Alexan

Alexan is an antineoplastic drug that has cytotoxic activity, affecting a variety of cellular forms at the S-stage.

The drug contains an element called cytarabine; it is involved in intracellular metabolic processes, during which a derivative with therapeutic activity is formed from it – cytarabine-5-triphosphate (also called ara-CTP).

The component cytarabine belongs to the subgroup of antimetabolites, which are pyrimidine antagonists.

Indications Alexana

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

In addition, it is prescribed for other forms of leukemia, including myeloblastic leukemia in the chronic phase (during blast crisis), as well as the active phase of lymphocytic leukemia.

It can be used for the treatment and prevention of leukemic meningitis (the drug must be administered intrathecally) – monotherapy is carried out or combined regimens are used.

It should be taken into account that the remission obtained after the administration of cytarabine is short-lived unless maintenance procedures are performed.

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

May be prescribed in combination to children with NHL.

Cytarabine is used in the treatment of various types of tumors; a positive response has been observed in some patients with solid tumors.

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Release form

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

Pharmacodynamics

The medicinal effect has a phase-specific form – its implementation is carried out exclusively at the S-stage of the cell cycle. The principle of medicinal activity of ara-CTP 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 the incorporation of cytarabine into DNA and RNA molecules.

In tests, the drug demonstrated cytotoxic effects against a range of mammalian cell cultures.

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Pharmacokinetics

After oral administration, cytarabine is inactive (because it exhibits a low degree of absorption and a high rate of metabolism). In the case of continuous intravenous injection, practically constant drug levels are formed in the plasma. After intramuscular or subcutaneous injections, the Cmax values of cytarabine are determined after 20-60 minutes; at the same time, after intramuscular and subcutaneous administration, the substance levels are lower than those recorded after intravenous injections.

Patients show significant inter-individual variability in cytarabine values when using the same doses (some tests suggest that such variations may be a predictor of therapeutic efficacy - with higher plasma values, the likelihood of achieving hematological remission is higher).

After intravenous injection, the drug poorly crosses the BBB, which is why when used in people with neuroleukemia it should be administered intrathecally.

Under the influence of nucleotidases, the active element is transformed into an active variety inside healthy bone marrow, as well as blast leukemic cells. The active derivative is then subjected to metabolic processes with the formation of inactive components (mainly inside liver tissues, and also, to a lesser extent, inside the blood with tissues). The ratio of deoxycytidine kinase to cytidine deaminase values (involved in the metabolism of cytarabine) is very important, because it helps to identify cellular sensitivity to drugs.

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

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

The half-life of the drug from the central nervous system tissues is 3-3.5 hours.

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Dosing and administration

Treatment is performed in a 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, cardiac and hepatic function tests are performed, as well as a quantitative blood test. Before prescribing a drug, it is necessary to weigh the benefits against the likelihood of risks. During the treatment cycle, a quantitative blood test is performed daily, and it is recommended to record serum uric acid values (in case of hyperuricemia, the necessary supportive measures are taken).

When using drugs, you need to carefully select solvents (especially for intrathecal injections). When administering large doses, you cannot use solvents containing preservatives. It is necessary to administer a saline solution of NaCl or 5% glucose.

In case of high-speed infusions, patients tolerate high doses of Alexan quite well, compared to low-speed infusions (this is due to rapid metabolic processes and short exposure in case of fast infusion). In clinical terms, no advantages of the fast type of administration over the slow one were found.

It can be administered intravenously (infusion or injection) or intrathecally or subcutaneously. In the case of subcutaneous injections, the dose is 0.02-0.1 g/m2, ^depending on the indications.

Dosage sizes for different disorders.

Achieving remission in case of leukemia.

To achieve remission in this case, it is necessary to use intermittent or long-term treatment.

In case of a long cycle, a bolus method is used – 2 mg/kg per day (10-day course). If there is no result (and toxic effect), the dose can be increased to 4 mg/kg per day – until remission is achieved or signs of toxicity appear.

Infusions are administered at a dose of 0.5-1.0 mg/kg of the drug per day (the duration of the infusion is a maximum of 24 hours). After 10 days, the dose can be increased to 2 mg/kg; such treatment is continued until remission is achieved or toxic manifestations occur.

In case of an interrupted cycle, 3-5 mg/kg of the drug is administered intravenously per day (5 days). After that, a 2-9-day break is taken and a new cycle is carried out. With such a scheme, treatment is carried out until remission is achieved or toxicity develops.

Bone marrow begins to recover approximately by day 7-64 (on average, this occurs by day 28). The volume of the drug may be increased if there is no therapeutic effect and toxicity. The duration and frequency of cycles are calculated depending on the clinical picture and the values of functional bone marrow activity.

After achieving remission, it is necessary to perform maintenance procedures - 1-2 intravenous or intramuscular injections per week in a single dose of 1 mg/kg.

Therapy for NHL.

Adults are given a variety of regimens that include several different chemotherapeutic agents.

For children, a combined method is also used, which takes into account the histological type and phase of the tumor. Only the attending physician can select the dose.

Using large portions.

If high doses are required, it is often administered via intravenous infusion at 2-3 g/m2 ⁽ duration – 1-3 hours) at 12-hour intervals. The cycle is 4-6 days.

Intrathecal administration of medication.

The drug is used in this way in monotherapy or in combination with hydrocortisone and methotrexate. The dose is selected taking into account the type of disease (it should be taken into account that in the 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 case of intrathecal administration, the dosage range is usually within 5-75 mg/m2 ⁽ on average 30 mg/m2 ⁾. Alexan should be used once every 4 days until a normal cerebrospinal fluid level is achieved. The doses are selected taking into account the effect of the previous treatment, the severity of the symptoms and the tolerability of the drug.

When the indicators improve, therapy should be continued. If it is necessary to dilute the medication for intrathecal injections, only preservative-free saline NaCl solution can be used.

Special categories of patients undergoing treatment.

In case of problems with the secretory activity of the kidneys or with the functioning of the liver, the drug should be used with extreme caution. A higher probability of toxicity is expected in these patients with therapy with high doses.

People over 65 years of age should closely monitor their blood function, because their tolerance to the drug is impaired. If necessary, they are prescribed supportive measures, and therapy with large doses is allowed only after assessing all possible risks.

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Use Alexana during pregnancy

If it is necessary to use Alexan in the 1st trimester, the risks of complications in the fetus should be taken into account and the advisability of performing treatment and maintaining the current pregnancy should be assessed.

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

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

Both women and men are required to use highly effective contraceptives during treatment and for six months after its completion.

When using cytarabine (especially in combination with alkylating agents), there is a risk of suppression of the sex glands and the development of amenorrhea and azoospermia.

The drug has not been tested in pregnant women, but cytarabine is teratogenic in some animals.

During the tests, healthy babies were born and monitored until they reached 7 years of age (most of them were free of disease, but one of the children died of gastroenteritis after 80 days from birth, and in addition, some others had disease).

Theoretically, with systemic use of the drug in the 1st trimester, defects in the distal zones of the limbs with their deformation may appear, and in addition, deformation of the ears may occur. Along with this, the introduction of cytarabine to pregnant women can cause anemia, thrombocyto-, pancyto- or leukopenia, as well as eosinophilia, hyperpyrexia, sepsis, changes in EBV values, increased IgM values, and death in newborns during the neonatal phase.

There is no information regarding the drug's excretion in breast milk. If Alexan is needed, breastfeeding should be discontinued for the duration of treatment.

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Contraindications

Alexan should not be used in people who have recently used myelosuppressants for treatment (except in situations where the administration of the drug is necessary to save life).

Main contraindications:

• thrombocytopenia or leukopenia, as well as anemia of non-malignant etiology (bone marrow aplasia), except for situations when drugs are administered according to strict indications;
• cytarabine-related hypersensitivity;
• infections in the active phase and acute stage.

Caution when using the medication is required in the following situations:

• weakened liver or kidney function (because this increases the likelihood of developing neurotoxicity);
• high blast cell counts or large tumors (due to the high likelihood of hyperuricemia);
• the presence of ulcers (it is necessary to constantly monitor the progress of the disease in order to promptly detect the development of bleeding).

Live vaccines should not be administered to a patient being treated with Alexan. Driving is also prohibited during treatment.

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Side effects Alexana

The severity of adverse effects and toxicity associated with cytarabine depends on the dose size. Often, patients experience suppression of hematopoietic function and adverse effects related to the gastrointestinal tract when treated with the drug.

The introduction of therapeutic doses may provoke freckles, pancreatitis, local symptoms and epidermal rashes. Colitis (with detection of latent blood) and peritonitis were observed during complex treatment.

In addition, you can expect the following side effects:

• infectious or invasive infections: pneumonia, sepsis or phlegmon in the injection area, with different localization of damage, provoked by the activity of viruses, bacteria, saprophytes and parasites with fungi (infections are associated with a weakening of the immune system during treatment and can have both low intensity and potentially fatal danger);
• blood disorders: thrombocytopenia, granulocytopenia, leukopenia or reticulocytopenia, as well as anemia, bleeding and megaloblastosis;
• disorders of the cardiovascular system: pericarditis, arrhythmia, chest pain and cardiomyopathy;
• CNS disorders: neuritis, dizziness, or headaches. Use of large doses may result in cerebellar and cerebral dysfunction, which includes confusion, polyneuropathy, nystagmus, and seizures. Quadriplegia or paraplegia, as well as necrotizing leukoencephalopathy, may occur after intrathecal use. The likelihood of neurotoxicity is higher with intrathecal use, as well as with a combination of neurotoxic regimens and large doses of cytarabine;
• problems with visual function: hemorrhagic conjunctivitis (with burning and pain in the eye area, photophobia, deterioration of vision and lacrimation) and keratitis. With intrathecal administration, vision loss may occur. To prevent hemorrhagic conjunctivitis, local GCS are used;
• respiratory disorders: RDS (sudden), pneumonia, pulmonary edema, dyspnea, sore throat and interstitial pneumonitis;
• Gastrointestinal lesions: loss of appetite, ulcers in the mouth or esophagus, inflammation affecting the mucous membranes, stomatitis, nausea, diarrhea, ulcers in the anorectal area, vomiting, pain in the lower abdomen and dysphagia. Along with this, necrotizing colitis, esophagitis, perforation in the gastrointestinal tract, cystic intestinal pneumatosis, peritonitis and vomiting when administering medicinal liquid may occur;
• urinary disorders: urinary retention or disturbances, and also renal failure;
• subcutaneous layer and epidermis: erythema, ulcers, bullous dermatitis, urticaria, vasculitis, burning and pain in the area of the feet and palms, alopecia, hyperpigmentation and exocrine neutrophilic hidradenitis;
• problems with the hepatobiliary system: liver dysfunction, increased liver enzymes and jaundice;
• other symptoms: rhabdomyolysis, hyperuricemia, arthralgia, hyperthermia, pain in the sternum or muscles, and thrombophlebitis at the injection site;
• allergic manifestations: angioedema or anaphylaxis.

Side effects of the drug also include a decrease in polymorphonuclear granulocytes and platelets. If they decrease significantly, treatment should be suspended or completely discontinued.

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

Development of cytarabine syndrome.

With such a disorder, pains affecting muscles and bones, weakness, hyperthermia, conjunctivitis and maculopapular rashes occur. The development of the syndrome can occur after 6-12 hours from the moment of injection. Often, the syndrome is eliminated with the help of GCS. If the condition improves, treatment is continued using a combination of the drug and GCS, and if there is no result, the medication is completely discontinued.

Special manifestations when administering large doses of drugs:

• blood damage: development of pancytopenia (also severe);
• gastrointestinal disorders: liver abscess, intestinal perforation, necrosis accompanied by intestinal obstruction, peritonitis, liver disease with hyperbilirubinemia and hepatic vein thrombosis;
• visual disturbances: toxic effect on the cornea;
• problems with cardiovascular function: fatal cardiomyopathy;
• Systemic signs: nystagmus, ataxia, tremor, difficulty concentrating, dysarthria and coma.

Overdose

Overdosage of the drug suppresses bone marrow activity, causing profuse bleeding, neurotoxic lesions, and potentially fatal infections.

Intravenous administration of 12 infusions (60 minutes each) at 12-hour intervals in a single dose of 4.5 g/m2 ^caused incurable and fatal CNS damage.

In case of intoxication, it is necessary to stop treatment and carry out supportive procedures (including transfusion of whole blood or platelet mass, and along with this, antibiotic therapy).

In case of accidental overdose during intrathecal use, CSF drainage is performed, accompanied by exchange administration of isotonic NaCl.

Hemodialysis can reduce serum cytarabine levels, but there is no information regarding the efficacy of dialysis in cytarabine poisoning.

Cytarabine has no antidote.

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Interactions with other drugs

Cytarabine is able to increase the cytotoxic and immunosuppressive activity of myelosuppressants and oncolytic drugs, as well as radiation therapy in combination procedures. The complex treatment method may require changes in drug dosages.

The drug significantly weakens the effectiveness of the element 5-fluorocytosine. These drugs cannot be combined.

Alexan changes the equilibrium plasma values of digoxin, but does not affect its level. It is recommended to switch to digitoxin during the use of cytarabine.

In vitro tests show that the drug reduces the effect of gentamicin in Klebsiella pneumoniae infections. In the case of such lesions and the need for cytarabine, the option of changing the antibiotic therapy should be considered.

The drug weakens the effects of flucytosine.

The drug weakens the immune response, which could theoretically lead to fatal infections in the case of vaccination using live vaccines. During the use of cytarabine, only inactivated vaccines are allowed, but it should be taken into account that their effectiveness is weakened.

The drug must not be combined with other solutions (except for infusion substances, which are offered as solvents).

Physical incompatibility is noted with such drugs as oxacillin, nafcillin, insulin with 5-fluorouracil, heparin, sodium methylprednisolone succinate and methotrexate with benzylpenicillin.

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Storage conditions

Alexan must be stored at temperatures no higher than 25°C.

Shelf life

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

If a solvent is used (5% glucose or isotonic NaCl), the stability of the drug is maintained for 4 days (at 2-8°C) or 24 hours (at 10-25°C).

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

Application for children

There is no precise information regarding the safety of the drug administration in pediatrics. There is information about the occurrence of delayed ascending paralysis in a progressive form in children with myelocytic leukemia who were administered the drugs in combination, which eventually led to death.

Analogues

Analogues of the drug are the medications Cytarabine and Cytosar with Cytastadin.

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