Alexan - instructions for use, dose, side effects, contraindications

Active substanceCytarabineCytarabine

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Alexan®

solution for injections

Ebewe Pharma Gesmb.b. Nfg. KG Austria

Cytarabine

lyophilizate for injections

BELMEDPREPARATY, RUP Republic of Belarus

Cytarabine-LENS®

lyophilizate for injections

LENS-PHARM, LLC Russia

Cytosar®

lyophilizate for injections

Pfizer Inc. USA

Cytostadine

solution for injections

SHTADA Artznajmittel AG Germany

Dosage form: & nbspinjection

Composition:

1 ml of a solution of 20 mg / ml contains:

active substance: cytarabine 20.0 mg;

Excipients: sodium chloride 6.00 mg, sodium lactate 60% solution 4.16 mg, lactic acid (regulator pH) 0.018 mg, water for injection up to 1 ml.

1 ml of a solution of 50 mg / ml contains:

active substance: cytarabine 50.0 mg;

Excipients: sodium lactate 60% solution 10.40 mg, lactic acid (regulator pH) 0.045 mg, water for injection up to 1 ml.

Description:

Transparent colorless liquid.

Pharmacotherapeutic group:antitumour agent - antimetabolite

ATX: & nbsp

L.01.B.C.01 Cytarabine

Pharmacodynamics:

The active substance of the drug Aleksan is cytarabine. Cytarabine belongs to the group of antimetabolites of pyrimidine metabolism, inhibits the synthesis of DNA in the cell, mainly in Sphase of the cell cycle. Antileukemic activity of the drug is obtained as a result of phosphorylation in arabinosyl cytosine triphosphate (Ara-CTF),which competitively inhibits DNA polymerase. Also, the synthesis of DNA is inhibited by the incorporation of cytarabine into DNA. The cytotoxic effect is dose-dependent.

Several mechanisms of development of cytarabine resistance are known: inhibition of membrane transport, deficiency of phosphorylating enzymes, increased activity of inactivating enzymes, reduced affinity of DNA polymerase. Maintaining a high intracellular concentration of Ara-CTP is crucial for the development of the cytotoxic effect.

Pharmacokinetics:

After intravenous administration cytarabine quickly and almost completely turns into an inactive uracil-metabolite Ara-U under the action of cytidine deaminase in the liver and in other tissues. The half-life (T_1/2) of the initial phase is 1.4-7.5 minutes, the final phase is about 10-200 minutes, on average 120 minutes. Due to the low activity of deaminase in the central nervous system, the excretion of cytarabine from the cerebrospinal fluid is slow and the half-life is 2-11 hours.

With continuous intravenous infusion of cytarabine in usual doses (100-200 mg /m² body surface), concentrations of 0.04-0.6 μmol / L are achieved.With subcutaneous or intramuscular injection, the maximum concentrations of cytarabine in the plasma are reached after 20-60 minutes, while they are significantly lower than with intravenous administration. The maximum concentration of cytarabine in blood plasma at the same dose varies greatly in different patients. Then a two-phase decrease in concentration occurs.

The volume of cytarabine distribution is 0.7 l / kg. Cytarabine penetrates the blood-brain barrier. After a continuous infusion into the cerebrospinal fluid, a concentration equal to 10-40% of the concentration in the blood plasma is achieved. Connection with plasma proteins - 2-20% .

When ingested cytarabine as a result of phosphorylation under the action of nucleotidases quickly turns into active metabolite Ara-CTF in leukemic and normal bone marrow cells. The formation of the inactive metabolite Ara-U under the action of cytidine deaminase occurs mainly in the liver, and to a lesser extent in other tissues and blood.

The excretion of cytarabine from the plasma is biphasic. Within 24 hours in urine, about 80% of the cytarabine administered is found, of which 71-96% is presented as an inactive metabolite and 4-10% is unchanged cytarabine.

Indications:

- Acute non-lymphoblastic and / or lymphoblastic leukemia (remission induction, as well as maintenance therapy);

- prevention and treatment of neuroleukemia (intrathecal injection as a monotherapy, in combination with other antitumor drugs);

- non-Hodgkin's lymphomas;

- Blast crises in chronic myelogenous leukemia.

High-dose cytarabine therapy:

- refractory to therapy non-Hodgkin's lymphomas;

- refractory to therapy acute non-lymphoblastic and / or lymphoblastic leukemia, as well as variants with unfavorable prognosis; relapses of acute leukemia;

- secondary leukemia after previous chemotherapy and / or radiation therapy;

- manifest leukemia after the transformation of the preleukosis;

- acute non-lymphoblastic leukemia in patients younger than 60 years of age (for consolidation of remission);

- Blast crises in chronic myelogenous leukemia.

Contraindications:

- Hypersensitivity to cytarabine and other components of the drug;

- anemia, leukopenia, thrombocytopenia not oncological etiology (including bone marrow aplasia); with the exception of cases when the application is necessary "according to vital" indications.

- Pregnancy and the period of breastfeeding.

Carefully:

In patients with hepatic and / or renal failure (due to an increased risk of side effects, especially with high-dose therapy), with drug-induced oppression of hematopoiesis, with bone marrow infiltration by tumor cells, with acute infectious diseases of the virus (including chicken pox, shingles), fungal or bacterial nature (risk of severe complications and generalization of the process), diseases in which there is an increased risk of hyperuricemia (Urate gout or nephrolithiasis).

In the treatment of cytarabine, as with the use of other drugs that suppress immunity, vaccination with live vaccines should be avoided.

In patients older than 60 years, the use of high doses of cytarabine is possible after a thorough assessment of the benefit / risk ratio.

Pregnancy and lactation:

Pre-clinical studies have shown that cytarabine has embryotoxic and teratogenic effects. Therefore, during pregnancy, the use of the drug AlexA is contraindicated.

It is not known whether cytarabine with breast milk, therefore, in order to avoid the toxic effect of the drug on the baby, breastfeeding should be stopped for the period of treatment.

Dosing and Administration:

The scheme and method of application vary with the use of different chemotherapy regimens. The use of Aleksan ® is possible only in specialized clinics under the supervision of doctors. When administered orally, the drug AlexA is not active.

The drug AlexA can be used both in monotherapy, and in combination with cytostatics and, in some cases, glucocorticosteroids.

The drug Alexa can be administered intravenously (bolus or drip), subcutaneously, intramuscularly (usually only used for maintenance of remission), and also intrathecally.

The average daily dose - 100-200 mg / m². For patients of advanced age or with reduced reserves of hematopoies, the daily dose should not exceed - 50-70 mg / m².

Induction of remission in acute leukemia: in combination with other antitumor drugs - 100 mg / m²/ day in the form of continuous fast or slow intravenous infusion for 5-10 days or intravenously every 12 hours for 7 consecutive days. In total, 4-7 treatment courses are conducted. Intervals between courses - not less than 14 days.

High-dose therapy: high-dose therapy in the treatment of leukemia with poor prognosis, as well as refractory leukemia and relapses, is performed with the drug AlexA in a dose of 2-3 g / m² the surface of the body in the form of intravenous infusion of 1-3 hours, with a 12-hour interval, for 4-6 days in the form of monotherapy or in combination with other antitumor drugs.

Intratekalnaya therapy (treatment of leukemia of the central nervous system): In acute leukemia, the dose of AlexA is 5-75 mg / m². The frequency of administration can vary from once a day for 4 days to 1 time in 4 days. Most often cytarabine apply to 30 mg / m² body surface every 4 days before the normalization of the indicators, followed by another additional introduction. However, the dose and intervals between administrations depend on the clinical situation. Due to the fact that the dosage and mode of administration of the drug AlexA depend on specially developed schemes of polychemotherapy, in each individual case it is necessary to refer to the special literature.

With renal and hepatic insufficiency it is necessary to carefully apply the drug AlexA and, if necessary, reduce the dose, especially in patients with severe impairment of liver and kidney function.

Cytarabine is excreted by hemodialysis. It is not recommended to apply the drug directly before and immediately after the dialysis session.

In elderly patients (over 60 years) The use of high-dose therapy is only possible after a thorough assessment of the benefit / risk ratio.

Preparation of a solution for infusion

The drug AlexA in the required dose is diluted in 0.9% solution of sodium chloride or in a 5% solution of dextrose. The concentration of cytarabine should not exceed 100 mg / ml.

When the intrathecalIntroduction of the drug AlexA can be used 0.9% solution of sodium chloride or 5% solution of dextrose. Do not use solvents containing preservatives.

It is recommended to first select 5-8 ml of cerebrospinal fluid, mix it with the injection solution in the syringe, and then slowly reverse the introduction of the resulting solution.

The solution must be taken from the vial immediately before use. Apply only freshly prepared clear solutions and only once!

Side effects:

According to the World Health Organization (WHO), adverse reactions are classified according to their frequency of development as follows: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, <1/1000) and very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Adverse reactions caused by cytarabine, depend on the dose, mode of administration and duration of therapy. The most common side effects of the digestive system, on the part of the blood system.

Infectious and parasitic diseases

infrequently: viral, bacterial, fungal, parasitic or saprophytic infections of any location, sepsis, immunosuppression.

Violations of the blood and lymphatic system

often: anemia, megaloblastosis, leukopenia, thrombocytopenia, reticulocytopenia.

Disorders from the metabolism and nutrition

Frequent: anorexia, hyperuricemia.

Disturbances from the nervous system

often: neurotoxicity, oppression of consciousness, dysarthria, nystagmus (when high doses are used);

infrequent: headache, neuritis, peripheral sensory neuropathy, peripheral motor neuropathy.

Disturbances on the part of the organ of sight

often: reversible hemorrhagic conjunctivitis (photophobia, burning in the eyes, increased lacrimation, visual impairment), keratitis.

Heart Disease

infrequent: pericarditis;

rarely: heart rhythm disturbances.

Disorders from the gastrointestinal tract

often: abdominal pain, nausea, vomiting, diarrhea, inflammation or ulceration of the oral and / or rectal mucosa;

infrequently: esophagitis, ulcers of the esophagus, necrotic colitis, cystic pneumatosis of the intestine, peritonitis.

Disturbances from the liver and bile ducts

often: reversible effects on the liver with an increase in "hepatic" transaminases;

infrequently: jaundice, a violation of liver function with hyperbilirubinemia.

Disturbances from the respiratory system, chest and mediastinal organs

infrequently: pain in the throat, shortness of breath, pneumonia, interstitial pneumonitis.

Disturbances from the skin and subcutaneous tissues

often: erythema, rash, bullous dermatitis, vasculitis, urticaria, alopecia;

infrequently: skin ulceration, itching of the skin, pigmentation of the skin, burning pain in the palms and soles of the feet;

rarely: neutrophilic exocrine hydradenitis.

Disturbances from musculoskeletal and connective tissue

infrequent: myalgia, arthralgia.

Disorders from the kidneys and urinary tract

infrequently: impaired renal function, urinary retention.

General disorders and disorders at the site of administration

Frequent: thrombophlebitis at the injection site, fever, inflammation of subcutaneous fat at the injection site;

infrequently: phlegmon at the injection site.

Cytarabine Syndrome

Fever, muscle pain (myalgia), pain in the bones, sometimes pain in the chest, spotty papular rash, conjunctivitis, nausea, malaise, which appear 6-12 hours after drug administration.

Additional side effects with high-dose cytarabine therapy

Hematological toxicity

Pronounced pancytopenia, which can last 15-25 days with a more severe than with the usual doses, bone marrow aplasia.

Disturbances from the nervous system

When treating with high doses of cytarabine, toxic manifestations from the brain, especially the cerebellum, occur in 3-37% of cases of treated patients. More common side effects include personality changes, decreased concentration, dysarthria, ataxia, tremor, nystagmus, headache, confusion, drowsiness, dizziness, coma, convulsions, etc.

The occurrence of neurotoxicity in patients older than 55 years may be even higher.

Other predisposing factors in the development of neurotoxicity in the use of cytarabine are a violation of liver and kidney function, central nervous system (CNS) damage in the previous treatment (for example, radiation therapy) and the abuse of ethanol.

In most cases, CNS disorders are reversible.

The risk of developing the toxicity of the central nervous system increases if intravenous administration of high doses of cytarabine is combined with other CNS toxic treatments (eg, radiation therapy).

Some cases of severe toxic effects on the spinal cord, which led to quadriplegia and paralysis, necrotic encephalopathy, blindness and other isolated manifestations of neurotoxicity, are described.

Toxic manifestations of the cornea and conjunctiva

Cases of reversible corneal damage and hemorrhagic conjunctivitis have been described. These phenomena can be prevented or reduced with the use of eye drops with glucocorticosteroids.

Disorders from the gastrointestinal tract

When treating with high doses of cytarabine, the manifestation of general symptoms of toxicity from the gastrointestinal tract may be more pronounced.There are reports of perforation of the intestine, of necrosis of the intestine with the development of intestinal obstruction and peritonitis.

Also after the high-dose chemotherapy with cytarabine, abscesses of the liver, Badda-Chiari syndrome (thrombosis of the hepatic veins) and pancreatitis were observed.

Disturbances from the respiratory system, chest and mediastinal organs

Severe and sometimes fatal manifestations of toxicity from the side of the lungs, pulmonary edema / acute respiratory distress syndrome may occur with the use of cytarabine in high doses. Such a pulmonary reaction is probably caused by damage to the capillaries of the alveoli. According to the literature sources, the frequency of occurrence is 10-26%, it is more difficult to specify the frequency of occurrence of this complication, as patients during the onset of the side effect usually were in a stage of relapse, when other factors could contribute to the occurrence of this reaction.

Other

The occurrence of cardiomyopathy (including fatal outcome, using cytarabine in high doses in combination with cyclophosphamide) and rhabdomyolysis after cytarabine in high doses has been reported.One case of development of anaphylaxis, as a result of cardiac arrest, which required the necessary resuscitation measures, is described. The reaction occurred immediately after intravenous administration of cytarabine.

The development of side effects from the gastrointestinal tract is reduced if cytarabine injected infusion. Local use of glucocorticoids is recommended as prevention of hemorrhagic conjunctivitis.

When cytarabine is used, especially in combination with alkylating agents, gonadal function, manifested by amenorrhea or azoospermia, occurs. The severity of this side effect depends on the dose, duration of therapy and can be irreversible.

Side effects at intrathecal application of cytarabine

Expected systemic reactions: bone marrow depression, nausea, vomiting. Sometimes, development of severe spinal cord toxicity is possible, which can lead to quadriplegia and paralysis of the muscles, necrotizing encephalopathy, blindness and other isolated manifestations of neurotoxicity.

Overdose:

Symptoms: vomiting, diarrhea, marked inhibition of bone marrow function, bleeding, development of infection,symptoms of neurotoxicity (impaired consciousness, motor disorders, convulsions, cognitive disorders).

Treatment: there is no specific antidote. If an overdose occurs, then symptomatic therapy (blood transfusion) is necessary. AT In case of severe overdose, after intrathecal administration, immediately replace the cerebrospinal fluid with isotonic saline.

Cytarabine is excreted by hemodialysis. However, information on the effectiveness of hemodialysis in case of an overdose of cytarabine is absent.

Interaction:

Do not mix in one syringe or dropper with other drugs: pharmaceutically incompatible with heparin, insulin, methotrexate, fluorouracil, oxacillin, benzylpenicillin, methylprednisolone.

Joint application with other antitumor myelosuppressive drugs or radiotherapy increases the cytotoxic, as well as immunosuppressive activity of these drugs. In patients receiving chemotherapy, including vincristine, prednisolone and cyclophosphamide with cytarabine or procarbazine, the equilibrium concentration reversibly decreases digoxin in blood plasma (impaired absorption due to toxic effects on the intestinal mucosa), as well as reduced renal excretion of the glycoside. An alternative for such patients may be considered the use of digitoxin, the equilibrium plasma concentration of which does not change.

Conducted in vitro the interaction between gentamicin and cytarabine revealed the existence of antagonism, which may reduce the sensitivity of strains Klebsiella pneumoniae to gentamicin.

Possible loss of efficiency fluorocytosine with simultaneous use with cytarabine.

Immunosuppressive drugs (azathioprine, chlorambucil, glucocorticosteroids, cyclophosphamide, ciclosporin, mercaptopurine, tacrolimus) increase the risk of developing infectious complications.

Killed virus vaccines - due to suppression of normal mechanisms of protection by cytarabine, the formation of antibodies can be reduced.

Live viral vaccines - due to suppression of normal mechanisms of protection by cytarabine, potentiation of viral replication is possible, increased side effects, decreased antibody production.

Special instructions:

The use of Aleksan® preparation should be carried out under the supervision of a qualified doctor who has experience working with antitumor chemotherapeutic drugs and only in a hospital setting. Aleksan® can be used both as a monotherapy and in combination with other antitumor drugs. The dose and scheme of taking the drug is selected individually. In the case of combination therapy, the cumulative myelosuppressive effect of all drugs included in the treatment regimen should be taken into account.

Care should be taken when using AlexAlex. Dilute the drug in aseptic conditions in a specially designated room. This should be handled by trained personnel. It is necessary to take all measures to prevent the solution of cytarabine from getting into the skin and mucous membranes, in particular to use protective clothing (robe, cap, mask, glasses and disposable gloves). If you get cytarabine on the skin or mucous membranes, rinse thoroughly with soap and water or (eyes) with plenty of water. Cytarabine greatly suppresses the function of the bone marrow.Therapy with AlexA should be started with caution in patients with pre-existing myelosuppression. It is necessary to regularly monitor the clinical analysis of blood (daily with induction therapy), the concentration of uric acid in the plasma, the function of the bone marrow, liver, kidneys, central nervous system, lungs. With a decrease in platelets below 50,000 /mm³ or polymorphonuclear granulocytes below 1000 / mm³, you should suspend or change the treatment regimen. Number of uniform elements in the peripheral blood can continue to fall after drug withdrawal and reach a minimum level after 12-24 days. If there are indications, you can resume therapy with clear signs of hematopoiesis recovery from the results of the bone marrow examination.

It should be borne in mind that it is possible to develop complications such as bleeding (secondary to thrombocytopenia) and severe infection (secondary to granulocytopenia).

There are reports of the development of severe toxicity from the CNS, GI tract and lungs (different from the one that develops with standard cytarabine therapy regimens), sometimes with the development of a lethal outcome.Possible reversible damage to the cornea of the eye; a violation of the function of the brain, especially the cerebellum, which, as a rule, are reversible, drowsiness, convulsions; severe gastrointestinal ulcers, including cystic pneumatosis of the intestine, which can lead to the development of peritonitis; sepsis, liver abscess, pulmonary edema.

It was reported on the occurrence of peripheral motor and sensory neuropathy after joint use of high doses of cytarabine, daunorubicin and asparaginase in adult patients with acute non-lymphoblastic leukemia. Therefore, care should be taken when using high doses of cytarabine and adjusting doses in a timely manner to avoid irreversible neurological disorders.

There are reports of the development of delayed progressive ascending paralysis, which resulted in the death of children with acute myelogenous leukemia after intrathecal and intravenous administration of cytarabine in usual doses in combination with other drugs.

In patients who have previously been treated with a damaging effect on the central nervous system, such as intrathecal chemotherapy or radiation therapy, the use of high doses of cytarabine increases the risk of neurotoxicity.

With rapid intravenous injection of cytarabine, often there is nausea, vomiting for several hours after use. It is possible to reduce the incidence and severity of these side effects when the drug is used infusion.

In the literature, cases of the development of peritonitis and colitis with a positive sample of latent blood in combination with neutropenia and thrombocytopenia in patients with the usual doses of cytarabine in combination with other medications have been described. Patients were successfully treated without surgery.

There are reports of the occurrence of cardiomyopathy (including fatal) with cytarabine in high doses in combination with cyclophosphamide.

When a cytarabine syndrome occurs, Aleksan® should be discontinued and glucocorticosteroids treated. With the effectiveness of steroid therapy, cytarabine treatment can be continued.

For the prevention of hemorrhagic conjunctivitis, topical application of glucocorticosteroids is recommended.

Care must be taken when using the drug in patients with impaired liver and kidney function.

When carrying out high-dosage therapy and intrathecal therapy, solutions containing benzyl alcohol should not be used.

Like other antineoplastic agents, the drug Alexa can lead to the development of hyperuricemia due to rapid decay of tumor cells. It is recommended to prevent hyperuricemia in patients with a high content of blast cells or with large tumor masses (for example, with non-Hodgkin's lymphomas): ensure the intake of allopurinol and a sufficient amount of fluid.

Vaccination of patients undergoing Alexan® therapy should be performed very carefully, after careful evaluation of the hematologic status and with the consent of the physician administering cytarabine therapy. The interval between the end of immunosuppressive therapy and vaccination depends on the type of immunosuppressant, underlying disease and other factors and varies from 3 months to 1 year.

Cytarabine is excreted from the body during hemodialysis. Therefore, patients who are on dialysis should not administer the drug AlexA directly before and during dialysis.

Women and men, as well as their sexual partners during treatment and within 6 months after its completion, should use reliable contraception.

Special precautions for the destruction of unused medications

The remnants of the preparation, all tools and materials used for the preparation of injectable solutions and the administration of the drug AlexA, must be destroyed in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account the existing regulatory acts on the destruction of hazardous waste.

Effect on the ability to drive transp. cf. and fur:

Patients receiving chemotherapy may have a reduced ability to drive a vehicle and work with mechanisms, so if possible, refrain from engaging in potentially hazardous activities, requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Solution for injection, 20 mg / ml and 50 mg / ml.

Packaging:

Primary packaging

5 ml (concentration 20 mg / ml), 10 ml, 20 ml or 40 ml (concentration 50 mg / ml) in vials of colorless glass, sealed with a stopper from chlorobutyl rubber, an aluminum cap and covered with a plastic lid.

Secondary packaging

1 bottle with instructions for use in a cardboard box.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N016185 / 01

Date of registration:30.11.2009

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp27.09.2015

Illustrated instructions

Instructions

Alexan® (Alexan®)