buy winstrol

Pharmacodynamics buy winstrol – a reversible inhibitor of chymotrypsin-like activity of the 26S-proteasome in mammalian cells. This proteasome is a large protein complex that cleaves proteins conjugated to ubiquitin. The ubiquitin-proteasome pathway plays a key role in the regulation of intracellular concentrations of certain proteins and thus supports intracellular homeostasis. Inhibition of proteasome activity prevents this selective proteolysis, which may affect many signal transduction cascades in the cell reaction. Violation of the maintenance of homeostasis mechanisms can lead to cell death. In vivo buy winstrol induced tumor growth delay in many experimental models, including multiple myeloma.

In experiments in vitro, ex vivo and animal models buy winstrol enhanced the differentiation and osteoblast activity and inhibits osteoclast function. These effects were observed in patients with multiple myeloma with multiple foci of osteolysis receiving buy winstrol therapy.

Pharmacokinetics

When buy winstrol administered intravenously in doses of 1.0 mg / m and 1.3 mg / m² to patients with multiple myeloma maximum concentrations of drug in plasma are respectively 57 and 112 ng / ml. At the subsequent administration of the drug in maximum plasma concentrations are in the range 67-106 ng / ml for a dose of 1.0 mg / m² and 89-120 for a dose of 1.3 mg / m². The average half-life of the drug with repeated administration of 40-193 hours.

The drug is rapidly eliminated after the first dose compared to subsequent doses. After the first administration in doses of 1.0 mg / m and 1.3 mg / m² of the average total clearance is respectively 102 and 112 l / h, and after the subsequent administrations – respectively 15-32 l / h.

When administered in a dose of 1.3 mg / m² subcutaneously or intravenously to patients with multiple myeloma total systemic exposure after repeated administration of the same dose (AUClast) were equivalent for both routes of administration (155 ng? H / mL when administered subcutaneously and 151 ng? h / mL when administered intravenously). Cmax after subcutaneous administration (20.4 ng / ml) was lower than after the intravenous injection (223 ng / ml). The geometric mean ratio AUClast was 0.99, and 90% confidence intervals – 80,18-122,80%. Tmax was 30 minutes when administered subcutaneously and 2 minutes after intravenous injection.

Following single or multiple dose administration of 1.0 mg / m² and 1.3 mg / m² buy winstrol average volume of distribution in patients with multiple myeloma is 1659-3294 liters (489-1884 l / m²). This suggests that buy winstrol intensively distributed in peripheral tissues. At concentrations of buy winstrol 100-1000 ng / ml of drug binding to plasma proteins is 83% on average. The fraction of buy winstrol bound to plasma proteins is not dependent on the concentration.

In the context of in vitro metabolism of buy winstrol mainly carried cytochrome P450 – CYP3A4, CYP2C19 and CYP1A2.

Participation of CYP2D6 and CYP2C9 isoenzymes in the metabolism of buy winstrol significantly. The main route of metabolism is the cleavage of the boron atoms with the formation of two metabolites, which are further hydroxylated to form several other metabolites. Metabolites buy winstrol does not inhibit the proteasome 26S.

elimination of buy winstrol Way in humans have not been studied.

The influence of age, gender and race on the pharmacokinetics of buy winstrol has not been studied.

Pharmacokinetic studies of buy winstrol in cancer patients with impaired hepatic function were performed on 60 patients with varying degrees of severity of liver dysfunction (see. Table 5) with buy winstrol dose of 0.5-1.3 mg / m². Mild disturbances of liver function have no effect on the pharmacokinetics of buy winstrol. Patients with impaired liver function moderate and severe observed 60% increase in AUC (area under the curve “concentration-time”) of buy winstrol compared to patients with normal liver function. For patients with impaired liver function moderate and severe decrease recommended starting dose of buy winstrol. It takes careful observation of such patients.

The pharmacokinetics of buy winstrol doses 0.7-1.3 mg / m² intravenously 2 times a week in patients with mild, moderate or severe renal impairment, including patients on dialysis, is comparable to the pharmacokinetics of the drug in patients with normal renal function.

Indications

Velcade ® is designed for the treatment of

 

  • multiple myeloma
  • mantle cell lymphoma

Contraindications

 

  • Hypersensitivity to buy winstrol, boron, and mannitol;
  • Pregnancy and lactation;
  • Children’s age (lack of application experience);
  • acute diffuse infiltrative pulmonary disease;
  • pericardium defeat
  • simultaneous use with potent inducers of CYP3A isoenzyme (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort).

Carefully

 

  • severe liver dysfunction and moderate;
  • severe renal impairment;
  • seizures or epilepsy in history;
  • fainting;
  • diabetic neuropathy in history;
  • concomitant use of antihypertensive drugs;
  • Dehydration during diarrhea or vomiting;
  • constipation;
  • the risk of chronic heart failure;
  • Simultaneous reception of inhibitors or substrates of CYP3A4, concomitant use of substrates of CYP2C9 isoenzymes, oral hypoglycemic drugs.

Dosing and Administration

Velcade ® is administered intravenously for 3-5 seconds or subcutaneously.

The drug Velcade ® is shown only for intravenous and subcutaneous administration. When intrathecal deaths were recorded.

When administered intravenously, the solution concentration would be 1 mg / ml. When administered subcutaneously solution concentration should be 2.5 mg / ml.

concentration of the solution must be calculated very carefully due to the difference in concentration of the solution for intravenous injection and solution for subcutaneous injection.

Monotherapy

Recurrent recurrent multiple myeloma and mantle cell lymphoma

The recommended dose of buy winstrol at 1.3 mg / m² body surface area twice a week for 2 weeks (days 1, 4, 8 and 11), followed by 10-day intervals (days 12-21). Between the introduction of successive doses of the drug Velcade ® must be at least 72 hours.
The degree of clinical response should be assessed after 3 and 5 cycles of treatment.
Holding 2 additional cycles of treatment is recommended in case of achieving a complete clinical response.
When the duration of treatment of more than 8 Velcade cycles ® can be used standard scheme or the scheme of maintenance therapy relapsed multiple myeloma – weekly for 4 weeks (days 1, 8, 15, 22) followed by a 13-day rest period (days 23-35).
Patients in whom drug therapy Velcade ® not He gave a clinical response (progression or stable disease after 2 or 4 cycles, respectively), the combination of high-dose dexamethasone with Velcade drug can be assigned ® . In this case, 40 mg dexamethasone is administered orally with each dose Velcade ® : 20 mg per day of administration Velcade ® and 20 mg per day after administration Velcade ® . Thus, reception dexamethasone produce 1, 2, 4, 5, 8, 9, 11 and 12 days, a total of 160 mg over 3 weeks.

Correction of the dose and resume therapy

With the development of haematological toxicity grade 4 non-hematological or any toxic effect of the 3rd degree, with the exception of neuropathy, treatment with Velcade ® should be suspended. After the disappearance of the symptoms of the toxicity of treatment with Velcade ® can be resumed at a dose reduced by 25% (the dose of 1.3 mg / m² was reduced to 1.0 mg / m²; a dose of 1.0 mg / m² was reduced to 0.7 mg / m²) .
When associated with Velcade ® neuropathic pain and / or peripheral sensory neuropathy dose is changed in accordance with table 1. There were cases of severe autonomic neuropathy, leading to termination or suspension of therapy. In patients with severe neuropathy history Velcade ® can only be used after careful assessment of risk / benefit ratio.

Table 1 . Recommended dose change in the development of drug-induced Velcade ® neuropathic pain and / or peripheral sensory or motor neuropathy.

 

Severity of peripheral neuropathy Changing the dosage and frequency of administration
Grade 1 (paraesthesia, weakness and / or extinction of reflexes) with no pain or loss of function The dose and administration regimen did not require correction
Grade 1 with pain or Grade 2 (dysfunction, but not daily activity) Reduce dose to 1.0 mg / m²
or
change the mode of administration of 1.3 mg / m² 1 day a week
Grade 2 with pain or Grade 3 (violation of the activities of daily living) Suspend the use of Velcade ® until the disappearance of symptoms of toxicity. Then resume the treatment, reducing the dose of Velcade ® 0.7 mg / m² and reducing the frequency of administration to once a week.
4-th degree (sensory neuropathy, leading to disability or motor neuropathy, life threatening or leads to paralysis) Discontinue the use of Velcade ®

Combination therapy

Multiple myeloma in patients who have not received prior treatment, and who are not candidates for stem cell transplantation

The recommended dose in combination with melphalan and prednisone

Velcade ® is administered intravenously for 3-5 seconds or subcutaneously in combination with melphalan and prednisone, taken orally. 6, nine-week cycles, as shown in Table 2. In cycles 1-4 Velcade ®applied 2 times a week (days 1, 4, 8, 11, 22, 25, 29 and 32), and in cycles 5-9 – 1 time per week (days 1, 8, 22 and 29).

Table 2 . The recommended dosing regimen Velcade ® , used in combination with melphalan and prednisone in previously untreated patients with multiple myeloma, which is not shown stem cell transplantation

 

Velcade ® 2 times a week (cycles 1-4)
A week 1 2 3 4 5 6
Velcade ®
(1,3 mg / m²)
day – – day,
April 1
Day
August 11
period
of rest
Day
22 25
Day
29 32
period
of rest
Melphalan (9 mg / m²) +
Ppednizon (60 mg / m²)
day day day day
1 2 3 4
– – period
of rest
– – – – period
of rest
Velcade ® 1 time per week (cycles 5-9)
A week 1 2 3 4 5 6
Velcade ® 1,3 mg / m² day – – –
1
day 8 period
of rest
day 22 day 29 period
of rest
Melphalan (9 mg / m²) +
Ppednizon (60 mg / m²)
day day day day
1 2 3 4
period
of rest
period
of rest

Correction dose combination therapy with prednisone and melphalan

Before starting a new cycle of treatment:

 

  • Platelet content should be? 70,000 / microliter
  • Absolute neutrophil count (ANC)? 1000 / ul
  • Non-hematological toxicities should be reduced to 1 degree or to the initial level

Table 3 . Dose adjustment during subsequent treatment cycles

 

Toxicity Correction or postponement dose
Hematological toxicity during the previous cycle:
• Prolonged neutropenia or thrombocytopenia, grade 4, or thrombocytopenia with bleeding In the next cycle, the dose of melphalan to be reduced by 25%
• The content of platelet ≤30000 / l or ANC ≤750 / L on the day of Velcade ® (except day 1) Postpone the introduction of Velcade ®
• Multiple delay the introduction of Velcade ® in one cycle (? 3 times when administered 2 times a week or? 2 times when administered one time per week) The dose of Velcade ® is reduced by 1 level (from 1.3 mg / m² to 1.0 mg / m², with 1.0 mg / m² to 0.7 mg / m²)
Non-hematological toxicity? 3 degrees Use of the drug Velcade ® lay before reducing hematological toxicity of 1 degree or to the initial level. After that, treatment with Velcade ® can be resumed at a dose reduced by 1 level (from 1.3 mg / m² to 1.0 mg / m², with 1.0 mg / m² to 0.7 mg / m²). With the development of neuropathic pain and / or peripheral neuropathies associated with Velcade ® , lay administering another dose and / or dose adjusted as described in Table 1.

For more information about melphalan and prednisone is given in the instructions for medical use of these drugs.

Multiple myeloma in patients who have not received prior treatment, and who are candidates for stem cell transplantation

Recommended dosage

The recommended starting dose of buy winstrol when used in combination with other drugs was 1.3 mg / m² body surface area twice a week for 2 weeks (days 1, 4, 8 and 11), followed by a break of 10-18 days, is one treatment cycle. It is necessary to carry out 3 to 6 of these cycles. Between the introduction of successive doses of the drug Velcade ® must be at least 72 hours. The
dose adjustment in patients who have shown the transplantation of stem cells should be carried out according to the recommendations described in Table 1.
Guidelines for dosage of drugs used in combination with the drug Velcade ® , are shown in the respective instructions for medical use.

Recurrent Multiple Myeloma

The recommended dose for use in combination with pegylated liposomal doxorubicin

Guidelines for dose and dose adjustment Velcade ® described above under “monotherapy”.
Pegylated liposomal doxorubicin is used at a dose of 30 mg / m² on the 4th day of a 3-week cycle receiving Velcade ® as an intravenous infusion lasting 1 hr. At once after the administration of buy winstrol.
Additional information about the pegylated liposomal doxorubicin given in the medical use of the drug instructions.

The recommended dose when used in combination with dexamethasone

Guidelines for dose and dose adjustment of the drug Velcade ® described above under “monotherapy”.
Dexamethasone is taken orally at a dose of 20 mg per day on the day of Velcade ® and on the subsequent day.
For more information about dexamethasone is given in the medical application of this instruction drug.

Repeated multiple myeloma therapy

In case of recurrence in patients who previously responded to therapy with Velcade ® (monotherapy or combination therapy), treatment should be started with the highest tolerated dose.
Dosing instructions are described in the “monotherapy”.

Previously untreated mantle cell lymphoma

The recommended dose for use in combination with rituximab, cyclophosphamide, doxorubicin and prednisone

Guidelines for dose and dose adjustment Velcade ® described above under “monotherapy”. It is necessary to carry out 6 cycles of therapy with buy winstrol. If the patient’s response to therapy for the first time observed during the 6th cycle, it is recommended to hold another 2 additional cycles of therapy with Velcade ® .
The first day of each 3-week cycle of therapy with Velcade ® is necessary to enter the following drugs in as an intravenous infusion: rituximab at a dose of 375 mg / m², cyclophosphamide 750 mg / m² and doxorubicin 50 mg / m². Prednisone is taken orally in a dose of 100 mg / m on days 1, 2, 3, 4 and 5 of each cycle of therapy with Velcade ® .

Dose adjustment during therapy previously untreated mantle cell lymphoma

Before starting a new cycle of treatment (Cycle 1, except):

 

  • Platelet content should be? 100,000 / microliter and absolute neutrophil count (ANC)? 1500 / l
  • The hemoglobin concentration should be? 8 g / dL (? 4.96 mmol / L)
  • Non-hematological toxicities should be reduced to 1 degree or to the initial level

With the development of haematological toxicity grade 3 non-hematological or any toxic effect of the 3rd degree, with the exception of neuropathy, treatment with Velcade ® should be suspended. Guidelines for dose adjustments are shown in Table 4.

Table 4 . Dose adjustment during therapy in patients with previously untreated mantle cell lymphoma

 

Toxicity Correction or postponement dose
Hematological toxicity:
• Neutropenia? 3 degrees with fever or grade 4 neutropenia lasting more than 7 days, platelet count ≤10000 / l Therapy with Velcade ® should be suspended for up to 2 weeks until the patient will be observed the following indicators: ANC? 750 / L, platelet count? 25000 / L
• If the toxicity is not permitted after the suspension of treatment to the above parameters, the therapy should completely stop
• If toxicity is allowed to indicators: the ANC? 750 / L platelets? 25000 / l, the dose of the drug Velcade ® should be reduced by 1 level (from 1.3 mg / m² to 1.0 mg / m², or 1.0 mg / m² to 0.7 mg / m²)
• platelet count <25,000 / l or ANC <750 cells / mm on the day of Velcade ®(except day 1) Postpone the introduction of Velcade ®
Non-hematological toxicity? Grade 3 Use of the drug Velcade ® deferred until reduction of hematological toxicity to 2 degrees or less. After that, treatment with Velcade ® can be resumed at a dose reduced by 1 level (from 1.3 mg / m² to 1.0 mg / m², or 1.0 mg / m² to 0.7 mg / m²). With the development of neuropathic pain and / or peripheral neuropathies associated with Velcade ® , lay administering another dose and / or dose adjusted as described in Table 1.

Information on the dosing regimen of rituximab, cyclophosphamide, doxorubicin, and prednisone, see the instructions for medical use of these drugs.

Special patient groups

Patients with impaired renal function

The degree of renal impairment did not affect the pharmacokinetics of the drug Velcade ® . Therefore, for patients with renal insufficiency correction dose is not required. Since dialysis may reduce the concentration of the drug Velcade ® in the blood, the drug should be administered after hemodialysis.

Patients with impaired hepatic function

In patients with mild impaired hepatic function does not require an initial dose changes. It is necessary to appoint the recommended dose. Patients with impaired liver function moderate and severe should be given Velcade ® at a reduced dose (see. Table 5).

Table 5 . Recommended changes starting dose of Velcade ® in patients with impaired hepatic function

 

The severity of liver dysfunction The concentration of bilirubin The activity of AST Changing the initial dose
easy ≤1,0x ULN > ULN Not required
> 1,0x – 1,5x ULN any Not required
Central > 1,5x – 3x ULN any Required to appoint Velcade ® at a reduced dose of 0.7 mg / m² in the first cycle. Consideration should be given to increase the dose to 1.0 mg / m² or further dose reduction to 0.5 mg / m² in the subsequent cycles, depending on patient tolerability.
Weight > 3x ULN any

AST = aspartate aminotransferase
ULN = upper limit of normal

Mode of application

Velcade ® is an anticancer agent. In the preparation of the solution and treatment with the drug should be cautious. Observe appropriate aseptic measures. It is recommended to wear gloves and other protective clothing to prevent skin contact. The drug should not be mixed with other medicinal products, with the exception of 0.9% sodium chloride solution.

Preparation of the solution for intravenous administration

The contents of the vial are dissolved in 3.5 ml of 0.9% sodium chloride solution. The concentration of the prepared solution for intravenous administration -. 1.0 mg / ml of
prepared solution is transparent and colorless. Upon detection of mechanical impurities or discoloration can not use the prepared solution.
The resulting solution was administered by intravenous bolus injection duration 5.3 seconds through a peripheral or central venous catheter, which was then washed with 0.9% sodium chloride solution for injection.

Preparation of the solution for subcutaneous injection

The contents of the vial are dissolved in 1.4 ml of 0.9% sodium chloride solution. The concentration of the prepared solution for subcutaneous administration -. 2.5 mg / ml of
prepared solution is transparent and colorless. Upon detection of mechanical impurities or change the color of the prepared solution can not be used.
The resulting solution is administered subcutaneously in the thigh (right or left) or the abdomen (right or left). It is necessary to constantly change their place of administration of the drug. Each subsequent injection should be administered at a minimum distance of 2.5 cm from the previous injection. Can not be administered the drug in sensitive areas, damaged areas (redness, bruising), and also in the region where the needle insertion is difficult.
In the case of local reactions in subcutaneous Velcade ® can use a less concentrated solution for subcutaneous administration (1 mg / ml instead of 2.5 mg / ml for a vial of the contents was dissolved in 3.5 ml of 0.9% sodium chloride solution) or go to the intravenous administration of the drug.

Side effect

Serious adverse reactions were observed infrequently during therapy with Velcade ® and include heart failure, tumor lysis syndrome, pulmonary hypertension, reversible rear encephalopathy syndrome, acute, diffuse infiltrative lung disease. In addition, in rare cases, autonomic neuropathy was observed. The most frequently during therapy with Velcade ® were observed following adverse reactions: nausea, diarrhea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory), headache, paresthesia, loss of appetite, shortness of breath, rash, herpes zoster and myalgia.

The following are adverse reactions that were considered possibly or probably related to the use of Velcade ® .

Adverse reactions are grouped by system-organ class and frequency of occurrence. The frequency of adverse reactions were classified as follows: (? 1/1000 and <1/100)? Very often (? 1/10), common (? 1/100, <1/10), uncommon, rare (1/10000 and < 1/1000) and the frequency is not known (frequency can not be estimated from the available data). In each frequency band unwanted reactions are shown in decreasing order of severity.

Infections and infestations:
often – herpes simplex, herpes zoster (including disseminated and ophthalmoherpes), pneumonia, fungal infections;
rarely – infection, bacterial, viral infections, sepsis (including septic shock), pneumonia, Herpes infection, herpetic meningoencephalitis, bacteremia (including staph), barley, influenza, inflammation of the subcutaneous fat, infection associated with the use of medical devices, skin infections, ear infections, staphylococcal infections, dental infections,
rarely – meningitis (in including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, chronic fatigue syndrome.

Neoplasms benign, malignant and unspecified (including cysts and polyps):
rarely – malignant neoplasms, plazmotsitarny leukemia, kidney cancer, tumors, mycosis fungoides, benign tumors.

Violations of the hematopoietic system and lymphatic system:
very often – thrombocytopenia, neutropenia, anemia,
often – leukopenia, lymphopenia,
rarely – pancytopenia, febrile neutropenia, coagulopathy, leukocytosis, lymphadenopathy, hemolytic anemia,
rarely – disseminated intravascular coagulation (DIC) , thrombocytosis, elevated blood viscosity syndrome, disorders of the platelet, thrombocytopenic purpura, blood disorders, bleeding diathesis, lymphocytic infiltration.

Violations of the immune system:
seldom – angioedema, hypersensitivity,
rarely – anaphylactic shock, amyloidosis, the reaction with the formation of immune complexes (Type III).

Disorders of the endocrine system:
rarely – Cushing’s syndrome, hyperthyroidism, violation of secretion of antidiuretic hormone;
rarely – hypothyroidism.

Metabolic and Nutritional Disorders:
very often – loss of appetite,
often – dehydration, hypokalemia, hyponatremia, changes in the concentration of glucose in the blood, hypocalcemia, changes in enzyme activity,
rarely – tumor lysis syndrome, lack of weight gain, hypomagnesemia, hypophosphatemia, hyperkalemia, hypercalcemia , hypernatremia, change in the concentration of uric acid, diabetes, fluid retention,
rarely – gipermagniemiya, acidosis, disruption of water and electrolyte balance, the excessive accumulation of fluid, hyposalemia, hypovolemia, hyperchloremia, hyperphosphatemia, metabolic disorders, vitamin deficiency of B, vitamin B12 deficiency , gout, increased appetite, intolerance to alcohol.

Mental disorders:
often – disorders and mood disorders, anxiety disorders, sleep disorders,
rarely – changes in mental status, hallucinations, psychotic disorder, confusion, restlessness,
rarely – suicidal thoughts, adjustment disorder, delirium, loss of libido.

Disorders of the nervous system:
very often – neuropathy, peripheral sensory neuropathy, dysesthesia, neuralgia,
often – motor neuropathy, loss of consciousness (including syncope), dizziness, dysgeusia, lethargy, headache,
infrequent – tremor, peripheral sensorimotor neuropathy, dyskinesia, balance disorder, memory loss (excl. dementia), encephalopathy, posterior reversible encephalopathy syndrome, neurotoxicity, seizures, post-herpetic neuralgia, speech disorder, a syndrome of “restless legs”, migraine, sciatica, impaired concentration, abnormal reflexes, parosmiya;
seldom – cerebral hemorrhage, intracranial hemorrhage (including subarachnoid), brain edema, transient ischemic attack, coma, an imbalance of the autonomic nervous system, autonomic neuropathy, cranial nerve palsy, paralysis, paresis, presyncope, lesions of the brain stem syndrome , cerebrovascular disease, radicular syndrome, psychomotor hyperactivity, spinal cord compression, cognitive disorders, movement disorders, disorders of the nervous system, sciatica, excessive salivation, muscle hypotonia.

Violations of the organ of vision:
often – eye swelling, visual impairment, conjunctivitis;
rarely – bleeding in the eye, infection eyelids, inflammation of the eyes, double vision, dry eye, eye irritation, eye pain, increased lacrimation, eye discharge,
rare – loss cornea, exophthalmos, retinitis, scotoma, eye damage (including age), dacryoadenitis, photophobia, photopsia, optic neuropathy, different degrees of visual impairment (up to blindness).

Violations of the organ of hearing and balance:
often – vertigo,
rarely – ringing in the ears, hearing loss (deafness), discomfort in the ear;
rarely – bleeding, vestibular neurons ear damage.

Violations of the heart:
rarely – cardiac tamponade, cardiopulmonary shock, atrial fibrillation of the heart (including atrial fibrillation), heart failure (including left and right ventricles), aritimiya, tachycardia, palpitations, angina, pericarditis ( including pericardial effusion), cardiomyopathy, ventricular dysfunction, bradycardia,
rarely – atrial flutter, myocardial infarction, atrioventricular block, cardiovascular disorders (including cardiogenic shock), ventricular fibrillation tachysystolic type “pirouette”, angina unstable, heart valve disease, coronary insufficiency, sinus arrest.

Violations of the cardiovascular system:
often – a decrease in blood pressure, orthostatic hypotension, increased blood pressure,
rarely – stroke, deep vein thrombosis, bleeding, thrombophlebitis (including surface), circulatory collapse (including hypovolemic shock) , phlebitis, flushing, hematoma (including perirenal), decreased peripheral circulation, vasculitis, hyperemia (including ocular);
rarely – embolism, peripheral vascular disease, lymphedema, pallor, rodonalgia, vasodilatation, discoloration of veins, venous failure.

Disorders of the respiratory system, thoracic and mediastinal disorders:
often – shortness of breath, nasal bleeding, infection of the upper and lower respiratory tract, cough,
rarely – pulmonary embolism, pleural effusion, pulmonary edema (including acute) pulmonary alveolar hemorrhage, bronchospasm, chronic obstructive pulmonary disease, hypoxemia, nasal airways, hypoxia, pleural effusion, hiccups, runny nose, hoarseness, wheezing;
rare – respiratory failure, acute respiratory distress syndrome, apnea, pneumothorax, atelectasis, pulmonary hypertension, hemoptysis, hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnoea, pulmonary fibrosis, disorders of the bronchi, hypocapnia, interstitial lung disease, infiltration of the lungs, a feeling of tightness in the throat, dry throat, increased secretion of the upper respiratory tract, throat irritation, cough upper respiratory tract syndrome .

Disorders of the gastrointestinal tract:
often – nausea, vomiting, diarrhea, constipation,
often – bleeding from the gastrointestinal tract (including mucosal bleeding), dyspepsia, stomatitis, violation of gastrointestinal tone, pain in the throat and pharynx, abdominal pain (including gastrointestinal pain, and pain in the spleen), disorders of the mouth, flatulence;
rare – pancreatitis (including chronic), vomiting blood, swelling of the lips, obstruction of the digestive tract (in including ileus), abdominal discomfort, ulceration of the oral mucosa, enteritis, gastritis, bleeding from the gums, gastroesophageal reflux disease, colitis (including pseudomembranous colitis), ischemic colitis, inflammation of the gastrointestinal mucosa, dysphagia , irritable bowel syndrome, disorders of the gastrointestinal tract, tongue coating, violation of gastrointestinal motility disorders of the salivary glands.
rarely – acute pancreatitis, peritonitis, tongue edema, ascites, oesophagitis, cheilitis, fecal incontinence, atonic anal sphincter fekaloma, ulceration and perforation of the gastrointestinal tract, gingival hypertrophy, megacolon, discharge from the rectum, blisters in the throat, pain in the lips, periodontitis, anal fissure, a change in bowel movement rhythm rectalgia, violations of the chair.

Violations of the hepatobiliary system:
often – changes in the activity of “liver” enzymes;
Infrequent – hepatotoxicity (incl hepatic impairment), hepatitis, cholestasis,
rarely – liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, hepatic haemorrhage, cholelithiasis disease.

Violations of the skin and subcutaneous tissue:
often – rash, pruritus, erythema, dry skin;
rarely – erythema multiforme, urticaria, acute febrile neutrophilic dermatosis, toxic skin eruption, toxic epidermal necrolysis, Stevens-Johnson syndrome, dermatitis, changes in the structure of hair, petechiae, ecchymosis, skin lesions, purpura, skin tumors, psoriasis, rash, night sweats, pressure sores, acne, blisters, violation of skin pigmentation,
rarely – skin reactions, lymphocytic infiltration of Jessner, palmar-plantar eritrodizesteziya, subcutaneous bleeding, net livedo, skin induration, papule, photosensitivity reactions, seborrhea, cold sweat, skin lesions, unspecified, erythrose, skin ulcer, nail infections.

Violations of the musculoskeletal system and connective tissue:
very often – musculoskeletal pain,
often – muscle cramps, pain in the extremities, muscle weakness;
rarely – muscle twitching, swelling of joints, arthritis, joint stiffness, myopathy, a feeling of heaviness;
rarely – rhabdomyolysis, temporomandibular joint syndrome, fistula, joint effusion, pain in the jaw, bone disorders, infection and inflammation of musculoskeletal and connective tissue, synovial cyst.

Violations of the kidney and urinary tract:
often – renal dysfunction,
rarely – acute renal failure, chronic renal failure, urinary tract infections, complaints from urinary tract infections, hematuria, urinary retention, impaired urination, proteinuria, azotemia, oliguria, pollakiuria;
rare – irritation of the bladder.

Violations of the genital organs and the breast:
infrequently – vaginal bleeding, genital pain, erectile dysfunction,
rarely – a violation of testicular function, prostate, breast violation of function, pain of the epididymis, epididymitis, pain in the pelvic area, ulceration of the vulva.

Congenital, familial and hereditary disorders:
rarely – aplasia, malformation of the gastrointestinal tract, ichthyosis.

General disorders and disturbances caused by the method of application:
very often – pyrexia, fatigue, asthenia,
often – edema (including peripheral), chills, pain, discomfort,
rarely – the deterioration of overall physical health, swelling of the face, reaction at the site administration, disorders of the mucous membranes, chest pain, gait disturbance, feeling cold, extravasation, complications from the use of a catheter change thirst, discomfort in the chest, feeling the changes in body temperature, pain at the injection site,
rarely – death (in including flash), multiple organ failure, bleeding at the injection site, a hernia, a violation of the healing process, inflammation, phlebitis at the injection site, soreness, ulcers, irritable, non-cardiac chest pain, pain at the site of catheter insertion, foreign body sensation.

Changes in laboratory parameters:
often – a decrease in body weight;
rare – hyperbilirubinemia, changes in protein indicators, weight gain, changes in blood parameters, increasing the concentration of C-reactive protein;
rarely – changes in blood gases, changes in ECG (including increase tooth QT), prothrombin time change, lowering the pH of gastric juice, increase of platelet aggregation, increase of troponin I, and virus detection serology change, changes in urine analysis.

Injury, poisoning and complications of procedures:
infrequently – fall, concussion;
rarely – transfusion reactions, fractures, stiffness, facial injuries, joint injuries, burns, fractures, pain during the procedure, radiation injury.

Surgical and therapeutic procedures:
rarely – activation of macrophages.

Patients with mantle cell lymphoma
Safety-Velcade ® in these patients were similar to c corresponding figures in patients with multiple myeloma. Significant differences between the two groups of patients were as that thrombocytopenia, neutropenia, anemia, nausea, vomiting, pyrexia and more common in patients with multiple myeloma as compared to patients with mantle cell lymphoma; and peripheral neuropathy, rash and itching – in patients with mantle cell lymphoma.

Overdose

Overdose exceeding the recommended dose for more than 2 times, was accompanied by a sharp decline in patients with blood pressure and thrombocytopenia with fatal.

The specific antidote to the drug Velcade ® is not known. In case of overdose should be monitored indicators of patient vital signs and perform appropriate therapy to maintain blood pressure (infusion therapy, a vasoconstrictor and / or inotropic agents) and body temperature.

Interaction with other drugs

In in vitro studies and in vivo studies showed buy winstrol properties of a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6 and 3A4.

From small contribution isozyme CYP2D6 in the metabolism of buy winstrol (7%), people with low activity of this isoenzyme are not expected to change in the overall distribution of the drug.

Investigation of the influence of the drug interaction with a strong inhibitor of CYP3A4 ketoconazole on the pharmacokinetics of the drug Velcade ® showed an increase in the average AUC values (area under “concentration-time” curve) of buy winstrol on average by 35%. Therefore, you should carefully monitor patients receiving buy winstrol at the same time and a strong inhibitor of CYP3A4 isoenzyme (ketoconazole, ritonavir).

In a study of the influence of the drug interaction with a potent inhibitor of the isoenzyme CYP2C19 on the pharmacokinetics of omeprazole Velcade ® , revealed no significant change in the pharmacokinetics of buy winstrol.

Investigation of the effect of drug interactions with rifampicin – a potent inducer of CYP3A4 isoenzyme – on the pharmacokinetics of the drug Velcade ® showed a decrease in mean AUC values (area under “concentration-time” curve) for buy winstrol on average by 45%. Therefore it is not recommended to use Velcade ® with potent inducers of CYP3A4, as the effectiveness of therapy can be reduced. For CYP3A4 inducers include rifampin, carbamazepine, phenytoin, phenobarbital and St. John’s wort. In the same study we evaluated the effect of dexamethasone – a weak inducer of CYP3A4. Based on the results of the study revealed no significant change in the pharmacokinetics of buy winstrol.

Investigation of drug interactions with the combination of melphalan-prednisone showed an increase in the average values of AUC (area under the curve “concentration-time”) of buy winstrol at 17%. This change is not considered clinically significant.

Diabetic patients treated with oral hypoglycemic drugs, cases of hypoglycemia and hyperglycemia account.

When using buy winstrol in combination with drugs that may be associated with peripheral neuropathy (such as amiodarone, antiviral agents, isoniazid, nitrofurantoin or statins) and drugs to lower blood pressure, care should be taken.

special instructions

Treatment with Velcade ® should only be undertaken under the supervision of a physician who is experienced in the use of anticancer chemotherapy.

When unintentional introduction of Velcade ® intrathecal deaths were recorded. The drug Velcade ® is shown only for intravenous and subcutaneous administration. Do not administer intrathecally.

Prior to and during each cycle of therapy is necessary to conduct a complete blood count with leukocyte and platelet count.

Thrombocytopenia / Neutropenia

Therapy with Velcade ® may result in thrombocytopenia and neutropenia. The smallest number of platelets is usually observed on the 11th day of the cycle and restored to the beginning of the next cycle.The cycle frequency of increase and decrease in platelet count was observed in clinical trials in patients with multiple myeloma and mantle cell lymphoma. There are no data supporting the growing thrombocytopenia or neutropenia during any mode of dosing. With a decrease in platelet count <25,000 / microliter therapy with Velcade ® should be suspended. When restoring platelet counts, treatment should continue in small doses in a careful comparison of the possible benefits and risks of treatment. For the treatment of hematological toxicity may be used colony stimulating factors, platelet transfusion and erythrocyte massy.Pri an application with melphalan and prednisone when the platelet count? 30,000 / microliter, drug therapy should be suspended.

Gastrointestinal disorders

In order to prevent nausea and vomiting it is recommended to use antiemetics. If diarrhea occurs antidiarrheal drugs administered. To prevent or treat dehydration patients need to spend rehydration therapy and maintain water and electrolyte balance. Reported cases of intestinal obstruction (rare).

PML (PML)

On the very rare cases of viral infection by John Cunningham of unknown etiology that led to progressive multifocal leukoencephalopathy and death has been reported in patients taking the drug Velcade ® .Patients diagnosed with PML received immunosuppressive therapy prior to or simultaneously with the use of Velcade ® . In most cases, PML was diagnosed within 12 months after the first dose of the drug Velcade ® . Patients should be monitored on a regular basis for the emergence or worsening neurological symptoms or signs that may indicate PML. If you suspect a patient of PML should be sent to a specialist in the field of PML, and to take appropriate diagnostic measures. It is necessary to halt the use of Velcade ® in case of diagnosis of PML.

Peripheral neuropathy

If neuropathy occurs, a supportive therapy. Typically, the incidence of peripheral neuropathy reaches a maximum at 5 cycles of treatment with Velcade ® . When new or strengthen existing symptoms of peripheral neuropathy may require dose reduction and change of mode of administration of the drug Velcade ® . Patients should be under constant supervision because of the possibility of occurrence of neuropathy symptoms (burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness). The incidence of neuropathy with subcutaneous administration of the drug Velcade ® is lower than that of intravenous administration.
There have been cases of autonomic neuropathy, severe, leading to the termination or suspension of therapy.
Early and regular monitoring of the presence of neuropathy symptoms with neurological assessment should be performed in patients taking the drug Velcade ® in combination with drugs capable of causing neuropathy (eg, thalidomide). Thus it is necessary to consider the appropriate dose reduction or discontinuation of treatment.

convulsions

In patients with absence seizures or epilepsy history describes infrequent cases of seizures. When treating patients with any risk factors for seizures, requires special care.

Orthostatic hypotension

Therapy with Velcade ® is often accompanied by orthostatic hypotension. In most cases it is weak or moderate, and can be observed during the treatment. Rarely observed brief loss of consciousness. In patients with syncope in the history of diabetic neuropathy receiving antihypertensive drugs, as well as in patients with dehydration during diarrhea or vomiting should be careful. Patients should be instructed on the need to see a doctor in case of dizziness, feeling “lightheaded” or fainting. With the development of orthostatic hypotension is recommended hydration, administration of glucocorticoids and / or sympathomimetic agents; If necessary, reduce the dose of antihypertensive drugs.

Heart failure

When using buy winstrol described the development or enhancement of existing chronic heart failure. By the development of signs and symptoms of heart failure may predispose fluid retention. Patients with risk factors or a history of cardiac disease should be closely monitored.

Liver failure

Cases of acute liver failure in patients who are on a background of buy winstrol therapy at the same time as taking concomitant treatment with other medicines. Such signs of liver function abnormalities, as an increase in liver enzymes, hyperbilirubinemia, or hepatitis, usually held at the abolition of the drug Velcade ?. Data on the status of these patients after the resumption of therapy with Velcade ® is limited.
Patients with symptoms of abnormal liver function, should be prescribed Velcade ® at lower initial doses and monitor for occurrence of toxicity, as buy winstrol is metabolized by liver enzymes, and its concentration can be increased when abnormal liver function medium – severe (see “dosage and Administration” section.).

Reversible encephalopathy syndrome back

In patients receiving Velcade ® was observed posterior reversible encephalopathy syndrome – a rare, reversible neurological disorder that can be accompanied by cramps, high blood pressure headache, lethargy, confusion, blindness, and other visual and neurological disturbances. To confirm the diagnosis is carried out magnetic resonance imaging of the brain. With the development of reversible posterior encephalopathy syndrome should stop taking the drug Velcade ® . Resumption of therapy with Velcade Safety ® after the previously identified reversible encephalopathy syndrome back unknown.

Reactivation of the virus Herpes zoster

The attending physician should consider the possibility of antiviral prophylaxis in patients receiving therapy with Velcade ® . In patients receiving therapy with Velcade ® , melphalan and prednisone, reactivation of the virus Herpes zoster incidence was higher as compared to patients treated with melphalan and prednisone (14% and 4%, respectively). Conduct antiviral prophylaxis significantly reduces the frequency of reactivation of the virus Herpes zoster.

Impaired lung function

In rare cases, the use of Velcade? there is an acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome. Some of these conditions have led to the death. In the case of lung function disorders symptoms or worsening of existing symptoms should immediately make a diagnosis and prescribe patients to appropriate treatment.
In clinical studies, two patients (out of 2-hoo) receiving high-dose cytarabine (2 g / m² per day) by continuous infusion over 24 hours with daunorubicin and drug Velcade ® for relapsed acute myeloid leukemia, died of acute respiratory distress syndrome in the early course of treatment, and the study was completed. Thus, this treatment regimen with coadministration of high-dose cytarabine (2 g / m² per day), by continuous infusion is not recommended for 24 hours.

tumor lysis syndrome

In connection with the possible development of hyperuricemia associated with tumor lysis syndrome, patients during therapy is recommended to determine the concentration of uric acid and creatinine in serum. To prevent hyperuricemia recommended excessive drinking, if necessary -. Allopurinol and alkalization urine
Using the drug Velcade ® in patients while taking oral hypoglycemic agents, should be carefully monitored in blood glucose concentration and carry out the correction dose hypoglycemic agents if necessary.
During the treatment of any of sexual partners is recommended to use reliable methods of contraception.
When working with the drug Velcade ® should comply with the general rules for handling cytotoxic drugs.

Reactions of immune complex type

Reactions of immune type, such as serum sickness, arthritis rash, proliferative glomerulonephritis have been reported infrequently. It is necessary to halt the use of buy winstrol in the event of serious reactions.

Effects on ability to drive a car and moving machinery.

Patients should be warned of the possibility of occurrence during treatment with Velcade ® dizziness, syncope, visual disturbances or other adverse events that may affect the ability to drive vehicles. If you have these symptoms, patients are advised to refrain from driving and other activities potentially hazardous activities that require high concentration and psychomotor speed reactions.

release Form

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Form release JSC “Pharmstandard-UfaVITA.”
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