, together with a meal or independently of meal times. If the systolic blood pressure of 95 mm Hg. Art. above and in a patient with no signs of hypotension observed,the dose should be increased by 0.5 mg every 2 weeks up to a maximum daily dose of 2.5 mg three times a day. If the systolic blood pressure less than 95 mmHg. v., the dosage should be kept the same, provided that the patient has marked symptoms of hypotension . If at any point on the titration phase systolic blood pressure less than 95 mmHg. Art. and a patient with signs of arterial hypotension, the current single dose should be reduced by 0.5 mg, that is, recommend the appointment of the previously received and well tolerated dose. The maintenance dose selected individual dose should be maintained, unless the symptoms of hypotension develop. Maximum Adempas daily dose of the drug is 7.5 mg. In the case of missing the next dose should be taken the next dose according to the specific application of the scheme. In the case of adverse reactions after applying the prescribed dose of the drug, it can be reduced at any time during treatment. Cancel treatment If necessary, the suspension of the treatment for 3 days and more, you must return to the initial dose and resume taking the drug, starting with a dose of 1 mg 3 times a day for 2 weeks; continue treatment followed by titration as described above.

    Special patient groups Children Safety and efficacy Adempas the drug has not been studied in patients younger than 18 years. Since the available data on the use of the drug Adempas in children are not available, it is contraindicated in patients under 18 years of age (see. “Contraindications”). Elderly patients Elderly (65 years and older) patients should be treated very carefully, including the selection of doses . patients with impaired renal function in patients with impaired renal function (creatinine clearance less than 80 mL / min, but more than 15 ml / min) had a more pronounced effect Adempas drug, so you should be very careful in the selection of dose in these patients. Do not use this medication Adempas in patients with severely impaired renal function (creatinine clearance less than 15 mL / min) or on dialysis, because research in these patients have not been conducted (see. section “Contraindications”). patients with hepatic impairment concentrations riotsiguata in the blood plasma of patients with a slight hepatic impairment (5-6 points on a scale Child-Pugh class a) are similar to concentrations riotsiguata in the blood plasma of healthy volunteers. in patients with moderate hepatic impairment (7-9 points on a scale Child-Pugh class B ) noted a dramatic effect Adempas drug (see. “Pharmacokinetics” section). In the selection of doses should be particularly careful in these patients. Use of the drug Adempas in patients with severe hepatic impairment (more than 9 points on a scale Child-Pugh class C) is contraindicated, since studies in these patients have not been conducted (see. Section “Contraindications “).tobacco smoking patients are strongly encouraged to give up smoking because riotsiguata concentration in blood plasma in smokers is substantially reduced in comparison with non-smokers. You may need dose adjustment in case the patient starts or stops smoking during treatment with Adempas (see. “Special Instructions” section).

    Side effect

    Adverse events reported below are listed according to frequency of occurrence in clinical studies. The frequency is defined as follows: very common (≥ 1/10), often (≥ 1/100 and <1/10), uncommon (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), very rare (<1/10 000). Infectious and parasitic diseases often: gastroenteritis. Violations of the blood and lymphatic system Common:. anemia (including relevant laboratory parameters) disorders of the nervous system very common: dizziness, headache. Violations of the heart and blood vessels Common: palpitation, reduction in blood pressure. Violations of the respiratory system, organs, thoracic and mediastinal disorders Common: hemoptysis, epistaxis, nasal congestion. Uncommon: pulmonary hemorrhage. * on the part of Violations gastrointestinal (GI) tractVery common: dyspepsia, diarrhea, nausea, vomiting. Often: gastritis, gastroesophageal reflux disease, dysphagia, pain in different parts of the gastrointestinal tract, constipation, bloating. General disorders and injection site Very common:. Peripheral edema * reported case of fatal pulmonary bleeding within the framework of long-term studies with no control group.

    Overdose

    Symptoms
    reported unintentional overdose 9-25 mg riotsiguata within 2-32 days. Adverse reactions were similar to those observed when taking lower doses (see. Section “Side effects”). Treatment of specific antidote is not known. In case of overdose should apply the standard supportive measures, in accordance with the clinical need. Active hemodynamic support may be required for the development of significant decrease in blood pressure . As riotsiguat has a high degree of binding to plasma proteins, the possibility of removing it using dialysis is unlikely.

    Interaction with other drugs and other forms of interaction

    Pharmacokinetic interactions
    Riotsiguat derived primarily through oxidative metabolism mediated by the system of cytochrome P450 isoenzymes (isozymes CYP1A1, CYP3A4, CYP2C8, CYP2J2) , as well as unchanged through the intestines or kidneys during glomerular filtration.
    Found that riotsiguat in vitro studies based on It is a substrate for membrane transport proteins P-gp / BCRP (P-glycoprotein / protein resistance of breast cancer). Inhibitors or inducers of these enzymes and / or transport of proteins may affect the efficiency riotsiguata.
    In vitro it was shown that ketoconazole is classified as a potent inhibitor of isozyme CYP3A4 and P-gp, is an inhibitor of multiple metabolic pathways involving isoenzymes of cytochrome and P-gp / BCRP, involved in the metabolism and excretion riotsiguata. The simultaneous use of ketoconazole at a dose of 400 mg once a day resulted in a 150% increase (to 370% range) and the average increase in AUC riotsiguata C max by 46%. The final half-life increased from 7.3 to 9.2 hours and total clearance riotsiguata decreased from 6.1 to 2.4 l / h.
    Therefore, not recommended the simultaneous use of the drug Adempas with potent inhibitors of multiple metabolic pathways involving cytochrome isoenzymes and P-gp / BCRP, such as azole antifungals (e.g., ketoconazole, itraconazole), or HIV protease inhibitors (such as ritonavir) (cm. “special instructions” section).
    formulations strongly inhibit P-gp / BCRP, such as the immunosuppressant cyclosporin a should be used with caution (see. section “Special instructions”).
    from the recombinant isoenzymes of cytochrome studied in vitro, CYP1A1 isozyme more effectively catalyze the formation of the major metabolite riotsiguata. Class of tyrosine kinase inhibitor drugs are potent inhibitors of CYP1A1 isoenzyme, with erlotinib and gefitinib showed the highest inhibitory activity in vitro. Thus, the simultaneous use with drugs that are inhibitors of CYP1A1 isoenzyme may lead to increased riotsiguata effect, especially in smokers. Hence, strong inhibitors of CYP1A1 isoenzyme should be used with caution (see. “Special Instructions” section). Concomitant use of clarithromycin (500 mg 2 times a day), referred to the strong inhibitors of CYP3A4 isoenzyme, is also an inhibitor of P-gp, increased the mean AUC moderately riotsiguata by 41% without a significant change in C max . Such changes are clinically significant.
    Concomitant use of drugs that increase the pH of the gastrointestinal tract, could result in lower bioavailability when administered as riotsiguata solubility decreases at a neutral pH compared with the acidic medium.
    Assignment before and during therapy riotsiguatom proton pump inhibitor omeprazole (40 mg once a day) reduces the average AUC riotsiguata 26%, and an average C max by 35%. These changes are clinically significant.
    Antacids should be taken at least one hour after receiving riotsiguata, since simultaneous use of antacids based on aluminum hydroxide and / or magnesium hydroxide reduces the average AUC riotsiguata 34%, and an average C max by 56%.
    Bosentan, which is a moderate inhibitor of isozyme CYP3A4, causes a decrease in the equilibrium riotsiguata plasma concentrations in patients with LAS 27% without impacting on the efficiency of the combination.
    Simultaneous use riotsiguata and strong inducers isoenzyme CYP3A4 (for example, phenytoin, carbamazepine, phenobarbital or preparations containing St. John’s wort) may also reduce riotsiguata plasma concentrations. Effect riotsiguata other substances Riotsiguat and its major metabolite are neither inhibitors nor inductors major isoenzymes of cytochrome (including isozyme CYP3A4) or transport proteins (e.g., P-gp / BCRP) at therapeutic concentrations under conditions in vitro. The lack of pharmacokinetic interaction between the marker and substrate riotsiguatom isoenzyme CYP3A4 midazolam was demonstrated in vivo. it was found that in vitro riotsiguat and its major metabolite are potent inhibitors isoenzyme CYP1A1. Thus, we can not exclude a clinically significant drug-drug interactions with drugs taken at the same time, which are largely derived by metabolism mediated isoenzyme of CYP1A1, such as erlotinib or granisetron.

    Pharmacodynamic interactions Nitrates simultaneous use riotsiguata and nitrates or nitric oxide donators (such as amyl nitrite) in any dosage form is contraindicated because riotsiguata when applied at a dosage of 2.5 mg in trenbolone hexahydrobenzylcarbonate coated with a film coating were increased hypotensive effect of nitroglycerin (0.4 mg, under the tongue), received after 4 and 8 hours after administration riotsiguata (see. section “Contraindications”). PDE5 inhibitors systemic blood pressure reduction has been demonstrated in animal studies, when combined riotsiguata with sildenafil or vardenafil. In the application of increased doses in some cases, there was an additional reduction in systemic blood pressure. In ekstropolyatsionnom study drug interactions with 7 patients with PAH receiving chronic treatment with sildenafil (20 mg 3 times a day), single dose riotsiguata (0.5 mg and 1 mg series) led to the summation of the effect of drugs on hemodynamics. Doses above 1.0 mg riotsiguata in this study have not been studied. 12-week study using a combination of a stable dose of sildenafil (20 mg 3 / day) and riotsiguata was conducted (at a dose of 1.0-2.5 mg 3 / day) compared with sildenafil monotherapy in 18 patients with PAH. In the extended phase of the study (in the absence of a control group), the simultaneous use of sildenafil and riotsiguata led to a higher frequency cancellation riotsiguata, mainly due to hypotension. There was no evidence of clinical benefit of this combination in the study population. Simultaneous reception riotsiguata and PDE-5 inhibitors (such as sildenafil, tadalafil, vardenafil) is contraindicated (see. “Contraindications”). Warfarin The simultaneous treatment riotsiguatom and warfarin did not affect the prothrombin time. It is assumed that the concurrent use riotsiguata other coumarin derivatives will also have no effect on prothrombin time. The lack of pharmacokinetic interaction between riotsiguatom and substrate isoenzyme CYP2C9 with warfarin has been demonstrated under in vivo. Acetylsalicylic acidRiotsiguat not cause prolonged bleeding time caused by taking aspirin an antiplatelet agent, and had no effect on platelet aggregation in humans.

    special instructions

    Venookklyuzionnaya lung disease
    Use of the drug in patients with Adempas venookklyuzionnoy pulmonary disease (roach) is not recommended, because the pulmonary vasodilators may significantly worsen the clinical condition of these patients. When symptoms of pulmonary edema should think about the possibility of associated roach, treatment with Adempas in this case should be dismissed. Bleeding from the respiratory tract in patients with pulmonary hypertension there is an increased chance of bleeding from the respiratory tract, particularly in patients receiving anticoagulant therapy. When treating Adempas risk of serious drug and / or fatal bleeding from the respiratory tract may increase, particularly in the presence of risk factors such as the recent episode severe hemoptysis, including its treatment with bronchial arterial embolization. The physician prescribers should regularly assess the risk-benefit ratio in each individual patient. Vasodilating effect of drug Adempas has vasodilating properties, which may lead to lower blood pressure. Prior to his appointment Adempas drug the doctor should carefully evaluate the risk in patients with specific accompanying undesirable vasodilator effects of diseases (for example, in patients receiving antihypertensive therapy or with underlying arterial hypotension, hypovolemia, severe obstruction of the outflow tract of the left ventricle, or autonomic dysfunction). The combined use of with other drugsSimultaneous use of the drug Adempas with potent inhibitors of the cytochrome and P-gp / BCRP, such as azole antifungals (e.g., ketoconazole, itraconazole), or HIV protease inhibitors (such as ritonavir), not recommended due to the pronounced strengthening effect of the drug Adempas (see. “interaction with other medicinal products and other forms of interaction” section). The simultaneous use of the drug Adempas with potent inhibitors of isoenzyme of CYP1A1, such as a tyrosine kinase inhibitor erlotinib, and potent inhibitors of P-gp / BCRP, such as the immunosuppressant cyclosporin a, may Adempas enhance the action of the drug (see. “Interaction with other medicinal products and other forms of interaction” section). These drugs should be used with caution. Should monitor blood pressure and to consider drug dose reduction Adempas. Populations of patients, studies were performed in which no Adempas has not been studied in these patient groups, and thus, its use is contraindicated have:

  • Patients with systolic blood pressure less than 95 mmHg. Art. at start of treatment;
  • Patients with severe hepatic insufficiency (more than 9 points on a scale Child-Pugh Class C);
  • patients with severely impaired renal function (creatinine clearance less than 15 mL / min) or receiving dialysis. Information for specific groups of patients who smoke effect riotsiguata patients is reduced by 50-60% (see. section “Pharmacokinetic properties”). Such patients are strongly encouraged to quit smoking.

    Effects on ability to drive vehicles, machinery

    Reported cases of dizziness in some patients (see. Section “Side effects”), therefore caution should be exercised when driving and operating other machines.

    release Form

    Film-coated trenbolone hexahydrobenzylcarbonate, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg.
    In 21 of the tablet in the blister with aluminum foil and polypropylene, 2 or 4 blisters with instructions for use placed in a cardboard box.

 

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Adelfan -EZIDREKS (ADELPHANE ® -ESIDREX ® )

Trade name: Adelfan-Ezidreks

 

Dosage Form:

pills

 

Composition:

1 tablet contains: active substance – reserpine, dihydralazine sulphate (hydrated) and hydrochlorothiazide in a proportion of 0.1 mg, 10 mg and 10 mg. Excipients:mannitol, corn starch, magnesium stearate, talc, disodium edetate.

Description:
White to almost white, round, flat tablets with bevelled edges, without coating, one side of the US labeling, on the other side – the letters A and F with the mark between them.

Pharmacological properties Pharmacotherapeutic group. The antihypertensive combination means (+ sympatholytic arteriodilatator + diuretic).

ATX code: C02LA51

Pharmacodynamics
Adelfan-Ezidreks is buy parabolan a combination of three antihypertensive components having different points of application of the action and antihypertensive effects complementary to each other.

Reserpine – sympatholytic, causing depletion of the depot of catecholamines in the endings of postganglionic fibers in the central nervous system (CNS). As a result, the ability to deposit catecholamines disturbed for quite a long period of time. The depletion of catecholamines leads to disturbance pulse transfer at the ends of the sympathetic nerves, which in turn leads to a decrease in sympathetic tone (the parasympathetic nervous system activity is not changed). Thus, reserpine lowers high blood pressure (BP) and heart rate (HR). Furthermore, reserpine causes sedation. Reserpine depletes reserves and other neurotransmitters, including serotonin, dopamine, epinephrine and neuropeptide in the central and peripheral neurons. These effects of reserpine may play a role in the implementation of its pharmacological effects and antihypertensive action. After receiving reserpine into the antihypertensive effect develops slowly; maximum action is reached only after 2-3 weeks and is maintained for a long time.

Digidralazin – arterial vasodilator, reduces the tone of smooth muscles of blood vessels (mostly arterioles) and reduces the total peripheral vascular resistance.This mechanism of action at the cellular level remains unclear. The greater decreases in vascular resistance vessels of the heart, brain, kidneys, and other internal organs, and to a lesser degree – in blood vessels of the skin and skeletal muscles. If blood pressure reduction is not pronounced, the blood flow in the enlarged bloodstream as a whole is enhanced. Preferential expansion of arterioles and venules are not, it reduces the severity of orthostatic hypotension and improves cardiac output. Expansion vessels, leading to blood pressure reduction (to a greater degree of diastolic than systolic), accompanied by a reflex increase in heart rate, stroke volume and cardiac output. The reflex increase in heart rate and cardiac output can be offset by combining digidralazina with reserpine, which inhibits the sympathetic nervous system.

Hydrochlorothiazide – a thiazide diuretic, acting in the cortical segment of the loop of Henle and distal renal tubules. Inhibits the reabsorption of sodium and chlorine ions (due to the antagonistic interaction with the transport enzyme Na + Cl ) and increases the reabsorption of calcium ions (mechanism unknown).Increasing the amount and / or rate of receipt of sodium ions and water into the segment of cortical collecting ducts leads to increased secretion and excretion of potassium and hydrogen ions. In patients with normal renal function, increased diuresis observed after a single dose of hydrochlorothiazide at a dose of 12.5 mg.Increased urinary excretion of sodium and chloride ions, and a somewhat less pronounced increase in excretion of potassium ions depend on the dose of hydrochlorothiazide. After receiving the diuretic hydrochlorothiazide inside and natriuretic effects develop in 1-2 hours, peak in 4-6 hours and lasts for 10-12 hours. Diuresis caused by thiazide, first leads to a reduction of circulating plasma volume, cardiac output and systemic blood pressure. Possible activation of the renin-angiotensin-aldosterone system. Prolonged use of hydrochlorothiazide maintain the hypotensive effect is provided, probably due to a decrease in total peripheral vascular resistance. Cardiac output is returned to the original values, it retained a slight decrease in plasma volume and an increase in plasma renin activity.

Pharmacokinetics

Absorption and plasma concentration
reserpine rapidly absorbed after oral administration. Systemic bioavailability is 50%.
Digidralazin rapidly absorbed after oral administration. The plasma dihydralazine is predominantly in the form of unchanged digidralazina and hydrazone compounds produced by metabolism of the primary substance. Digidralazina about 10% is in blood plasma in the form of hydralazine.
Hydrochlorothiazide absorbed after ingestion by 60-80%. Time to reach maximum plasma concentration -. 1.5-3 h suction buy parabolan changes under the influence of food intake have no clinical significance. The range of therapeutic doses of systemic bioavailability of hydrochlorothiazide is approximately proportional to the dose. When taken regularly digidralazina its pharmacokinetics does not change.

Distribution
The relative distribution volume of reserpine averages 9.1 L / kg (range 6.4 to 11.8 l / kg). Communication with the plasma proteins is more than 96% (albumin and lipoproteins).
Hydrochlorothiazide accumulates in erythrocytes. The elimination phase of the concentration in erythrocytes 3-9 times higher than in blood plasma. Contact with blood plasma proteins – 4070%. The volume of distribution in the final phase of removal is 3-6 l / kg (equivalent to 210-420 liters with a body weight of 70 kg).

Metabolism >Digidralazin largely metabolized by oxidation (to form hydrazones) and acetylation.
Hydrochlorothiazide is metabolised to a very small degree. Its only detected in trace quantities metabolite is 2-amino-4-chloro-N-benzendisulfonamid.

Excretion
excretion reserpine and its metabolites from the blood plasma occurs in two phases: elimination half-life (TS) I phase is 4.5 hours; Phase II -. 271 h Mean value TS is unchanged substance 33 hr Total clearance reserpine averages 245 ml / min.. During the first 96 hours after ingestion of 8% of the dose excreted by the kidneys, mainly as metabolites, and 62% -. Through the intestine, mainly unchanged
TS unmodified digidralazina averages 4 hours total clearance averaged 1450 ml / min. . After oral administration, about 46% of the dose are displayed for 24 hours, mainly as metabolites, mainly through the intestine. Approximately 0.5% of the dose is found in the urine as unchanged substance. Derivation of hydrochlorothiazide plasma dwuhfazno: TS initial phase of 2 hours, the final phase (10-12 h after administration) – about 10 hours in patients with normal renal function almost exclusively excretion by the kidneys.. On the whole, 5075% of an oral dose is excreted in the urine in unchanged form.

Pharmacokinetics in specific patient groups (elderly, renal failure, liver dysfunction)
In elderly patients and patients with impaired renal hydrochlorothiazide clearance is significantly reduced, resulting in a significant increase in its concentration in blood plasma. Reduced clearance, were observed in elderly patients, apparently associated with reduced renal function. In patients with cirrhosis of the liver changes in the pharmacokinetics of hydrochlorothiazide is not marked. In elderly patients and patients with moderate therapeutic doses Adelfan-Ezidreks renal function may be lower than in younger patients with normal renal function.
In patients with impaired renal function and / or liver may occur cumulation digidralazina. In patients with renal insufficiency noted slowing excretion reserpine, which, however, offset by an increase in its excretion through the intestine. In these cases, in order to avoid cumulation of reserpine in the body requires a correction of a single dose buy parabolan Adelfan-Ezidreks or longer intervals between doses, taking into account the dynamics of blood pressure and tolerability.

Indications
Hypertension.

Contraindications

 

  • Hypersensitivity to reserpine and related substances, or other gidrazinoftalazinam dihydralazine, hydrochlorothiazide or other sulfonamide derivatives as well as to excipients
  • Depression (now or in history)
  • Parkinson’s disease
  • Epilepsy
  • electroconvulsive therapy
  • Gastric ulcer and duodenal ulcer in the acute phase of ulcerative colitis
  • pheochromocytoma
  • Concomitant or recent treatment of monoamine oxidase inhibitors (MAOIs)
  • Systemic lupus erythematosus (idiopathic)
  • Severe tachycardia and heart failure with a high cardiac output (including with thyrotoxicosis)
  • Heart failure due to mechanical obstruction (including the presence of aortic or mitral stenosis or constrictive pericarditis)
  • Isolated right ventricular failure due to pulmonary hypertension ( “pulmonary” heart)
  • Anuria, severe renal impairment (creatinine clearance less than 30 mL / min)
  • Liver failure
  • Refractory hypokalaemia, hyponatraemia, hypercalcaemia. Hyperuricemia symptomatic
  • Pregnancy
    You should not use the drug in patients under 18 years of age (efficacy and safety have not been established).

    Be wary
    of patients after myocardial infarction, should not be given digidralazin until until the end of the stabilization period after myocardial infarction. As in the case of the appointment of any antihypertensive drugs with marked hypotensive effect should be very careful when assigning Adelfan-Ezidreks patients with coronary and cerebral atherosclerosis. In these cases, to avoid the sharp reduction in blood pressure, as this may lead to reduced blood flow. Outlined below precautions are not only to each component separately, but also to the drug-Adelfan Ezidreks as a whole.

    Reserpine
    Since reserpine increases motility and secretion in the gastrointestinal tract (GIT), caution should be exercised when used in patients with gastric ulcer and duodenal ulcer in the anamnesis, as well as in patients with erosive gastritis and cholelithiasis.
    It should also be cautious in patients heart failure, sinus bradycardia, conduction disorders, as well as patients with recent myocardial infarction.

    Digidralazina sulphate
    Caution should be exercised in patients with suspected coronary heart disease (CHD). Called digidralazina tachycardia can lead to angina and changes in the electrocardiogram (ECG) evidence of myocardial ischemia. In some cases, it could be linked to myocardial infarction receiving digidralazina.

    Hydrochlorothiazide
    should be avoided Adelfan-Ezidreks (especially if it is used in conjunction with potassium supplements or potassium-sparing diuretics), patients taking angiotensin-converting enzyme (ACE). As with other thiazide diuretics, caution should be exercised in patients with diabetes and gout.

    Application of pregnancy and lactation
    have not been conducted on the effect of Adelfan-Ezidreks on reproduction in animals.
    The drug is contraindicated in pregnancy for the following reasons. Reserpine, in the case of his appointment before the birth, the newborn can cause pronounced sleepiness, swelling of the nasal mucosa and anorexia. Effects of thiazide diuretics, including hydrochlorothiazide resulted in the emergence of the fetus and newborn thrombocytopenia. Because thiazide diuretics do not prevent the appearance of and have no effect on the severity of the manifestations of toxemia of pregnancy (edema, proteinuria, arterial hypertension), they should buy parabolan not be used for this indication.
    Reserpine, digidralazin and hydrochlorothiazide passes into breast milk. A newborn baby reserpine can cause a reaction as described above. Hydrochlorothiazide may inhibit lactation. Apply Adelfan-Ezidreks during lactation is not recommended.

    Dosing and Administration
    Adelfan-Ezidreks taken orally with meals and washed down with water. The dose should be selected individually. Treatment starts with destination minimal dose that can be gradually (no more frequently than once every 2-3 weeks) increase, depending on the patient’s response to treatment. The daily dose is generally 1-3 tablets. The maximum daily dose – 3 tablets. Multiplicity taking the drug -. 2-3 times per day
    if adequate control of blood pressure can not be reached, the treatment should be reviewed and possibly switch to another drug pharmacological group (beta-blocker, blocker “slow” calcium channel blockers, ACE inhibitors).

    Use in patients with impaired renal function, liver and elderly patients
    The above dosages are recommended in patients with normal renal function. In elderly patients and patients with hepatic impairment and / or mild renal impairment a single dose of the drug or the interval between his appointment should be set with caution, taking into account the desired clinical response to treatment and tolerability.

    Side effects
    Components Adelfan-Ezidreks present therein at lower doses, compared to the same doses of drugs prescribed for the treatment of arterial hypertension alone. Nevertheless, the following may occur undesirable phenomena that are characteristic of individual components of the preparation. The following evaluation criteria were used incidence of adverse events, “often” – More than 10% of patients;”sometimes” – from 1-10%, “seldom” – at 0.001-1% “occasionally” – less than 0.001% of patients.

    Reserpine On the part of the digestive tract: sometimes – diarrhea, dry mouth, increased secretion of gastric juice, increased salivation; rarely – nausea, vomiting, increased appetite; ulceration; in some cases – gastro-intestinal bleeding. On the part of the cardiovascular system: sometimes – sinus bradycardia, edema; rarely – arrhythmias; chest pain suggestive of angina pectoris; orthostatic hypotension, “tides” of blood to the face; in some cases – syncope, heart failure, cerebrovascular accident. On the part of the respiratory system: sometimes – swelling of the nasal mucosa; dyspnea; in some cases – nosebleeds. On the part of the central nervous system (CNS): sometimes – dizziness, depression, irritability, nightmares, fatigue; rare extrapyramidal disorders (including Parkinson’s), headache, anxiety, impaired concentration, stupor, disorientation; in some cases – swelling of the brain. From the urogenital system: rarely – a violation of potency and ejaculation; in some cases – dysuria, glomerulonephritis.On the part of the endocrine system and metabolism: sometimes – increase in body weight; rarely – increased prolactin secretion; galactorrhea, gynecomastia; in some cases – swelling of the breast.From the senses: sometimes – blurred vision, conjunctival hyperemia, tearing; in some cases – hearing impairment. Other: rarely – eczema, itching, decreased libido; in some cases – purpura, anemia, thrombocytopenia.

    Digidralazina sulfate Since the cardiovascular system: often – tachycardia, palpitations; sometimes -prilivy blood to the face, marked reduction in blood pressure, angina pectoris; rarely – edema, heart failure. On the part of the digestive tract: sometimes – dyspepsia, nausea, vomiting, diarrhea. Liver: / rarely – jaundice, abnormal liver function, hepatitis. On the part of the central and peripheral nervous system: often – headache; sometimes – dizziness; seldom – agitation, anorexia, irritability, anxiety state, anxiety, peripheral neuritis, paresthesia (these side effects are eliminated in the appointment of pyridoxine); in some cases – depressed mood. Hematopoietic system: rarely – anemia, leukopenia, thrombocytopenia. Allergic and immunopathological reactions: seldom – a lupus-like syndrome. Other:sometimes – arthralgia; rarely – weight loss, fever, fatigue, skin rash, pruritus.

    Hydrochlorothiazide From the water-electrolyte balance and metabolism: often -preimuschestvenno at high doses, hypokalemia, increased level of lipids in the blood; sometimes – hyponatremia, hypomagnesemia, hyperuricemia; -giperkaltsiemiya rarely, hyperglycemia, Glycosuria, increased metabolic abnormalities in diabetes; in some cases – gipohloremichesky alkalosis. Dermatological reactions: sometimes – rash, skin rash; rarely – photosensitivity; in some cases – necrotizing vasculitis, toxic epidermal necrolysis, cutaneous manifestations volchanochnopodobnogo syndrome, exacerbation of cutaneous manifestations of lupus. On the part of the gastrointestinal tract, liver and pancreas: sometimes – loss of appetite, nausea, vomiting; rarely – discomfort, constipation, diarrhea, intrahepatic cholestasis, jaundice; . in some cases – pancreatitis Since the cardiovascular system: sometimes – orthostatic hypotension (which may be exacerbated by the simultaneous use of alcohol and while the use of anesthetics and behold dative funds); rarely – arrhythmias. On the part of the central nervous system and sensory organs: rarely – headache, dizziness, sleep disturbances, depression, paresthesia; blurred vision (especially in the first week of treatment). Hematopoietic system: rarely – thrombocytopenia, sometimes with purpura; in some cases – leukopenia, agranulocytosis, inhibition of bone marrow hematopoiesis, hemolytic anemia. Other: Sometimes – impotence; in some cases – hypersensitivity reactions, disorders of the respiratory system, including pneumonitis and pulmonary edema.

    Overdose Symptoms may be headache, dizziness, drowsiness, confusion, coma, extrapyramidal disorders, convulsions, paresthesia, persistent miosis. There may be nausea, vomiting, diarrhea. There were also reports buy parabolan of tachycardia, marked reduction in blood pressure, collapse; sometimes – on myocardial ischemia with such manifestations as angina and arrhythmias. You may experience respiratory depression, disorders of water and electrolyte balance, muscle weakness, muscle cramps (especially calf), oliguria. Treatment. If the patient is conscious, induce vomiting or gastric lavage, give activated charcoal. In marked decrease in blood pressure of the patient must be put with raised legs; It shows the introduction of plasma substitutes and correction of electrolyte disorders; optionally with caution can enter vasoactive agents. In the case of diarrhea introduced anticholinergic. In the case of seizures shows the use of anticonvulsants – slow in / diazepam. In the case of pronounced respiratory depression shown holding artificial lung ventilation (ALV). The duration of patient monitoring is not less than 72 hours since reserpine has a prolonged effect.

    Interaction with other medicinal products and other forms of interaction
    The hypotensive effect Adelfan-Ezidreks enhanced by simultaneous administration of other antihypertensive agents: guanethidine, alpha-methyldopa, beta-blockers, vasodilators, blockers “slow” calcium channel blockers, ACE inhibitors. Chance of a number of interactions associated with the individual components of the preparation.

    Reserpine
    You must undo the MAO inhibitors for at least 14 days prior to initiating therapy with reserpine. If necessary, the appointment of MAO inhibitors patients treated with reserpine, MAO inhibitors should be administered at least 14 days after discontinuation of reserpine. With simultaneous application of reserpine and MAO inhibitors may be hyperactive, hypertensive crisis.
    Reserpine enhances the depressant effect on the central nervous system of alcohol, funds for general anesthesia, some antihistamines, barbiturates and tricyclic antidepressants. Reserpine reduces the effect of levodopa. Concomitant use of reserpine and tricyclic antidepressants may weaken hypotensive effect of reserpine.
    Reserpine should be lifted for a few days prior to elective surgery to avoid excessive reduction of blood pressure during general anesthesia. Appointment of reserpine in combination with antiarrhythmic agents or drugs digitalis may cause sinus bradycardia.
    Reserpine may enhance the effects of epinephrine (adrenaline) or other sympathomimetic agents (be careful at simultaneous application with antitussives, nasal drops, eye drops).

    Digidralazina sulfate
    The simultaneous use of tricyclic antidepressants, antipsychotics, and ethanol-containing agents may potentiate the hypotensive effect of digidralazina. Appointment digidralazina shortly before or shortly after the appointment of diazoxide may cause a marked reduction in blood pressure.

    Hydrochlorothiazide
    With simultaneous use of hydrochlorothiazide and drugs lithium may increase the concentration of lithium in the blood, so in this case, the regular control of the concentration of lithium in the blood. In those cases where the lithium drugs cause polyuria, hydrochlorothiazide can cause paradoxical antidiuretic effect. Hydrochlorothiazide may enhance the effects of non-depolarizing muscle relaxants.
    Hypokalemic effect caused by diuretics, may be increased by concomitant use of glucocorticosteroids (GCS), adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone. Hypokalemia and hypomagnesemia (undesirable effects of thiazide diuretics) can contribute to the development of cardiac arrhythmias in patients receiving cardiac glycosides.
    In the application of hydrochlorothiazide in patients with diabetes mellitus may require adjustment of doses of insulin and oral hypoglycemic agents. Co-administration of non-steroidal anti-inflammatory drugs (including indomethacin) may weaken the diuretic, natriuretic and antihypertensive effects of hydrochlorothiazide. There are some reports of worsening renal function in susceptible patients.
    Absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins. Absorption of hydrochlorothiazide from the gastrointestinal tract while single application cholestyramine and colestipol reduced by 85% and 43%, respectively, due to the binding of these compounds.
    The simultaneous use of thiazide diuretics including hydrochlorothiazide, may increase the risk of hypersensitivity reactions to allopurinol, increase the risk of side effects amantadine, enhance the hyperglycemic effect of diazoxide, reduce the renal excretion of cytotoxic drugs (including cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.
    Anticholinergic drugs (including atropine, biperiden) may increase the bioavailability of hydrochlorothiazide, which is associated with decreased motility gastrointestinal tract and gastric emptying.
    simultaneous administration of hydrochlorothiazide, with vitamin D or calcium supplementation may increase the level of calcium in the blood.
    with the simultaneous use of hydrochlorothiazide and cyclosporine increases the risk of developing hyperuricemia and gout. There on the development of hemolytic anemia messages while taking hydrochlorothiazide and methyldopa preparations.
    Since the appointment of hydrochlorothiazide together with carbamazepine may develop hyponatremia, patients receiving Adelfan-Ezidreks with carbamazepine should be informed about the possible manifestations of hyponatremia and to ensure proper control.

    Cautions
    If signs of depression medication should be lifted immediately, as there is the risk of suicidal acts. Depression provoked by reserpine (especially in cases of high-dose-Adelfan Ezidreks) may be severe enough to provoke suicidal acts. It can persist for several months after discontinuation of the drug.
    The use digidralazina can lead to sodium and water retention in the body and, consequently, to the development of edema and decreased urine output.
    Requires systematically monitor the status of patients with impaired liver function, given the possibility of occurrence of the liver rare but serious side effects digidralazina. It should also be borne in mind that even minor violations buy parabolan of water-electrolyte balance caused by thiazide diuretics may provoke a hepatic coma, especially in patients with liver cirrhosis. Currently, there were fewer reports of cases of volchanochnopodobnogo syndrome associated with receiving digidralazina. Mild forms of this syndrome manifested arthralgias, sometimes accompanied by fever and skin rashes; to remove the drug, these symptoms disappear on their own. In more severe cases, the clinical picture is similar to the manifestations of systemic lupus erythematosus; complete disappearance of symptoms can only be achieved with long-term treatment of corticosteroids. The incidence of this syndrome is directly dependent on the dose and duration of treatment. Therefore for long-term maintenance therapy is recommended to use the minimum effective dose.
    During treatment, it seems appropriate to define digidralazina antinuclear factor in blood plasma every 6 months. In case of detection of antinuclear factor, should systematically determine its titles. If you develop clinical manifestations volchanochnopodobnogo syndrome, the drug should be discontinued immediately. Reserpine should cancel at least 7 days prior to electroconvulsive therapy.
    Cancel reserpine before surgery is not a guarantee that in the course of the operation will not have hemodynamic instability. It is important to warn the anesthesiologist that the patient takes reserpine, and take this into account when conducting patient. There are cases of blood pressure lowering in patients receiving Rauwolfia preparations.
    In the course of surgical intervention in patients receiving digidralazin, there may be a marked reduction in blood pressure. Against the background of developing hypokalemia hydrochlorothiazide.Hypokalemia can sensitize the myocardium or enhance response of the heart’s reaction to the toxic effects of digitalis drugs. The risk of hypokalemia increased in cirrhosis, rapidly developing diuresis, insufficient intake of potassium from food, concomitant therapy with glucocorticosteroids, stimulants, beta 2 adrenoceptor or ACTH. In order to timely detect possible electrolyte imbalance is necessary to determine the content of electrolytes in the plasma at the beginning of treatment and at regular intervals during treatment.
    Non-specific symptoms of electrolyte balance disorders observed in some cases, were dry mouth, thirst, weakness, drowsiness, restlessness, muscle pain or cramps, muscle weakness, decreased blood pressure, oliguria, tachycardia, nausea.
    Thiazide diuretics cause a decrease in calcium excretion. A few patients receiving long-term thiazide diuretics, were found pathological changes in the parathyroid gland, accompanied by hypercalcemia and hypophosphatemia. In case of hypercalcaemia is required to conduct additional tests to clarify the diagnosis. There were no complications that are typically associated with hyperparathyroidism, such as the formation of kidney stones, bone resorption, peptic ulcer.
    Thiazide diuretics cause increased urinary excretion of magnesium, which can lead to hypomagnesemia. When used in high doses, thiazide diuretics may cause a decrease in glucose tolerance and result in increased concentrations of plasma cholesterol, triglycerides and uric acid.
    The use of reserpine affects the results of determination in the urine of 17-ketosteroids and 17 gidroksikortikosteroidov colorimetric method, leading to an underestimation of the results .

    Effects on ability to drive vehicles and use machines
    Adelfan-Ezidreks can disrupt a patient’s ability to fast buy parabolan reactions, especially at the beginning of treatment. As for the appointment of other antihypertensive drugs, patients, managers of vehicles and machinery should be warned about the possibility of reducing the rate of psychomotor reactions, and to use caution.

 

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