Overview
Side effects of the drug Bortezomib
According to the results of studies involving 228 patients with Stada myeloma, receiving bortezomib at a dose of 1.3 mg / m2 twice a week for 2 weeks with a 10-day break (treatment cycle duration is 21 days) for a maximum of no more than 8 cycles. The most common side effects were asthenic conditions, including increased fatigue, general weakness, malaise (65%), nausea (64%), diarrhea (51%), decreased appetite, including anorexia (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy, including peripheral sensory and exacerbation of peripheral neuropathy (37%), fever (36%), vomiting (36%), anemia (32%). At least 14% of patients reported at least one episode of 4th degree toxicity, the most common among them were thrombocytopenia (3%) and neutropenia (3%).
The most common serious side effects were fever (7%), pneumonia (7%), diarrhea (6%), vomiting (5%), dehydration (5%), nausea (4%). Side effects noted by the researchers as medication-related and causing discontinuation of treatment were noted in 18% of patients. The reason for stopping the drug was peripheral neuropathy (5%), thrombocytopenia (4%), diarrhea (2%), increased fatigue (2%).
Asthenic conditions (fatigue, general weakness, malaise). Asthenia was noted in 65% of patients, mainly of the 1st and 2nd degree of severity. Initially, increased fatigue was most often observed during the 1st and 2nd cycles of treatment of patients. Discontinued treatment due to increased fatigue in 2% of patients.
Gastrointestinal Disorders, observed in most patients - nausea, diarrhea, constipation, vomiting. Vomiting and diarrhea were most often severe. Discontinued treatment due to disorders of the gastrointestinal tract in 5% of patients. A decrease in appetite (anorexia) was noted as a side effect in 43% of patients.
Thrombocytopenia during treatment with Bortezomib was determined in 43% of patients, it was characterized by a dose-dependent decrease in the number of platelets during the period of bortezomib use (from the 1st to the 11th day) and returned to the initial level during the break (days from the 12th to the 21st) in every cycle. The platelet count decreased by 40% compared with the original. Platelet counts were less than 50 thousand cells / μl and less than 10 thousand cells / μl in 27 and 3% of patients, respectively. Thrombocytopenia was discontinued due to its severity in 4% of patients.
Peripheral Sensory Neuropathy. Neuropathy, including sensory and exacerbation of peripheral neuropathy, was observed in 37% of cases. Initial manifestations or exacerbation of previous neuropathy was noted throughout the treatment cycle. Neuropathy was the cause of drug withdrawal in 6% of cases. More than 80% of the patients participating in the study showed signs and symptoms of peripheral neuropathy compared with the initial state. The incidence of neuropathy was 5% in people without prior neuropathy. Symptoms improved or returned to baseline in some patients after discontinuation of the drug. A complete assessment of the Stada of the development of this type of toxicity on time was not performed.
Fever (38 ° C) was reported as a side effect in 36% of patients.
Neutropenia was determined in 26% of patients, while in 13% of cases it was moderately expressed and pronounced in 3%. The frequency of febrile neutropenia was ≤1%.
Hypotension (including reports of orthostatic hypotension) was observed in 12% of patients. Patients with orthostatic hypotension did not have this at the beginning of the study, half of the patients had previous hypertension, and 1/3 had peripheral neuropathy. Doses of antihypertensive drugs can be adjusted in patients receiving bortezomib. In 4% of patients with hypotension, including orthostatic, syncope was noted simultaneously.
Special instructions for the use of the drug Bortezomib
bortezomib can only be prescribed by a doctor with experience in conducting antitumor chemotherapy.
Peripheral neuropathy. If neuropathy occurs during treatment prescription medicine bortezomib (see ADVERSE EFFECTS), predominantly sensory (although other cases have been noted, including mixed sensory-motor neuropathy), maintenance therapy is performed. In patients with previous symptoms (numbness, pain or burning in the arms or legs) and / or signs of peripheral neuropathy, an exacerbation of the disease is possible. Patients should be monitored for the timely detection of symptoms such as burning sensation, hyperesthesia, hypesthesia, paresthesia, discomfort or neuropathic pain. With the appearance of new or intensification of existing symptoms of neuropathy, a dose reduction and a change in the dosage regimen may be required.
Hypotension. Since bortezomib therapy is accompanied by the development of orthostatic hypotension, caution should be exercised in treating patients who have had a history of episodes of loss of consciousness, receiving antihypertensive drugs, and also in patients with dehydration due to diarrhea or vomiting. When using bortezomib, the for this or enhancement of existing congestive heart failure, to which fluid retention may predispose. Before and during each cycle of therapy, a blood test should be performed to determine the leukocyte formula and platelet count.
Thrombocytopenia usually most pronounced on the 11th day of the cycle, platelet count is restored to its original value for the next cycle. With a decrease in platelet count of less than 25 thousand / μl, therapy should be stopped, while recovery - continue in reduced doses with a careful comparison of the possible benefits and risks of treatment. There are reports of gastrointestinal and intracerebral hemorrhages associated with thrombocytopenia caused by bortezomib. Colony-stimulating factors, platelet and red blood cell transfusions can be used to treat hematologic toxicity. Antiemetic drugs are used to prevent nausea and vomiting, antidiarrheal drugs are used for diarrhea, rehydration therapy and water-electrolyte balance are used to prevent or treat dehydration. In connection with the possible development of Bortezomib obstruction, dynamic observation of patients with constipation should be carried out. In connection with the possible development of hyperuricemia associated with tumor lysis syndrome, it is recommended to determine the concentration of uric acid and creatinine in the blood serum during therapy. To prevent hyperuricemia, drink plenty of water, if necessary, prescribe allopurinol and alkalize urine. In the treatment of patients with amyloidosis, caution should be exercised, since the influence of inhibition of the proteasome activity in diseases accompanied by an increase in protein content is not known. When working with the drug, the generally accepted rules for handling cytotoxic drugs should be observed.
Childhood: safety and efficacy in children have not been established.
Toxicity study. Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the test in vitro on the cells of the ovary of a Chinese hamster. Did not show genotoxic properties in tests in vitro (Ames test) and in vivo (micronucleus test in mice). An assessment of the effect of bortezomib on the state of reproductive tissues was carried out in studies of general toxicity. In a 6-month toxicological study in rats, degenerative processes in the ovaries were determined at doses of ≥0.3 mg / m2 (1/4 of the recommended clinical dose) and degenerative changes in the testes at a dose of 1.2 mg / m2. Thus, bortezomib can have an effect on the fertility of both sexes.
Use during pregnancy and lactation. Bortezomib can be prescribed during pregnancy only if the benefits of therapy exceed the potential risk to the fetus (adequate and strictly controlled studies in pregnant women have not been conducted). It is not known whether bortezomib crosses the placenta. In the case of its use during pregnancy or when planning pregnancy, it is necessary to warn the patient about the potential risk to the fetus. Women of reproductive age should use effective contraceptive methods during therapy. It is not known whether bortezomib passes into breast milk can used women. Since many drugs are excreted in breast milk and can have a serious adverse effect on breast-fed babies, breast-feeding should be stopped during bortezomib therapy.
Some side effects (increased fatigue, dizziness, orthostatic hypotension, visual impairment) may affect the ability to drive a car and perform activities that require an increased concentration of attention and speed of psychomotor reactions, so special care should be taken.
Drug Interactions Bortezomib
In studies in vitro on human liver microsomes, it was shown that bortezomib is a substrate for cytochrome P450 isoenzymes CYP 3A4, CYP 2D6, CYP 2C19, CYP 2C9, CYP 1A2. The condition of patients receiving both bortezomib and drugs that are inhibitors or inducers of CYP 3A4 should be carefully monitored due to the possibility of developing a toxic effect or reducing the effectiveness of therapy. During clinical trials, hypoglycemia and hyperglycemia were reported Xylaze patients with diabetes taking oral hypoglycemic agents. Patients taking bortezomib and oral hypoglycemic drugs at the same time may need to monitor blood glucose levels and adjust the dose of the hypoglycemic agent.
Overdose of the drug Bortezomib
Symptoms acute development of symptomatic hypotension and thrombocytopenia.
Treatment: monitoring hemodynamic parameters, maintaining vital functions, symptomatic therapy (including infusion therapy). Specific antidote unknown.
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Dosage form
Bortezomib in Moscow
Highly selective reversible inhibitor of proteasome activity 26S, is a modified boric acid.
The proteasome 26S is present in the nucleus and cytosol of all eukaryotic cells and is a key component that catalyzes the breakdown of the main proteins involved in cell life cycle management. Bortezomib inhibits the chymotrypsin-like action of the proteasome, causes inhibition of proteolysis and leads to apoptosis.
Myeloma cells are almost 1000 times more susceptible to apoptosis caused by bortezomib than normal plasma cells.
The main factor explaining the ability of a bortezomib proteasome inhibitor to kill myeloma cells is its ability to block NF-kB activation. In normal cells, NF-kB (which exists as the p50-p65 dimer) is bound to the inhibitory protein LkB, which keeps it inactive in the cytosol.
Some tumors contain activated forms of NF-kB, and the proteasome plays an important role in this activation, since it catalyzes the proteolytic generation of the NF-kB p50 subgroup from the inactive p150 precursor and the destruction of the LkB inhibitory protein.
Activated NF-kB, penetrating the nucleus, Stada the cell survive and proliferate.
By inhibiting the proteasome and, therefore, inhibiting the activation of NF-kB, bortezomib helps to reduce the number of antiapoptotic Bortezomib, inflammatory molecules, cell adhesion molecules (which allow connective cells to attach to bone marrow cells) and cytokines (which stimulate myeloma cell growth).
Bortezomib causes a slowdown in the growth of human tumors in many experimental models, including multiple myeloma.
After a single iv injection, the concentration of bortezomib in the blood plasma decreases two-phase, the AUC is characterized by a fast initial phase of distribution and a longer final phase of excretion.
T1 / 2 bortezomib in the initial phase of distribution ranges from 5 to 15 hours.
