Alexan

Alexan is a drug of antineoplastic character, which has cytotoxic activity, affecting various cellular forms at the S-stage stage.

The drug contains in its composition an element such as cytarabine; It participates in intracellular metabolic processes in which it forms a therapeutic active derivative of cytarabine-5-triphosphate (also called ara-CTP).

The cytarabine component is a subgroup of antimetabolites that are pyrimidine antagonists.

Indications Alexana

It is used to achieve remission and further support it in people with non-lymphoblastic leukemia in the active phase.

In addition, it is prescribed for leukemia of a different form, including the myeloblastic type of leukemia in the chronic phase (during the blast crisis), as well as the active phase of a lymphocytic leukemia character.

It is possible to use for the treatment and prevention of meningitis of a leukemic character (it is necessary to inject an agent intrathecally) - monotherapy is carried out or combined schemes are applied.

It is necessary to take into account that the remission obtained after the administration of cytarabine is short, if the supporting procedures are not performed.

In large portions, the drug is prescribed for leukemia, against which there is a high probability of complications, relapse of leukemia in the active phase and refractory leukemia.

May be given in combination for children with NHL.

Cytarabine is used in the treatment of various forms of tumors; A positive reaction was observed in some patients with solid tumors.

[1]

Release form

The therapeutic component is released in the form of injection and infusion fluid - inside glass bottles (their capacity for 20 mg / ml is 5 ml, and for 50 mg / ml - 10, 20 or 40 ml). The box contains 1 such bottle.

Pharmacodynamics

The drug effect has a phase-specific form - its implementation is carried out exclusively at the S-stage of the cell cycle. The principle of ara-CTP drug activity is not fully defined; in theory, the cytotoxic effect develops when the action of DNA polymerase is slowed down. At the same time, cytotoxic activity may be associated with incorporation of cytarabine into DNA and RNA molecules.

During testing, the drug showed a cytotoxic effect on a specific range of cultures of breeding cells in mammals.

[2]

Pharmacokinetics

After ingestion, cytarabine does not show activity (because it demonstrates a low degree of absorption and a high metabolic rate). In the case of continuous intravenous injection inside the plasma, almost constant drug indicators are formed. After intramuscular or subcutaneous injections, the Cmax values of cytarabine are determined after 20–60 minutes; in this case, after i / m and s / c use, the indicators of the substance are lower than those recorded after i / v injection.

Patients have noticeable personal variability of cytarabine values when using the same portions (some tests allow us to conclude that such fluctuations can be a prognostic factor of therapeutic effectiveness — with higher plasma values, the probability of hematological remission is higher).

After IV injection, the drug does not pass well through the BBB, which is why it should be used intrathecal when used in people with neuroleukemia.

Under the influence of nucleotidase, the active element is transformed into an active species inside healthy bone marrow, as well as blast leukemic cells. Active derivative further undergoes metabolic processes with the formation of inactive components (mainly within the liver tissues, and, less, within the blood with the tissues). The ratio of deoxycytidine kinase with cytidine deaminase (participating in cytarabine metabolism) is very important, because it helps to identify cellular sensitivity with respect to drugs.

Approximately 13% of the substance is synthesized with whey protein (in the range of 0.005-1 mg / l).

In the case of high-speed infusion, the drug is excreted in 2 phases with the term half-life, which is first 10 minutes and then 1-3 hours. About 80% of the administered dose of drug is excreted in 24 hours through the kidneys (mainly in the form of derivatives).

The term elimination half-life of a medicament from the tissues of the central nervous system is 3-3.5 hours.

[3], [4], [5], [6], [7]

Dosing and administration

The treatment is performed at the hospital under the supervision of an oncologist, who has previously conducted therapy for similar diseases. The drug is used in monotherapy or in combination regimens.

Before the start of the treatment course, the heart and liver are tested, and in addition, a quantitative blood test. Before prescribing a drug, it is necessary to correlate the benefits and the probability of risks. During the treatment cycle, a quantitative blood test is performed daily, and at the same time it is recommended to record the serum values of uric acid (in case of hyperuricemia, the necessary supporting measures are taken).

When using drugs, one should carefully choose solvents (especially for intrathecal injections). With the introduction of high dosages can not use solvents containing preservatives. It is required to inject saline NaCl or 5% glucose.

In case of infusions at high speed, patients rather well tolerate high dosages of Alexan, in comparison with low infusion rates (this is caused by rapid metabolic processes and short exposure in the case of rapid infusion). In clinical terms, the advantages of a fast type of use over a slow one were not found.

Perhaps the use of a / in (infusion or injection) method, but also intrathecal or s / c administration. In the case of s / c injections, the portion is 0.02-0.1 g / m ², taking into account the indications.

The sizes of dosages at different violations.

Remission in case of leukemia.

To obtain remission in this case, you need to use intermittent or long-term treatment.

In the case of an extended cycle, a bolus method is used - 2 mg / kg per day (10-day course). If the result (and toxic effect) is absent, the portion can be increased to 4 mg / kg per day - until either remission is obtained or signs of toxicity occur.

For infusions, 0.5-1.0 mg / kg of drugs per day is used (the duration of the infusion is a maximum of 24 hours). After 10 days, the portion can be increased to 2 mg / kg; such treatment is continued until remission or toxic manifestations occur.

In the case of a discontinuous cycle, 3-5 mg / kg of the drug is administered per day by the IV method (5 days). After that, they make a 2-9-day break and carry out a new cycle. With such a scheme, treatment is carried out before obtaining remission or the development of toxicity.

The bone marrow begins to recover by about the 7-64th day (on average, this happens by the 28th day). The amount of medication may increase if there is no therapeutic effect and toxicity. The duration and frequency of cycles is calculated depending on the clinical picture and the values of the functional bone marrow activity.

After receiving remission, you need to perform maintenance procedures - 1-2 v / v or v / m injection per week in 1-fold portions of 1 mg / kg.

NHL therapy.

Adults use a variety of schemes with the introduction of several different chemotherapeutic agents.

For children, the combined method is also used, which takes into account the histological type and phase of the tumor. Only the attending doctor can pick up the portion.

Use large portions.

If the use of high dosages is required, they are often administered via infusion intravenously at 2–3 g / m ²  (duration — 1–3 hours) at 12-hour intervals. The cycle is 4-6 days.

Intrathecal administration of the drug.

In this way, the drug is used in monotherapy or in combination with hydrocortisone and methotrexate. The portion is selected, taking into account the type of the disease (it must be taken into account that in case of focal destruction of the central nervous system due to leukemia, intrathecal administration of the drug may be ineffective, which is why radiation therapy is recommended in such situations).

In the case of the intrathecal type of administration, the dosage range is usually in the range of 5-75 mg / m ²  (mean 30 mg / m ² ). It is necessary to apply Alexan 1 times in 4 days, until a normal level of CSF is obtained. Portions are selected based on the effect of previous treatment, severity of symptoms and tolerability of drugs.

When the performance improves, you need to continue therapy. When the need for dilution of the drug for intrathecal injections, can be applied only saline NaCl, not containing preservatives.

Special categories of treatment.

In case of problems with the secretory activity of the kidneys or with the work of the liver, it is necessary to use drugs with extreme caution. A higher likelihood of toxicity is expected in these patients with high-dose therapy.

Persons over the age of 65 need to closely monitor their blood function, because their drug tolerance is impaired. If required, they are assigned supportive measures, and therapy in large chunks is allowed only after evaluating all possible risks.

[14], [15], [16]

Use Alexana during pregnancy

If Alexan needs to be used in the first trimester, the risks of fetal complications should be taken into account and the feasibility of treatment and maintaining the current pregnancy should be assessed.

The probability of a negative impact on the fetus exists on the 2nd and 3rd trimesters, but in the specified periods it is less intense than on the 1st trimester.

There is information about the birth of healthy babies in patients who used the drug during pregnancy, but such newborns need constant medical supervision.

Both women and men in the treatment, as well as for six months after its completion is required to use highly effective contraceptives.

When using cytarabine (especially in combination with agents of an alkylating nature) there is a possibility of suppression of the sex glands and the occurrence of amenorrhea and azoospermia.

Testing of the drug in pregnant women was not performed, but for individual animals, cytarabine is teratogenic.

During testing, the birth of healthy babies was observed, which were monitored before the 7th anniversary (most of them had no diseases, but one of the children died due to gastroenteritis after 80 days from the moment of birth, and in addition, some others had diseases).

Theoretically, with systemic use of the drug in the first trimester, defects may appear in the distal zones of the extremities with their deformation, and in addition to this, deformation of the ears occurs. Along with this, administration of cytarabine to pregnant women can cause anemia, thrombocyto-, pancyto- or leukopenia, and also eosinophilia, hyperpyrexia, sepsis, changes in EBV values, increased IgM and death in the newborn during the neonatal phase.

There is no information regarding the indicators of drugs inside breast milk. With the need to use Alexan, you need to stop breastfeeding at the time of treatment.

[8], [9], [10], [11], [12]

Contraindications

Alexan should not be used in people who have recently used myelosuppressants for treatment (except in situations where the administration of a medicine is necessary for saving lives).

The main contraindications:

• thrombocyto- or leukopenia, as well as anemia, with non-cancerous etiology (bone marrow aplasia), except in situations where the drugs are administered according to strict indications;
• cytarabine-associated hypersensitivity;
• infections in the active phase and acute.

Caution in using the medication is required in such situations:

• impaired liver or kidney function (because it increases the likelihood of neurotoxicity);
• high rates of blast cells or a large neoplasm (due to the high likelihood of hyperuricemia);
• the presence of ulcers (it is necessary to constantly monitor the course of the disease in order to timely detect the development of bleeding).

It is not allowed to administer live vaccines to a patient treated with Alexan. It is also forbidden to drive a car during treatment.

[13]

Side effects Alexana

The severity of negative signs and toxicity associated with cytarabine depends on the size of the portion. Often, in patients with drug treatment, there is a suppression of hematopoietic function and negative manifestations associated with the work of the gastrointestinal tract.

The introduction of therapeutic dosages can provoke freckles, pancreatitis, local symptoms and epidermal rashes. With complex treatment, the appearance of colitis (with the detection of latent blood) and peritonitis was observed.

In addition, you can expect the appearance of such side effects:

• infectious or invasive infections: pneumonia, sepsis or phlegmon in the injection area, with different localization of the lesion, triggered by the activity of viruses, bacteria, saprophytes and parasites with fungi (infections are associated with weakening of the immune system during treatment and can have both weak intensity and potentially mortal danger );
• blood disorders: thrombocyto-, granulocyto-, leuco- or reticulocytopenia, and in addition to anemia, bleeding and megaloblastosis;
• CAS disorders: pericarditis, arrhythmia, pain in the sternum area and cardiomyopathy;
• CNS lesions: neuritis, dizziness or headaches. The use of large portions can lead to cerebellar and cerebral dysfunction, in which there is confusion, polyneuropathy, nystagmus and convulsions. After intrathecal application, quadri- or paraplegia may occur, as well as leukoencephalopathy of a necrotizing nature. The likelihood of neurotoxicity is higher with intrathecal use, and, moreover, with a combination of neurotoxic regimens and large portions of cytarabine;
• problems with visual function: a hemorrhagic type of conjunctivitis (there is a burning and pain in the eye area, photophobia, vision loss and tearing) and keratitis. With intrathecal administration, vision loss may occur. To prevent conjunctivitis of hemorrhagic nature, use local corticosteroids;
• respiratory disorders: RDS (sudden), pneumonia, pulmonary edema, dyspnea, pain in the throat and an interstitial type of pneumonitis;
• gastrointestinal lesions: loss of appetite, ulcers in the mouth or esophagus, inflammation that affects the mucous membranes, stomatitis, nausea, diarrhea, anorectal ulcers, vomiting, pain in the lower abdomen and dysphagia. At the same time, necrotizing colitis, esophagitis, perforation of the gastrointestinal tract, cystic intestinal pneumatosis, peritonitis and vomiting with the administration of medicinal fluid may occur;
• disorders of the urinary process: urinary retention or impairment, and in addition, kidney failure;
• subcutaneous layer and epidermis: erythema, ulcers, bullous dermatitis, urticaria, vasculitis, burning and pain in the area of the feet with the palms, alopecia, hyperpigmentation and exocrine type of neutrophilic hydradenitis;
• problems with the hepatobiliary system: hepatic dysfunction, increased liver enzymes and jaundice;
• other symptoms: rhabdomyolysis, hyperuricemia, arthralgia, hyperthermia, pain in the sternum or muscles, as well as thrombophlebitis in the injection area;
• allergic manifestations: angioedema or anaphylaxis.

Among the side effects of drugs is also a decrease in polymorphonuclear granulocytes and platelets. In the case of a significant decrease in them, the treatment must be suspended or completely stopped.

In men, Alexan can provoke incurable infertility, which is why a cryopreservation of sperm is necessary before starting treatment.

The development of cytarabine syndrome.

When such a violation occurs, pain, affecting the muscles and bones, weakness, hyperthermia, conjunctivitis and rash maculopapular nature. The development of the syndrome can occur after 6-12 hours from the moment of injection. Often the elimination of the syndrome is done with the help of corticosteroids. With the improvement of the condition, the treatment is continued using a combination of medication and GCS, and in the absence of a result, the medication is completely canceled.

Special manifestations with the introduction of large portions of drugs:

• blood lesions: development of pancytopenia (also severe);
• violations of the gastrointestinal tract: liver abscess, intestinal perforation, necrosis, accompanied by intestinal blockage, peritonitis, liver disease with hyperbilirubinemia and hepatic vein thrombosis;
• disorders of visual activity: toxic effects on the cornea;
• problems with cardiovascular function: death resulting cardiomyopathy;
• systemic signs: nystagmus, ataxia, tremor, concentration disorders, dysarthria and coma.

Overdose

In case of overdose with medication, the bone marrow activity is suppressed, which causes heavy bleeding, neurotoxic lesions and theoretically fatal infections.

Intravenous administration of 12 infusions (lasting for 60 minutes) with 12-hour intervals in 1-fold portion of 4.5 g / m ² caused incurable and fatal CNS damage.

In case of intoxication, treatment should be canceled and supportive procedures (among them, transfusion of whole blood or platelet mass, and with this, the implementation of antibiotic therapy).

In case of unintentional overdose during intrathecal use, CSF drainage is performed, followed by the exchange application of isotonic NaCl.

Hemodialysis can reduce serum cytarabine values, but there is no information available on dialysis performance during cytarabine poisoning.

Cytarabine does not have an antidote.

[17]

Interactions with other drugs

Cytarabine is able to increase the cytotoxic and immunosuppressive activity of myelosuppressors and oncolytic drugs, and in addition to this radiation therapy with combined procedures. Comprehensive treatment may require changes in the dosage of drugs.

The drug significantly weakens the effectiveness of the element 5-fluorocytosine. Combine these drugs can not.

Alexan leads to a change in the equilibrium plasma values of digoxin, but does not affect its level. When using cytarabine, it is recommended to switch to digitoxin.

With in vitro tests, the drug reduces the effects of gentamicin during infections with Klebsiella pneumonia. In the case of such lesions and the need to use cytarabine, it is necessary to consider the option of changing antibiotic therapy.

The drug reduces the effects of flucytosine.

The drug weakens the immune response, which can develop, in theory, fatal infections in the case of vaccination with live vaccines. During the use of cytarabine, only inactivated vaccines are allowed, but it must be borne in mind that their effectiveness is impaired.

It is impossible to combine the drug with other solutions (except for infusion substances, which are offered as solvents).

Physical incompatibility is observed with such agents as oxacillin, naftsilin, insulin with 5-fluorouracil, heparin, sodium succinate methylprednisolone, and methotrexate with benzylpenicillin.

[18], [19], [20], [21]

Storage conditions

Alexan is required to be kept at temperature marks not exceeding 25 ° C.

Shelf life

Alexan can be used within a 2-year term from the date of manufacture of the drug.

In the case of the use of a solvent (5% glucose or isotonic NaCl), the stability of the drug is maintained for 4 days (at rates of 2–8 ° C) or 24 hours (at values of 10–25 ° C).

The liquid retains microbiological purity within 24 hours (temperature 2-8 ° C) or 12 hours (temperature 10-25 ° C).

Application for children

Regarding the safety of the introduction of the drug in pediatrics accurate information is not available. There is information about the appearance of a myelocytic character in children with leukemia who were given medication in combination, delayed ascending paralysis in a progressive form, resulting in death.

Analogs

Analogs of drugs are medicines Tsitarabin and Cytosar with Cytestadine.

[22], [23], [24], [25]