Velcade

Velcade – antineoplastic means.

Form of release and structure

Dosage form – lyophilisate for preparation of solution for intravenous (in/in) and hypodermic (п / to) introductions: the white or almost white lyophilized weight or powder (in the blister 1 glass bottle with a capacity of 10 ml, in a cardboard pack 1 blister).

Active ingredient of Velcade – бортезомиб (PS-341), in 1 bottle – 3,5 mg.

Auxiliary components: Mannitolum, nitrogen.

Indications to use

• Mantiynokletochny lymphoma at patients with 1 line of therapy previous, at least;
• Multiple myeloma.

Contraindications

• Defeat of a pericardium;
• Acute forms of infiltrative and diffusion pathologies of lungs;
• Children's age;
• Period of pregnancy and breastfeeding;
• Hypersensitivity to boron, Mannitolum, a bortezomib.

With care it is necessary to appoint Velcade sick with the expressed renal failure, an abnormal liver function of average and heavy degree, spasms or epilepsy in the anamnesis, a diabetic neuropathy in the anamnesis, faints, dehydration after vomiting or diarrhea, at risk of development of chronic heart failure, a concomitant use of hypotensive drugs, a lock; in combination with peroral hypoglycemic means, CYP2C9 isoenzyme substrates, inhibitors or substrates of an isoenzyme CYP3A4.

Route of administration and dosage

Use of Velcade is shown for in/in and п / to introduction.

The treatment of drug demands care, observance of strict rules of an asepsis. Treatment has to take place in the stationary conditions, with attraction having experience of the address with antineoplastic means of specialists.

For dissolution of lyophilisate it is possible to use only 0,9% chloride sodium solution. Ready solution has to have transparent, colourless structure, in case of discoloration or existence in it of any inclusions it cannot be used.

Concentration of solution for in/in introductions has to make 1 mg/ml therefore contents of a bottle it is necessary to dissolve 0,9% of solution of sodium of chloride in 3,5 ml. Ready solution is entered through the central venous or peripheral catheter in the way in a bolyusny injection within 3-5 seconds. After the procedure a catheter it is necessary to wash out 0,9% chloride sodium solution.

Concentration of solution for п / to introduction has to make 2,5 mg/ml therefore it is necessary to add 1,4 ml of 0,9% of solution of sodium of chloride to contents of a bottle. П / to introduction it is shown to the right or left area of a hip or stomach with continuous alternation and is not closer than for 2,5 cm from the place of the previous injection. It is impossible to make п / to introduction to the sensitive or damaged body parts. At emergence of local reactions it is necessary to turn on into introduction or to reduce concentration of solution to 1 mg/ml.

At monotherapy it is shown in/in jet and п / to administration of Velcade.

The recommended dosing: an initial dose – 1,3 mg on 1 ^sq.m of a body surface in 1, 4, 8 and 11 days within 2 weeks, from 12 to 21 days – a 10-day break. Between procedures (introduction of doses) it is necessary to observe an interval not less than 72 hours.

Degree of the clinical answer is estimated after 3 and 5 cycles of therapy, on reaching the full clinical answer carrying out two cycles of treatment is in addition recommended.

At appointment more than 8 cycles of treatment, it is possible to apply the standard scheme or the scheme of a maintenance therapy at which administration of drug is made within 4 weeks in the 1, 8, 15 and 22 day with the subsequent period of rest within 13 days (with 23 on 35).

In the absence of the clinical answer, progressing of a disease after carrying out 2 cycles or stabilization of a disease after 4 cycles, purpose of drug in a combination with high doses of dexamethasone is possible. Dexamethasone appoint in a dose 40 mg inside with each dose of Velcade which is divided into 2 receptions: 20 mg in day of administration of drug and 20 mg in the first day after introduction. Thus, within 3 weeks of the patient accepts a total dose of dexamethasone of 160 mg (in 1, 2, 4, 5, 8, 9, 11 and 12 days).

In case of development of any not hematologic toxic effect of the 3rd degree (except a neuropathy) or hematologic toxicity of the 4th degree treatment should be suspended until total absence of symptoms of toxicity. It is necessary to resume therapy in the dose lowered by 25%.

At emergence against the background of therapy by Velcade of a peripheral touch neuropathy and/or neyropatichesky pain the dose of drug is adjusted according to weight of pathology. At 1 degree (without loss of function and pains) the peripheral neuropathy correction is not made, at 1 degree with pain and dysfunction (the 2nd degree) – the dose of drug is reduced to 1 mg on 1 ^sq.m of a body surface, at the 2nd degree with pain and 3 degrees (disturbance of daily activity) – therapy should be suspended before total disappearance of toxicity. Then treatment renew in a dose 0,7 mg on 1 ^sq.m with frequency rate of introduction once a week. At the 4th severity of a peripheral neuropathy use of drug should be cancelled.

At a heavy neuropathy in the anamnesis purpose of Velcade should be made only after detailed assessment of the relation of risk and advantage of therapy.

Dose adjustment is not required at a renal failure (the patient who is on dialysis, administration of drug is made after the procedure of dialysis).

At easy degree of an abnormal liver function change of an initial dose is not required. At average and heavy degree of an abnormal liver function the dose of Velcade should be lowered to 0,7 mg on 1 ^sq.m of a body surface in the first cycle, in the following cycles drug is appointed depending on portability – raise to 1 mg on 1 ^sq.m or reduced to 0,5 mg on 1 ^sq.m.

At a combination therapy in/in or п / to administration of Velcade combine with intake of Melphalanum and Prednisonum. Treatment assumes 9 six-week cycles from which with 1 on 4 drug 2 times a week use (days 1, 4, 8, 11, 22, 25, 29 and 32), and with 5 on 9 cycle – once a week (days 1, 8, 22 and 29). The dose of drug is appointed and adjusted by the attending physician taking into account indicators of maintenance of thrombocytes, neutrophils and not hematologic toxicity.

Side effects

• System of a hemopoiesis and lymphatic system: very often – anemia, a neutropenia, thrombocytopenia; often – a lymphopenia, a leukopenia; infrequently – a febrile neutropenia, a pancytopenia, hemolitic anemia, a lymphadenopathy, a Werlhof's disease; seldom – a syndrome of the disseminated intravascular coagulation;
• Alimentary system: very often – nausea, a loss of appetite, vomiting, a lock, diarrhea; often – dryness in a mouth, stomatitis, pain in a stomach, dyspepsia, a meteorism, a liquid chair, a hiccups, pains in a throat and a throat; infrequently – increase in appetite, colitis, an eructation, acute pancreatitis, paralytic intestinal impassability, a melena, enteritis, gastrointestinal bleeding, a dysphagy, pains in a spleen, gastritis, an esophagitis, a gastroesophageal reflux, hypersecretion of sialadens, petechias of a mucous membrane of a mouth, a fur, ulcerations in language, language discoloration; seldom – ischemic colitis;
• Cardiovascular system: often – decrease or increase in the arterial pressure (AP), arrhythmia, a heart consciousness, stenocardia, orthostatic and postural hypotension, cardiogenic shock, a cardiac standstill, a myocardial infarction, a hypokinesia of ventricles, an aggravation and development of chronic heart failure, a fluid lungs (including acute), a total atrioventricular block, a stop of a sinus node, tachycardia, fibrillation of auricles, a hematoma, phlebitis; infrequently – bradycardia, an atrial flutter, intracerebral bleeding, subarachnoidal hemorrhage, intracraneal hemorrhage, a stroke, a vasculitis, pulmonary hypertensia, stagnation of blood in lungs, an ecchymoma, petechias, a purpura, swelling of veins, change of coloring of veins, rushes of blood, bleeding of wounds; seldom – a cardiac tamponade, decrease in fraction of emission of a left ventricle, a pericardis, an embolism of peripheral vessels and/or a pulmonary artery, ventricular arrhythmias;
• Respiratory system: very often – an asthma; often – cough, nasal bleeding, a rhinorrhea, an asthma against the background of exercise stresses; infrequently – a hypoxia, an apnoea, a pleural exudate, a respiratory alkalosis, a bronchospasm, rhinitis, a tachypnea, a nose congestion, goose breathing, a hoarseness, a hyperventilation of lungs, pains in a thorax, a pneumorrhagia, feeling of constraint in a throat, an orthopnea, paranasal sinuses pain; seldom – pneumonia (including intersticial), a pneumonitis, a syndrome of acute respiratory insufficiency, pulmonary hypertensia, acute diffusion infiltrative damage of lungs, alveolar hemorrhage in a lung, respiratory insufficiency;
• Gepatobiliarny system: infrequently – a hypoproteinemia, hemorrhage in a liver, hepatitis, increase in activity of alaninaminotranspherase (ALT) and aspartate aminotransferase (nuclear heating plant), a hyperbilirubinemia; seldom – a liver failure;
• Mental disturbances: often – sleeplessness, a depression, uneasiness, confusion of consciousness; infrequently – sleep disorders, nonsense, changes of the mental status, excitement, hallucinations, irritability, the excited state, unusual dreams, differences of mood;
• Nervous system: very often – a headache, a peripheral neuropathy, paresthesia; often – dizziness (excepting вертиго), a tremor, a polyneuropathy, a dizesteziya, a food faddism, a hypesthesia; infrequently – spasms, a paraplegia, a motive peripheral neuropathy, paresis, taste loss, disturbance of concentration of attention, drowsiness, the abrupt movements, cognitive frustration, postural dizziness, disturbances of the speech, mononeuropathy, a syndrome of uneasy legs, a syncope; seldom – vegetative neuropathy, encephalopathy, a leykoentsefalopatichesky syndrome (reversible);
• Urinary system: often – a dysuria, a renal failure; infrequently – a renal failure (including acute), renal colic, an oliguria, a hamaturia, frequent urinations, an urine incontience, an urination delay, a proteinuria, difficulty of an urination, a back pain;
• Sense bodys: often – eye pain, decrease in clearness of sight, вертиго; infrequently – vision disorders, a hematopsia, a xerophthalmus, a photophobia, conjunctivitis, irritation of eyes, a conjunctiva hyperemia, the strengthened dacryagogue, a hearing disorder, a ring in ears; seldom – optical neuropathy, офтальмогерпес, a blindness, bilateral deafness;
• Immune system: infrequently – hypersensitivity; seldom – a Quincke's edema;
• Endocrine system: infrequently – disturbance of secretion of antidiuretic hormone;
• Metabolism: often – a hyperglycemia, a hypopotassemia, dehydration; infrequently – a cachexia, a hypercalcemia, a hyperuricemia, a hyperpotassemia, a hypernatremia, a hypocalcemia, a hypoglycemia, a hyponatremia, deficit of B12 vitamin, a hypophosphatemia, a hypomagnesiemia;
• Musculoskeletal system: very often – a mialgiya; often – ostealgias, weakness of muscles, skeletal and muscular pains, muscular spasms, extremity pains, dorsodynias, an arthralgia; infrequently – spasms of muscles, twitchings of muscles, muscular rigidity, hard mobility of joints, hypostases of joints, jaw pain;
• Reproductive system: infrequently – erectile dysfunction, pain in a small egg;
• Dermatological reactions: very often – skin rash; often – rash, an itch, urticaria, okologlaznichny hypostasis, reddenings, a xeroderma, eczema, sweating strengthening; infrequently – the generalized itch, a photosensitization, erythematic rash, bruise, makulezny rash, psoriasis, papular rash, dermatitis, generalized rash, a face edema, swelled a century, an alopecia, change of a xanthopathy, damage of nails, atopic dermatitis, night perspiration, change of structure of hair, small knots on skin, an ichthyosis; seldom – a syndrome It is twisted; very seldom – a toxic epidermal necrolysis, Stephens-Johnson's syndrome;
• Laboratory indicators: often – increase in activity of a lactate dehydrogenase in blood; infrequently – increase in activity of an alkaline phosphatase, gamma глутамилтрансферазы, amylases of blood, level of content of S-reactive protein, concentration of urea in blood, decrease in concentration of hydrocarbonates in blood;
• Others: very often – fervescence, strong fatigue, the surrounding herpes (including disseminated); often – grippopodobny symptoms, hypostases, weakness, an adynamy, feeling of an indisposition, peripheral hypostases, emergence of consecutive infection; infrequently – a fever, neuralgia, pressure sense and/or discomfort in a thorax, groin pain, increase in body weight, a syndrome of a lysis of a tumor, a complication because of a catheter; seldom – septic shock, a herpetic encephalomeningitis; very seldom – the progressing multifocal leukoencephalopathy;
• Local reactions: infrequently – phlebitis, a hyperemia, burning sensation, pain in the place of an injection; at an ekstravazation – an inflammation of a hypodermic fatty tissue.

At similarity of indicators of safety of use of Velcade at treatment of a mantiynokletochny lymphoma and multiple myeloma, the significant difference between them is that nausea, vomiting, a neutropenia, thrombocytopenia, anemia, fervescence is more often observed at patients with a multiple myeloma, and rash, an itch, a peripheral neuropathy – at patients with a mantiynokletochny lymphoma.

Special instructions

Treatment has to be carried out under observation of the doctor with practical experience of antineoplastic chemotherapy.

Intrathecal administration of drug leads to a lethal outcome.

Drug cannot be mixed with other medicines, the exception makes only 0,9% chloride sodium solution.

Prior to therapy and during each cycle carrying out an integrated analysis of blood with calculation of maintenance of thrombocytes and a leukocytic formula is necessary.

Velcade use most often causes development of passing thrombocytopenia, with the greatest decrease in level of thrombocytes by 11th day of a cycle. At quantity of thrombocytes less than 25 000/mkl therapy need to be suspended. Treatment of hematologic toxicity assumes use of colony stimulating factors, transfusions of an erythrocyte and platelet concentrate. After recovery of level of thrombocytes in blood use of drug can be continued after careful assessment of estimated advantage and risk of therapy.

During treatment performing rehydration therapy for maintenance of water and electrolytic balance is shown, at vomiting or diarrhea use of appropriate means is recommended.

Symptoms of a peripheral neuropathy is weakness, a hyperesthesia, a hypesthesia, paresthesia, a burning sensation and discomfort, neuropathic pain. When strengthening available or emergence of new symptoms the dose decline and change of the mode of use of drug with purpose of a maintenance therapy is possible.

Care at treatment of patients with epilepsy or spasms in the anamnesis is required.

Against the background of Velcade use orthostatic hypotension, sometimes with a temporary loss of consciousness often develops.

Extra care should be observed at treatment of patients with dehydration against the background of vomiting or diarrhea, with the instruction in the anamnesis on a diabetic neuropathy and faints, accepting antihypertensives. Patients have to be informed on need of the immediate address to the doctor at dizziness, feeling of "ease in the head" or a faint. At orthostatic hypotonia carrying out hydration, introduction of sympathomimetics and/or glucocorticoids, in case of need – a dose decline of antihypertensives is recommended.

Patients with risk factors of heart failure or with cardiac pathologies have to be in the anamnesis under careful medical control.

Patients with functional disorders of a liver should make appointment in lower initial doses, accompanying treatment with continuous monitoring regarding development of symptoms of toxicity.

Development of a reversible leykoentsefalopatichesky syndrome, the neurologic disturbance which is followed by spasms, a headache, increase in the ABP, confusion of consciousness, a lethargy, a blindness and other neurologic and visual disturbances is possible. At confirmation of the diagnosis a magnetic and resonant tomography of a brain it is necessary to cancel Velcade use.

Because of big risk of reactivation of the Varicella zoster virus, use of drug provides performing antiviral prevention.

At emergence or aggravation of symptoms of dysfunction of lungs it is necessary to carry out diagnosis and to immediately appoint the corresponding therapy.

As there is a risk of development of the hyperuricemia caused by a syndrome of a lysis of a tumor during treatment constant determination of level of creatinine and uric acid in blood serum is recommended. As prevention plentiful drink, urine alkalifying, Allopyrinolum is recommended to the patient.

At simultaneous use of peroral hypoglycemic means, it is regularly necessary to control the content of glucose in blood and to timely carry out dose adjustment of hypoglycemic drugs.

During treatment use of reliable methods of contraception is recommended.

The medical staff has to follow the standard rules of the address with cytotoxic means.

Because of risk of emergence against the background of therapy Velcade of dizziness, visual frustration, a faint and other side effects during treatment by the patient recommends to refrain from control of vehicles and mechanisms.

Medicinal interaction

Against the background of therapy only the attending physician can appoint Velcade simultaneous use of other medicines.

Terms and storage conditions

To store at a temperature up to 30 °C. To protect from children.

Period of validity – 3 years, after dissolution – no more than 8 hours at a temperature up to 25 °C.