Bortezomib

When ATH:
L01XX32

The antitumor agent, proteasome inhibitor. Bortezomib is a modified boric acid. Water solubility 3.3-3.8 mg / ml in a pH range 2–6,5. Molecular weight 384,24.

Pharmacological action.
Antitumor.

Application.

Mnozhestvennaya myeloma in patsientov, past, least, 2 treatment, who observed the progression of the disease after the last course.

Childhood (safety and effectiveness in children have not been established).

Can be given to pregnant women only if, if the benefits of treatment outweigh the potential risk to the fetus (adequate and well-controlled studies in pregnant women were not conducted). Unknown, whether bortezomib passes through the placenta. In the case of pregnancy or during planned pregnancy must notify the patient of the potential risk to the fetus. Women of childbearing age during therapy must use effective methods of contraception.

Category actions result in FDA - D. (There is evidence of the risk of adverse effects of drugs on the human fetus, obtained in research or practice, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk, if the drug is needed in life-threatening situations or severe disease, when safer agents should not be used or are ineffective.)

Bortezomib showed no teratogenic properties in preclinical toxicity studies in rats and rabbits at the highest dose tested (0,075 mg / kg; 0,5 mg / m² in rats and 0,05 mg / kg; 0,6 mg / m² rabbits) when administered during the period of organogenesis. These doses are approximately equivalent 1/2 Clinical dose 1,3 mg / m² based on body surface area.

In pregnant rabbits, receiving bortezomib during organogenesis at a dose of 0,05 mg / kg (0,6 mg / m²), there were significant post-implantation loss and decreased number of viable pups at birth. Cubs of these litters at birth also had lower body mass index.

Unknown, whether bortezomib penetrates into the breast milk of women. Because many drugs are excreted into breast milk and may have serious adverse effects on children, breastfed, at the time of bortezomib therapy must stop breast-feeding.

The results of two studies involving 228 patients with multiple myeloma, treated with bortezomib at a dose 1,3 mg / m² twice a week for 2 weeks with a 10-day break (the duration of treatment is 21 day) maximum for no more than 8 cycles.

The most common adverse events were asthenic conditions (including fatigue, general weakness, malaise) (65%), nausea (64%), diarrhea (51%), decreased appetite (including anorexia) (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (including peripheral sensory and worsening peripheral neuropathy) (37%), fever (36%), vomiting (36%), anemia (32%). At least 14% of patients experienced at least one episode 4 toxicity, the most common among them were thrombocytopenia (3%) and neutropenia (3%).

The following table shows the most common side effects, noted in clinical trials in patients, treated with bortezomib. All effects are included in the table were observed in patients ≥10%. The non-randomized study is often impossible to distinguish between adverse events, associated with drug administration and effects, due to illness.

Side effects, observed in clinical trials in patients treated with bortezomib (N=228)

Serious side effects. Serious side effects are defined as any event, Whatever the reason,, which had resulted in death, was life-threatening, require hospitalization or extended hospitalization current, leading to a significant powerlessness or otherwise considered important medical case.

During the study, serious side effects have been observed in 113 (50%) from 228 patients. The most common severe side effects were fever (7%), pneumonia (7%), diarrhea (6%), vomiting (5%), degidratatsiya (5%), nausea (4%).

Side effects, noted researchers as caused by taking medications and cause discontinuation of treatment, It has been observed in 18% patients. The reason for the cessation of drug administration served as peripheral neuropathy (5%), thrombocytopenia (4%), diarrhea (2%), fatigue (2%).

There were recorded two deaths, which were considered by researchers as presumably related to the study medication: one case of cardiac arrest due to cardio-pulmonary disease and one case — due to respiratory failure.

Asthenic conditions (fatigue, generalized weakness, malaise). Asthenia was observed in 65% patients and basically had 1 and 2 severity. Initially, fatigue observed most frequently during the 1st and 2nd cycles of therapy. Asthenia 3 severity was observed in 18% patients. Discontinued treatment because of an increased fatigue 2% patients.

Gastrointestinal Effects, observed in most patients-nausea, diarrhea, constipation, vomiting. Effects 3 and 4 severity were observed in 21% and they were identified as significant in 13% patients. Vomiting and diarrhea were heavy and had 3 severity in 7%, 4 the degree of is less than 1% patients. Discontinue treatment of disorders of the gastrointestinal tract 5% patients. Decreased appetite (anorexia) It was reported as an adverse event in 43% patients (3 severity — 3%).

Thrombocytopenia in the treatment of bortezomib was observed in 43% patients, it is characterized by a dose-dependent decrease in the number of platelets in the period of application of bortezomib (from 1 by 11 day) and returned to baseline levels during the break (days 12 by 21) in each cycle. Platelet counts decreased by 40% compared with the original. The values ​​were less than the number of platelets 50 th. cells / ml or less 10 th. cells / y 27 and 3% of patients, respectively. Discontinued treatment due to thrombocytopenia regardless of the degree of its severity 4% patients.

Peripheral sensory neuropathy. Neuropathy, including sensory and worsening peripheral neuropathy, He noted in 37% cases. Peripheral neuropathy 3 degree — 14%, There were no cases neuropathy 4 degrees. Initial symptoms or worsening of neuropathy was noted prior to treatment over the cycle. Neuropathy was the cause of drug withdrawal in 6% cases. More than 80% patients, surveyed, There were signs and symptoms of peripheral neuropathy in comparison with the initial state. The frequency of neuropathy 3 degree was 5% (2 from 41 patient) people with no prior neuropathy. Symptoms may improve or return to baseline levels in some patients to remove the drug. A complete assessment of the development of this depending on toxicity has not held.

Fever (>38 °C) It noted as a side effect from 36% patients and had 3 severity in 4% patients.

Neutropenia meets at 26% patients and had 3 severity in 13% cases and 4 the degree is in 3%. The incidence of febrile neutropenia was <1%.

Gipotenziya (including reports of orthostatic hypotension) I observed in 12% patients, Most cases have been 1 and 2 severity, in 4% - 3 degrees, no one was hypotension 4 severity. Patients, who noted orthostatic hypotension, We had no such early study, half of the patients had previous hypertension, in 1/3 -peripheral neuropathy. The doses of antihypertensive drugs can be adjusted in patients, receiving bortezomib. In 4% patients with hypotension, including orthostatic, occurred simultaneously fainting.

Serious side effects during clinical trials. Approximately 580 these patients experienced serious adverse effects (not described above), considered as possibly related to the treatment and noted at least one patient, bortezomib prepared as monotherapy or in combination with other chemotherapeutic agents. These studies were conducted in patients with hematological malignancies and tumors sólidnymi.

Diseases of the blood and lymphatic system: disseminated intravascular coagulation.

Heart disease: bouts of atrial fibrillation, auricular flutter, cardiac amyloidosis, cardiac arrest, congestive heart failure, myocardial ischemia, myocardial infarction, pericardial effusion, pulmonary edema, ventricular tachycardia.

Diseases of the digestive tract: ascites, dysphagia, fekaloma, hemorrhagic gastritis, gematemezis, pseudoileus, obstruction tolstogo kishechnika, obstruction tonkogo kishechnika, probodyeniye oil kishki, stomatitis, ground, acute pancreatitis.

Hepatobiliary System: giperʙiliruʙinemija, portalnoy veins thrombosis.

The immune system: anaphylactic reactions, hypersensitivity reactions.

Infections and infestations: bacteraemia.

Damage, poisoning, complications: fractures, subdural hematoma.

Metabolism and Metabolism: hypocalcemia, hyperuricemia, kaliopenia, giponatriemiya, tumor lysis syndrome.

Nervous system: ataxia, coma, dizziness, dysarthria, dysfunction of the autonomic nervous system, paralysis of the cranial nerves, seizures type grand mal, hemorrhagic stroke, movement disorders, spinal cord compression, tranzitornaya ishemicheskaya attack.

Psychiatry: ažitaciâ, confusion, psychosis, suicidal thoughts.

The kidneys and urinary tract: kidney stones, bilateral hydronephrosis, bladder spasm, hematuria, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferative.

Respiratory system: acute respiratory distress syndrome, atelectasis, exacerbation of chronic obstructive pulmonary disease, dysphagia, dyspnoea, shortness of breath on exertion, nose bleed, hemoptysis, gipoksiya, infiltration legkïx, pleural effusion, pneumonitis, respiratory distress, respiratory insufficiency.

Vascular: cerebrovascular disorders, deep vein thrombosis, peripheral embolism, pulmonary embolism.

Cooperation.

IN in vitro studies in human liver microsomes is shown, that bortezomib is a substrate for cytochrome P450 isoenzymes CYP3A4, CYP2D6, CYP2C19, CYP2C9, CYP1A2. The condition of patients, receiving both bortezomib and drugs, which are inhibitors or inducers of CYP3A4, It should be carefully monitored because of the possibility of toxic action, or reduce the effectiveness of therapy. During clinical trials reported hypoglycemia and hyperglycemia in patients with diabetes, taking oral hypoglycemic agents. Patients, while taking bortezomib and oral hypoglycemic drugs, You may need to monitor blood glucose levels and dose adjustment hypoglycemic agent.

Bortezomib is a weak inhibitor of hepatic microsomal cytochrome P450 isoenzymes CYP1A2 —, CYP2C9, CYP2D6, CYP3А4 с IC₅₀ >30 μM (>11,5 ug / ml). Bortezomib can inhibit the activity of CYP2C19 (IC₅₀=18 μM; 6,9 ug / ml) and increase the exposure of substances, which are substrates for this enzyme. Bortezomib does not induce CYP3A4 and CYP1A2 activity in primary cultures of human hepatocytes.

Overdose.

We describe a case of overdose bortezomib (exceeding the recommended doses over 2 times) patient with sepsis, have been fatal.

Symptoms: Acute development of symptomatic hypotension and thrombocytopenia.

Treatment: hemodynamic monitoring, maintaining vital functions, simptomaticheskaya therapy (incl. infuzionnaya therapy). Spetsificheskiy antidote unknown.

Dosing and Administration.

B /. The recommended dose 1,3 mg / m² bolus over 3-5 seconds twice a week for 2 Sun (in 1, 4, 8 and 11 day) after a 10-day break (12-21 days). For a long-term therapy 8 cycles can be administered the drug to the standard scheme or regimen — 1 once a week for 4 Sun (days 1, 8, 15 and 22) after 13-day break (23-35 days). Between the introduction of successive doses of bortezomib should be at least 72 no.

Precautions.

Bortezomib can be administered only by a physician, with experience in cancer chemotherapy.

Peripheral neuropathy. If you have neuropathy (cm. Side effects), predominantly sensory (Although there was other cases, incl. mixed sensory-motor neuropathy), supportive therapy. Patients with symptoms prior (insensitivity, pain or burning in the hands or feet) and / or signs of peripheral neuropathy may increase disease. There should be monitoring of patients for early detection of symptoms, as a burning sensation, giperesteziya, gipesteziya, paraesthesia, discomfort or neuropathic pain. When new or strengthen existing symptoms of neuropathy may require dose reduction and changes in dosage regimen.

Gipotenziya. Because bortezomib therapy accompanied by the development of orthostatic hypotension (cm. Side effects), which may occur during therapy, you should exercise caution when treating patients, with a history of episodes of loss of consciousness, receiving antihypertensive drugs, as well as in patients with dehydration during diarrhea or vomiting.

When using bortezomib described the development or enhancement of existing Congestive heart failure, to which may predispose fluid retention.

Prior to and during each cycle of therapy should be carried out blood count with leukocyte and platelet counts.

Thrombocytopenia usually the most pronounced on the 11th day of the cycle, platelet count recovered to its initial value for the next cycle (cm. Side effects). By reducing the number of platelets less 25 th. / ml therapy should be suspended, When restoring the number of platelets is to continue in small doses with careful comparison of the possible benefits and risks of treatment. There have been reports of gastrointestinal and intracerebral′nyh hemorrhages, associated with the called bortezomibom thrombocytopenia. For the treatment of hematological toxicity can be applied to the colony-stimulating factors, Platelet transfusion and eritrocitarna mass.

To prevent nausea and vomiting antiemetic drugs used, If you experience diarrhoea Antidiarrhoeal-HP, to prevent or treat dehydration-rehydration therapy and maintenance of vodno-elektrolitnogo balance. In connection with the possible development of intestinal obstruction should be dynamic observation of patients with constipation.

In connection with the possible development of hyperuricemia, associated with tumor lysis syndrome, during therapy is recommended to determine the concentration of uric acid and serum creatinine. To prevent gieperriquemii to drink —, If necessary, allopurinol and alkalinization of urine. In the treatment of patients with amiloidozom should exercise caution, tk. unknown impact of oppression activity of the proteasome in diseases, accompanied by an increase in protein content.

When working with the product should comply with the generally accepted rules of treatment with cytotoxic drugs.

Some side effects (fatigue, dizziness, orthostatic hypotension, blurred vision), may affect the ability to drive and to perform activities, require high concentration and psychomotor speed reactions, so be cautious.