Concentrate for the preparation of a solution for infusions in the form of a transparent, almost colorless liquid.
1 ml
Clofarabine 1 mg
Excipients: sodium chloride - 9 mg, water d / and - up to 1 ml.
20 ml - bottles of glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
PHARMACHOLOGIC EFFECT
Mechanism of action: clofarabine is a purine nucleoside antimetabolite. Its antitumor effect, apparently, is due to 3 mechanisms:
- inhibition of DNA polymerase, leading to the cessation of DNA chain extension and / or DNA synthesis / repair;
- inhibition of ribonucleotide reductase with depletion of the cellular reserve of deoxynucleotide triphosphate (dNTP);
- violation of the integrity of the mitochondrial membrane with the release of cytochrome C and other apoptosis factors, which leads to programmed cell death, and even lymphocytes outside the fission phase.
Clofarabine must first diffuse or be transported to target cells, where it is sequentially phosphorylated by intracellular kinases to mono- and diphosphate, after which an active conjugate, clofarabine 5'-triphosphate, is formed. Clofarabine has a high affinity for one of the enzymes that activate phosphorylation, deoxycytidine kinase, which exceeds the affinity of the natural substrate of deoxycytidine kinase-deoxycytidine.
In addition, clofarabine has a higher resistance to destruction in cells under the influence of adenosine deaminase and a reduced susceptibility to phosphorylated cleavage, compared to other active substances of the same class, whereas the degree of affinity of clofarabine triphosphate with DNA polymerase? and ribonucleotide reductase is equal to or greater than that of deoxyadenosine triphosphate.
Pharmacodynamic effects: In vitro studies have shown that clofarabine slows down cell growth and exerts a cytotoxic effect on many rapidly proliferating cell lines in tumors of hematopoietic cells and solid tumors. Also clofarabine showed activity against lymphocytes and macrophages at rest. In addition, clofarabine slowed tumor growth and, in some cases, caused regression of a number of mouse and mouse tumor xenografts implanted in mice.
Clinical efficacy and safety
The efficacy and safety of clofarabine has been studied in patients with acute lymphoblastic leukemia (mean age 12 years) who were diagnosed at the age of 21 years and who had a second or subsequent relapse and / or refractory to treatment (ie, ineffectiveness at least two previous courses of chemotherapy). 95% of patients previously received 2-4 courses of induction chemotherapy schemes, in 30% of patients, at least one transplantation of hematopoietic stem cells was performed before.
The use of clofarabine in 94% of patients led to a sharp and rapid decrease in the number of leukemia cells in the peripheral blood. Complete remission was achieved in 12% of patients (median duration of remission 47.9 weeks), complete remission with the exception of complete platelet count recovery in blood was achieved in 8% of patients (with a median duration of 28.6 weeks), partial remission was achieved in 10% of patients (with median duration of 11.0 weeks), inefficiency of treatment was observed in 54% of patients. Remissions were observed with different immunophenotypes of acute lymphoblastic leukemia, including pre-B-cell and T-cell.
PHARMACOKINETICS
The pharmacokinetics of clofarabine with its repeated intravenous infusion introduction was studied in 40 patients aged 2-19 years with relapsing or refractory to treatment with acute lymphoblastic leukemia (ALL) and acute myeloid leukemias (AML).
V d (in the equilibrium state) is 172 l / m 2 . Binding to blood plasma proteins is 47.1%, with albumin of blood serum - 27.0%.
T 1/2 of clofarabine is 5.2 h, T 1/2 of clofarabine triphosphate (metabolite of clofarabine) is more than 24 h.
The total ground clearance is 28.8 l / h / m 2, the renal clearance is 10.8 l / h / m. The kidneys deduce 57% of the administered dose.
Multivariate analysis showed that the clofarabine pharmacokinetics is weight-dependent and although it was found that the number of leukocytes in the peripheral blood affects the pharmacokinetics of clofarabine, this factor was not sufficient to select an individual dose for the patient depending on the magnitude of the leukocytosis. With a wide range of patient body weight, IV infusion of clofarabine at a dose of 52 mg / m 2 of body surface resulted in an equivalent exposure.However, C max of clofarabine was inversely proportional to the body weight of the patient, therefore in small children at the end of infusion C max may be higher than in a child weighing 40 kg (the most common body weight of children in this study) receiving the same dose Clofarabine per 1 m 2 of the body surface. Therefore, children with a body weight of less than 20 kg should consider increasing the infusion time (see section "Dosage regimen").
Clofarabine is excreted both by the kidneys and by the adrenal route. About 60% of the administered dose of clofarabine after 24 hours is excreted by the kidneys unchanged. Clofarabine clearance significantly exceeds glomerular filtration, which indicates that the main mechanisms of renal elimination are not only glomerular filtration, but also tubular secretion. However, since clofarabine is not practically metabolized by cytochrome P450 isoenzymes (CYP), the pathways of extrarenal excretion are currently unknown.
There were no apparent differences in pharmacokinetics in patients with ALL or AML, as well as in males or females.
In this population, no relationship was found between the systemic exposure of clofarabine or clofarabine triphosphate and the efficacy or toxicity of the drug.
Individual patient groups
Adults (age 21-65 years)
The pharmacokinetics of clofarabine in adults with relapsed or refractory AML after a single intravenous administration of clofarabine 40 mg / m 2 for 1 hour was comparable to the pharmacokinetics described above in patients aged 2-19 years with recurrent or refractory ALL or AML after two-hour intravenous infusion of clofarabine at a dose of 52 mg / m 2 for 5 consecutive days.
Patients with renal insufficiency
At the moment, data on the pharmacokinetics of clofarabine in patients with reduced QC is not enough. Nevertheless, the available evidence suggests that clofarabine can accumulate in the body of these patients.
Data from population pharmacokinetics in patients with pediatric patients with stable renal dysfunction of moderate severity (QC 30 to 60 ml / min) confirmed that in these patients, when the dose was reduced by 50%, the same systemic exposure of clofarabine was achieved as in patients with normal function of the kidneys receiving a standard dose of clofarabine.
Patients with hepatic insufficiency
There is no experience of using the drug in patients with hepatic impairment (see section "Special instructions").
INDICATIONS
- treatment of acute lymphoblastic leukemia (ALL) in children older than 1 year with relapse or refractoriness to therapy after using at least two previous chemotherapy regimens and in the absence of other methods of achieving persistent remission. Safety and efficacy were studied in patients aged no more than 21 years at the time of diagnosis.
DOSING MODE
Treatment should be carried out under the supervision of a doctor who has experience in treating patients with acute leukemia.
Adults (including elderly patients)
At present, there is insufficient data on the efficacy and safety of clofarabine in adults over 21 years of age.
Children (over 1 year old)
The recommended dose of clofarabine is 52 mg / m 2 body surface area, which is administered by IV infusion for at least 2 hours daily for 5 consecutive days. The surface area of ​​the body should be calculated based on the actual height and body weight of the patient before the start of each cycle. Cycles of therapy should be repeated every 2-6 weeks (from the first day of the previous cycle) after restoration of normal hematopoiesis (ie, with an absolute number of neutrophils [ACHN]> 0.75 × 10 9 / L) and the return of organ function to the initial state. In patients with severe toxicity, the dose in the next cycle should be reduced by 25% (see below).
In most patients who respond to clofarabine treatment, remission is achieved after one or two cycles of therapy. Therefore, in patients without hematologic and / or clinical improvement after 2 cycles of therapy, the attending physician should assess the relationship between the potential risk and the benefit of continuing treatment.
At present, there is limited experience in assessing the efficacy and safety of more than 3 cycles of clofarabine therapy.
Children (with a body weight of less than 20 kg)
To reduce anxiety and irritability, and to avoid creating excessively high concentrations of clofarabine in the blood, infusion time in children weighing less than 20 kg should be more than 2 hours (see section "Pharmacokinetics").
Patients with renal insufficiency
The limited data available indicate that clofarabine can accumulate in patients with reduced QC. The use of the drug in patients with severe renal failure (CC less than 30 ml / min) is contraindicated, with moderate and moderate renal insufficiency with this drug should be used carefully (see section "Special instructions"). In patients with moderate renal insufficiency of moderate severity (CK from 60 to 30 ml / min), a dose reduction of 50% is required (see the section "Pharmacokinetics").
Patients with hepatic insufficiency
The experience of using clofarabine in patients with impaired hepatic function (bilirubin serum> 1.5? VGN, ALT and ACT> 5? VGN) is not present, but it should be borne in mind that the liver is a potential target organ for toxic action. In this regard, clofarabine is contraindicated in patients with severe hepatic insufficiency, and should be used with caution in patients with mild and moderate hepatic impairment (see section "Special instructions").
Dose reduction in patients with hematologic toxicity
If the number of neutrophils is not restored 6 weeks after the start of the therapy cycle, aspiration or bone marrow biopsy should be performed to determine the possible refractoriness of the disease to treatment. If there are no signs of persistent leukemia, then after restoring the number of neutrophils to? 0.75? 10 9 / l, in the next cycle it is recommended to reduce the dose by 25% compared to the previous dose. If the number of neutrophils <0.5 Г— 10 9 / L is maintained for more than 4 weeks after the start of the last cycle, then in the next cycle it is recommended to reduce the dose by 25%.
Dose reduction in patients with non-hematologic toxicity
Infections
When a clinically significant infection develops in a patient, clofarabine therapy is postponed until the clinical symptoms of an infectious disease disappear, after which the therapy can be resumed with a full dose. With the re-development of a clinically significant infection, clofarabine therapy should be suspended until the clinical symptoms of the infectious disease disappear, then resume treatment, reducing the dose by 25%.
Non-infectious episodes (toxicity)
If a patient develops one or more severe toxic effects (3-degree toxicity according to the Common Cancer Institute of the United States National Cancer Institute, except for nausea and vomiting), therapy should be deferred until the toxic effect is resolved , and indicators of the patient's condition will return to baseline values ​​or until the moment when toxicity ceases to be severe in severity, and the potential benefit from continuing treatment with clofarabine will exceed a lawsuit related to its use. In this case, it is recommended to reduce single doses of clofarabine by 25%.
If the patient is repeatedly experiencing the same severe toxicity, therapy should be postponed until the patient returns to baseline values ​​or until toxicity ceases to be severe in severity, and the potential benefit of continuing clofarabine treatment will exceed the risk associated with his application. In this case, when using clofarabine, it is recommended to reduce the dose by another 25%.
If the patient develops a severe toxic effect for the third time, as well as signs of severe toxicity, do not respond to treatment for 14 days (excluding nausea and vomiting), or if there are life-threatening or disabling toxic effects (grade 4 toxicity according to NCI STS USA) , treatment with clofarabine should be discontinued.
Mode of application
The flavors of the drug Evoltra are intended only for single use!
The drug Evoltra - concentrate for the preparation of a solution for infusions of 1 mg / ml, must be diluted before administration. The drug is filtered using a sterile syringe filter with a pore size of 0.2 Ојm and then diluted with 0.9% sodium chloride solution to the volumes recommended in the table below. However, depending on the condition of the patient and the doctor's decision, the final volume of the prepared infusion solution may differ from the recommended volumes of the infusion solution. In the absence of a sterile filter with a pore size of 0.2 Ојm, the concentrate should be pre-filtered with a filter with a pore size of 5 Ојm, diluted and then introduced through a 0.22 Ојm filter mounted in an in-feed system.
The proposed scheme of dilution of the drug based on the recommended dose of clofarabine 52 mg / m 2 / day
Body surface area, m 2 Concentrate, ml * Total volume of prepared solution, ml
? 1.44? 74.9 100
From 1.45 to 2.40 From 75.4 to 124.8 150
From 2.41 to 2.50 From 125.3 to 130.0 200
* - 1 ml of concentrate contains 1 mg of clofarabine. In one 20 ml bottle contains 20 mg of clofarabine. Thus, for patients with a body surface area of? 0.38 m 2 , only a portion of the contents of one vial is required to prepare the recommended daily dose of clofarabine. However, for patients with a body surface area> 0.38 m 2, 1 to 7 vials are required to prepare the recommended daily dose of clofarabine.
The diluted concentrate should be a clear and colorless solution. Prior to administration, the solution is visually inspected to detect foreign particles and discoloration.
The drug Evoltra is recommended to be administered by IV infusion, although in ongoing clinical trials the drug was administered through a central venous catheter.The drug Evoltra should not be mixed with other drugs or other medications through the same system for intravenous administration.
From a microbiological point of view, the diluted solution should be administered to the patient immediately. If the preparation has not been administered to the patient immediately after preparation, the user is responsible for the storage time and storage conditions prior to use and, if the dilution does not occur in controlled and validated aseptic conditions, the storage time should not exceed 24 hours when the diluted solution is stored at a temperature of 15 В° C to 30 В° C.
SIDE EFFECT
The information in this section is based on data from clinical trials in which 115 patients (aged> 1 and n = 21 years) with ALL or with AML were treated with clofarabine at a dose of 52 mg / m 2 daily for 5 consecutive days. Undesirable reactions are divided into system-organic classes. To indicate the frequency of their development, the following classification was used: very often (? 10%); often (? 1% and <10%); infrequently (? 0.1% and <1%); rarely (? 0.01% and <0.1%); very rarely (<0.01%). The undesirable reactions observed during the post-marketing use of the preparation are included indicating the frequency of their occurrence: the frequency is unknown (according to available data it is not possible to estimate the frequency of development of the undesired reaction). In each frequency group, adverse reactions are presented in order of decreasing significance.
Patients with advanced stages of ALL or AML may have coexisting conditions that make it difficult to determine the cause of adverse reactions due to the variety of symptoms associated with the underlying disease, its progression, and simultaneous administration of a large number of other medications.
Virtually all patients (98%) had at least one adverse reaction, which was regarded as associated with clofarabine. Most commonly, nausea (61%), vomiting (59%), febrile neutropenia (35%), headache (24%), rash (21%), diarrhea (20%), pruritus (20%), fever (15%), fatigue syndrome (14%), anxiety (12%), inflammation of the mucous membranes (11%), and "hot flushes" of the blood to the skin (11%). In 68 patients (59%), there was at least one serious undesirable reaction associated with the use of clofarabine.
Infectious and parasitic diseases: often - septic shock, septicemia, bacteremia, pneumonia, herpes zoster, herpes simplex, oral candidiasis (candidiasis of the oral mucosa); frequency is unknown - colitis caused by Clostridium difficile.
Benign, malignant neoplasms and unspecified (including cysts and polyps) frequently - tumor lysis syndrome.
Blood disorders and lymphatic system: very often - febrile neutropenia; often - neutropenia.
Disorders of immune system: often - hypersensitivity.
Violations by the Metabolism and nutrition:often - anorexia, decreased appetite, dehydration; frequency is unknown: hyponatremia (for post-registration application).
Mental disorders: very often - anxiety; often - agitation, anxiety, altered mental status.
Disorders of the nervous system: very often - headache; often - somnolence, peripheral neuropathy, paresthesia, dizziness, tremor.
Violations by the organ of hearing and labyrinth disorders: often - Gipoakuzija (hearing loss).
Violations of the heart: often - pericardial effusion, and tachycardia.
Violations by vessels: very often - "tides" of blood to the skin; often - arterial hypotension; increased capillary permeability syndrome; hematoma.
Violations of the respiratory system and organs of thoracic and mediastinal disorders: often - respiratory distress syndrome, epistaxis, dyspnea, tachypnea, cough.
Violations of the digestive system: very often - nausea, vomiting; diarrhea; often - bleeding from the mouth, bleeding gums, hematemesis, abdominal pain, stomatitis, epigastric pain, rectalgia, ulcers of the oral mucosa; the frequency is unknown - increased activity of amylase and lipase in serum against the background of pancreatitis; enterocolitis (including neutropenic colitis, typhlitis and colitis caused by Clostridium difficile).
Violations of the liver and biliary tract: often - hyperbilirubinemia, jaundice, veno-occlusive disease, increased ALT and ACT.
General disorders and disturbances at the injection site:very often - fatigue, fever, inflammation of the mucous membranes; often - poliorganiaya failure, systemic inflammatory response syndrome, pain, fever, irritability, edema, peripheral edema, hot flashes, malaise.
Violations of the skin and subcutaneous tissue disorders: very often - a syndrome of palmar-plantar eritrodizestezii, itching; often - maculo-papular rash, petechiae, erythema, rash, itching, peeling of the horny layer of the epidermis, generalized rash, alopecia, generalized erythema, hyperpigmentation of the skin, erythematous rash, dry skin, rash; frequency is unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis.
Violations by musculoskeletal and connective tissue disorders:often - pain in the extremities, myalgia, bone pain, chest pain, arthralgia, pain in the neck and back.
Violations by the kidneys and urinary tract: often - hematuria.
Laboratory and instrumental data: often - weight loss.
Injury, poisoning and complications of manipulation: often - a bruise.
Description of the individual adverse events
Infectious and parasitic diseases
In applying klofarabina 18.3% of patients reported the development of bacterial, fungal and / or viral infections associated with the use klofarabina; when applied post-registration of deaths reported these infections. These infections can also lead to the development of septic shock, respiratory failure, renal failure and / or multiple organ failure.
Violations of the blood and lymphatic system
The most commonly in patients receiving therapy klofarabinom, anemia (83.3%), leukopenia (87.7%), lymphopenia (82.3%), neutropenia (63.7%) and thrombocytopenia (80.7%). Most of these events were? 3 severity.
When applied post-registration klofarabina reported with prolonged cytopenias (thrombocytopenia, anemia, neutropenia, leukopenia) and bone marrow insufficiency. When thrombocytopenia observed bleeding. It was also reported bleeding, including cerebral, gastrointestinal or pulmonary bleeding, which could be fatal.
Heart Disease
In 50% of patients had at least one violation of the heart. 11 cases out of 115 patients were assessed as related to klofarabinom and most often mentioned development tachycardia (in 6.1% of patients tachycardia was assessed as related klofarabinom).
At 9% of patients had pericardial effusion and pericarditis, which in most cases are asymptomatic with mild or clinically insignificant features detectable with echocardiography. In 2 patients pericardial effusion was clinically significant, and was accompanied by impaired hemodynamics.
Vascular disorders
In 55.7% of patients had at least one violation of the vessels. In 23 patients of the 115 violations of the vessels were regarded as related to the use klofarabina. The most frequently observed "tides" of blood to the skin and hypotension. However, the most serious cases of arterial hypotension was observed in patients with severe opportunistic infections.
Systemic inflammatory response syndrome and increased capillary permeability syndrome
In applying klofarabina reported with systemic inflammatory response syndrome (SIRS) and increased capillary permeability syndrome (due to the action klofarabina because there is a rapid decrease in the number of leukemic cells and cytokine release; symptoms and signs are tachypnea, tachycardia, hypotension, pulmonary edema) (see. section "Special instructions"). When the post-registration application klofarabina reported with increased permeability of vascular syndrome with fatal consequences.
Disorders from the digestive tract
Enterocolitis (including neutropenic colitis, typhlitis and colitis caused by Clostridium difficile), developing the application klofarabina can lead to complications in the form of necrosis, intestinal perforation or sepsis and end lethal.
When the post-registration application klofarabina informed about the development of gastrointestinal bleeding, which could end in death.
Patients receiving klofarabin, often noted the development of vomiting and diarrhea, which may be accompanied by the following symptoms: dehydration, dizziness, a feeling of "lightness" in the head, fainting and decrease in urine output (see "Cautions".).
Disorders of the liver and biliary tract
The liver is a potential target organ for toxic effect klofarabina. In 25.2% of patients had at least one adverse event of the liver and biliary tract. 6 serious adverse events were assessed as related to klofarabinom acute cholecystitis, cholelithiasis, liver hepatocellular fatal hyperbilirubinemia. We were also received 2 reports on the development of veno-occlusive disease in children.
In addition, in 50 of 113 patients receiving klofarabin, were significantly pronounced increase in ALT activity in serum (at least 3 degrees of severity NCI CTC USA); 36 out of 100 patients showed an increase ACT activity in serum and in 15 of 114 patients had increased bilirubin concentration in blood serum. Most cases increasing the activity of ACT ALT and observed for 10 days after administration and were allowed to klofarabina 2 degree and less than 15 days. Increase in serum bilirubin concentrations was reduced to 2 severity within 10 days.
When the post-registration application klofarabina pediatric and adult patients had adverse reactions severe liver toxicity in the form of veno-occlusive disease, which could end up lethal. Most of these patients received a conditioning regimen that included busulfan, melphalan and / or a combination of cyclophosphamide and total body irradiation.
Violations of the skin and subcutaneous tissue
development Stevens-Johnson syndrome and toxic epidermal necrolysis, including cases with fatal outcome, have been observed in patients receiving or have recently received treatment klofarabinom and other medications (eg, allopurinol or antibacterial agents), which are known to cause these syndromes. Also noted other states, accompanied by symptoms of exfoliation.
Disorders from the kidneys and urinary tract
The most common manifestation of nephrotoxicity klofarabina children had increased creatinine concentration in the serum (8% of patients - up to 3 or 4 degrees.).kidney impairment can facilitate reception nephrotoxic drugs, lysis of tumor and tumor lysis with hyperuricemia (see. the "Special instructions"). Also noted the development of hematuria and acute renal failure.
CONTRAINDICATIONS
- klofarabinu or hypersensitivity to excipients of the formulation;
- severe renal insufficiency;
severe hepatic impairment;
- Children up to age 1 year (lack of data on safety and efficacy of klofarabina in this age group);
- Pregnancy;
- lactation (breast-feeding should be discontinued prior to, during and after treatment with Evoltra in connection with the possibility of serious adverse reactions in children).
Carefully
- in renal failure mild or moderate severity (accumulation of the drug may require dose adjustments, see "Dosage.");
- with mild or moderate hepatic insufficiency (see section "Special instructions.");
- in patients who have undergone previous transplantation of hematopoietic stem cells (see "Cautions".).
PREGNANCY AND LACTATION
Pregnancy
There are no data on the use klofarabina in pregnant women. Klofarabin can cause the development of severe birth defects. The drug Evoltra should not be used during pregnancy. If pregnancy occurs during treatment klofarabinom, the patient should be warned of its possible adverse effects on the fetus.
Women of childbearing age and men who are having sex during treatment should use reliable methods of contraception.
Breastfeeding period
is not known whether klofarabin excreted or its metabolites in breast milk. However, because of the possibility of serious adverse reactions in children, breast-feeding should be discontinued prior to, during treatment and after treatment with Evoltra.
Effect on Fertility
Because klofarabina impact on reproductive function in humans is unknown, the child's conception, planning should be discussed with the patient in each case separately.
APPLICATION FOR FUNCTIONS OF THE LIVER
Precautions apply to patients with renal failure mild or moderate severity.
Not use this drug in patients with severe renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Precautions apply to patients with mild to moderate hepatic impairment.
Not use this drug in patients with severe liver failure.
APPLICATION FOR CHILDREN
Contraindicated for use under the age of 1 year the drug for children and adolescents (there is no data on the safety and efficacy of klofarabina in this age group).
SPECIAL INSTRUCTIONS
Evoltra drug is a potent anticancer agent with potentially significant hematological and non-hematological adverse reactions (see. The section "Side effect").
Patients receiving klofarabinom therapy should be carefully monitored following indicators:
- complete blood count with platelet count on a regular basis; in patients who develop cytopenias, these tests should be repeated more often;
- renal and hepatic function before treatment, during treatment and after active treatment; while substantially increasing the concentration of creatinine or bilirubin, the treatment should be stopped immediately klofarabinom;
- respiratory function, blood pressure, fluid and electrolyte balance and body weight during and immediately after the 5-day therapy klofarabinom.
We should expect the suppression of bone marrow function, which is usually reversible and dose-dependent. Patients treated klofarabinom therapy, there was severe bone marrow suppression, including, neutropenia, anemia, and thrombocytopenia. In addition, in clinical trials at the beginning of treatment, most patients were haematological disorders, which are manifestations of leukemia. Due to the attenuation existing immunity and prolonged neutropenia, which can develop in the treatment klofarabinom, patients are at risk of severe opportunistic infections, including sepsis, with potentially fatal consequences. Patients should be constantly observed for signs and symptoms of infection and implement appropriate therapy.
During treatment klofarabinom reported cases of enterocolitis, including neutropenic colitis, typhlitis and colitis caused by Clostridium difficile, which are often developed within 30 days of starting treatment and the application of combination chemotherapy. These diseases can lead to complications such as the development of necrosis, intestinal perforation, or septicemia, which can be fatal. Therefore patients should be monitored for early signs and symptoms of enterocolitis.
When applying klofarabina reported on the development of Stevens-Johnson syndrome and toxic epidermal necrolysis, including cases with fatal outcome. With the development of exfoliative or bullous rash, or in cases of suspected development of Stevens-Johnson syndrome and toxic epidermal necrolysis, klofarabinom therapy should be discontinued. Application klofarabina leads to a rapid decrease in the number of peripheral leukemic cells. Patients receiving therapy klofarabinom must constantly monitor for the occurrence their manifestations and lysis syndrome symptoms tumor and release of cytokines (such as tachypnea, tachycardia, hypotension, pulmonary edema), which may lead to the development of systemic inflammatory response syndrome (SIRS), increased capillary permeability syndrome and / or organ dysfunction.
- In the case of the expectations of hyperuricemia (occurs when tumor lysis syndrome) should consider prophylactic use of allopurinol.
- Patients must be on / in the introduction of liquids throughout the 5-day period klofarabinom treatment for reducing tumor lysis effects and other complications.
- Prophylactic use of corticosteroids (e.g., 100 mg / m 2 of hydrocortisone from the 1st to the 3rd day of the cycle klofarabinom therapy) may be useful in preventing the development of SIRS or increased capillary permeability syndrome.
When the early signs of SIRS, increased permeability of capillaries syndrome or severe organ dysfunction should immediately stop the introduction klofarabina and begin treatment of severe complications. Furthermore, the treatment should be discontinued klofarabinom by decreasing blood pressure for any reason during the 5-day period of administration. After stabilization
