2010/09/17

Alexan

Composition, structure and packing

Solution for injection transparent, colorless. 1 ml 1 vial. cytarabine 20 mg 100 mg.

Excipients: sodium chloride, sodium lactate, lactic acid, water, d / and. Solution for injection transparent, colorless.

1 ml 1 vial. cytarabine 50 mg 500 mg.

Excipients: sodium lactate, lactic acid, water, d / and. Solution for injection transparent, colorless.

1 ml 1 vial. cytarabine 50 mg 1 in

Excipients: sodium lactate, lactic acid, water, d / and.

Clinico-pharmacological group: The antitumor drug.

Pharmacological action

Antitumor drug. Refers to a group of antimetabolites pyrimidine metabolism and is an S-phase specificity drug. Inhibit the synthesis of DNA. As a result of phosphorylation becomes tsitozintrifosfat arabinose (Ara-CTP), which competitively inhibits DNA polymerase. In addition, there is evidence that DNA synthesis is inhibited also by incorporating cytarabine in DNA and RNA.

Possible development of resistance to cytarabine is associated with inhibition of membrane transport, lack of phosphorylating enzymes, increased activity of inactivating enzymes, reduced the affinity of DNA polymerase, or an increased pool of deoxy-CTP. Cytotoxic effect achieved with the establishment of permanent high intracellular concentrations of Ara-CTP.

Pharmacokinetics

Absorption and distribution

In continuous in / infusion cytarabine in conventional dose (100-200 mg/m2 body surface area) achieved concentrations of 0.04-0.6 mmol / liter. When n / introduction to plasma Cmax achieved within 20-60 minutes, then going on a two-phase reduction of concentration. Cytarabine penetrates through the BBB. After continuous infusion in the cerebrospinal fluid concentration is achieved, amounting to 10-40% of the concentration in plasma.

Binding to plasma proteins - 15%.

Metabolism

After the in / under the influence of the introduction of cytarabine tsitidindezaminazy quickly and almost completely biotransformiruetsya in the liver and other tissues in the inactive uracil metabolite (Ara-C). A minority of cytarabine being under the influence of kinase phosphorylation on the intracellular level, resulting in an active metabolite of Ara-CTP.

Withdrawal

T1 / 2 in the primary (α-phase) phase is 10 min, in a finite (β-phase) - about 1-3 hours because of the minimal activity of the deaminase in CNS excretion of cytarabine from the CSF is slow, with T1 / 2 of 2-11 h. In intact kidneys displayed 4-10% of the administered dose. In the first 24 h 71-96% of the administered drug is detected in the urine in the form of Ara-U.

Statement
nelimfoblastny acute and / or lymphoblastic leukemia (for induction of remission, as well as maintenance therapy);
prevention and treatment neuroleukemia (intrathecal introduction as a monotherapy and in combination with other antitumor drugs), non-Hodgkin's lymphoma;
treatment of blast crisis in CML.

Of high-tsitarabinovaya therapy:
refractory to therapy with non-Hodgkin's lymphoma;
refractory to therapy of acute lymphoblastic and / or nelimfoblastny leukemia, as well as options with a poor prognosis;
relapse of acute leukemia;
secondary leukemias after prior chemotherapy and / or radiotherapy;
manifest leukemia after transformation preleykozov;
nelimfoblastny acute leukemia in patients younger than 60 years (for the consolidation of remission);
blast crisis in CML.

Dosage regimen

The scheme and method of the drug Alexan vary when using different chemotherapy regimens. Before the appointment of the drug should be made to the literature. Alexan can type in / jet or drip, n / k, i / m (usually applied only during therapy aimed at maintaining remission), and intrathecally. Average daily dose - 100-200 mg/m2 body surface, for elderly patients or with reduced blood reserves - 50-70 mg/m2 body surface.

For induction of remission in acute leukemia in combination with other antitumor drugs prescribed to 100 mg/m2 body surface per day as a continuous i / v infusion for 7 days or 100 mg/m2 body surface / in every 12 hours 7 days in a row. Total spend 4-7 cure. The intervals between the courses - not less than 14 days. If by high-therapy for treatment of leukemia with a poor prognosis, as well as refractory leukemia and relapse Alexan prescribe a dose of 2-3 g / m 2 body surface in the form of in / infusion duration of 1-3 hours with 12-hour intervals for 2-6 days as monotherapy or in combination with other anticancer agents.

For intrathecal administration in acute leukemia is dose Alexan 5-75 mg/m2 body surface. The frequency of administration may vary from 1 times / day for 4 days to 1 times in 4 days.

Most Alexan designate to 30 mg/m2 body surface every 4 days before the normalization of the indices, followed by one additional injection. However, the doses and intervals between injections depend on the clinical situation. Due to the fact that the dose and mode of introduction of Alexan depend on specially designed schemes of chemotherapy in each individual case should be referred to special literature.

In renal and hepatic insufficiency is not necessary to reduce the dose of the drug in case of application of Alexan at normal doses. If carried out by high-therapy, the selection of doses should be taken into account the increased risk of complications in the CNS.

Terms of solution for infusion Alexan at the required dose is diluted in 0.9% sodium chloride or 5% dextrose. The concentration of cytarabine should not exceed 100 mg / ml. For perfusion Alexan can be used undiluted. When intrathecal, lumbar and intraventricular can use the original solution.

You must first make a selection 5-8 ml of cerebrospinal fluid, mix it with a solution of Alexan in the syringe, and then make a slow reverse the imposition of the solution obtained. Using this route of administration is not associated with risk of systemic toxic effects.

Side effect

Side effects depend on the dose, route of administration and duration of therapy.

On the part of the hemopoietic system: leucopenia, thrombocytopenia, anemia, megaloblastoz, reticulopenia. Reducing the number of leukocytes was biphasic, with the first maximum reduction is achieved in 7-9 day. This is followed by a brief recovery with a maximum at the 12 th day. In the second and more profound decrease in the minimum number of leukocytes observed in 15-24 days. In the next 10 days the number of leukocytes increases rapidly. Reducing the number of platelets observed by Day 5, the minimum is between 12-15 days. In the next 10 days has been a rapid increase in the number of platelets to the original level. The severity of these reactions depends on the dose and scheme administration.
On the part of the digestive system: nausea, vomiting, loss of appetite, stomach pain, diarrhea, inflammation or ulceration of the mucosa of the gastrointestinal tract (including the oral cavity, rectum, rarely - the esophagus). Nausea and vomiting most often followed by rapid in / introduction. In therapy of high-(2-3 g/m2) GI ulceration can be severe, may develop necrotizing colitis, small bowel necrosis, cystic pnevmatoza intestine leading to peritonitis.
Part of the liver and pancreas: abnormal liver function, jaundice. If of high-therapy - liver dysfunction with hyperbilirubinemia, sepsis, liver abscess. Also reported some cases of thrombosis of hepatic veins (Budd-Chiari syndrome), and pancreatitis during treatment of high-in combination with other anticancer agents.
On the part of the nervous system: neuritis, neurotoxicity, headache, dizziness.

Violations of the CNS is mainly observed during the treatment of high-(mainly detected dysfunction of the brain and cerebellum) - nystagmus, dysarthria, ataxia, confusion, personality changes, drowsiness, coma.

Violations of the central nervous system are reversible. It was also reported cases of peripheral motor and sensory neuropathy and late progressive ascending paralysis. In some cases, after intrathecal administration were noted nausea, vomiting, dizziness, fever, possibly related to the lumbar puncture. It may also manifest cumulative neurotoxicity, particularly in short intervals between doses. For intrathecal administration of the drug have been described isolated cases of necrotizing leukoencephalopathy, paraplegia and blindness.
From the senses: conjunctivitis (photophobia, burning eyes, marked lacrimation), keratitis, with of high-therapy - reversible ulcerative keratitis, hemorrhagic conjunctivitis, disorders of vision.
On the part of the musculoskeletal system: when of high-therapy - myalgia and / or arthralgia in the neck and lower extremities. Described a single case of rhabdomyolysis.
On the part of the respiratory system: sore throat, shortness of breath, pneumonia, diffuse interstitial pneumonitis (when used in high doses of 1 g/m2), progressive respiratory distress syndrome, leading to pulmonary edema and cardiomegaly with possible fatal outcome (with the use of high-Therapy) .
Since the cardiovascular system: cardiomyopathy (including fatal when using cytarabine in high doses in combination with cyclophosphamide), pericarditis, transient arrhythmia.
On the part of the urinary system: renal dysfunction, urinary retention, hyperuricemia and urate nephropathy.

Dermatological reactions: itching, Makulo-papular urticaria or rash, the appearance of pigmented spots on the skin, ulceration of the skin, alopecia, rarely - severe skin rash, leading to desquamation.

Allergic reactions: urticaria, anaphylaxis, edema.

Local reactions: inflammation of the subcutaneous fat at the injection site.

Infection: viral, bacterial, fungal, parasitic or saprophytic flora caused by infection of any location (including sepsis), usually mild or moderate severity, but can be severe and sometimes fatal (their development is due to reduced immunity).

Other: Fever, thrombophlebitis, and in some cases - a syndrome of inadequate ADH production. After 6-12 h after injection of the drug may develop Alexan tsitarabinovy syndrome: fever, muscle pain, bone pain, sometimes pain in the chest, maculopapular rash, conjunctivitis, malaise (the efficacy of GCS).

Contraindications
Pregnancy
Lactation (breastfeeding);
increased sensitivity to cytarabine and other components of the drug.

Precautions should be prescribed the drug if hepatic and / or renal failure (due to an increased risk of neurotoxicity, particularly for the treatment of high-), with drug-induced depression of blood, bone marrow infiltration by tumor cells, acute infectious viral disease (in t.ch . chickenpox, herpes zoster), fungal or bacterial etiology (risk of serious complications and the generalization of the process), diseases in which there is an increased risk of hyperuricemia (gout or urate nephrolithiasis).

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation. During therapy Alexan, and within 6 months after treatment, women and men of childbearing age should use reliable methods of contraception.

Application for violations of liver function

Patients with impaired liver function drug should be prescribed with caution, and perhaps in a reduced dose. Precautions should be prescribed the drug for hepatic failure (due to an increased risk of neurotoxicity, particularly for the treatment of high-).

Application for violations of renal function

Patients with impaired renal function the drug should be prescribed with caution, and perhaps in a reduced dose. Precautions should be prescribed the drug in renal failure (due to an increased risk of neurotoxicity, particularly for the treatment of high-).

Cautions

When working with the drug should take precautions designed for the treatment with cytostatics. Do not allow skin contact and mucous membranes, especially from the mucous membrane of the eye. Induction and consolidation therapy with the drug in acute leukemia Alexan should be in a specialized hospital, under the supervision of experienced oncologists and with careful monitoring. Regular determine the number of blood cells, bone marrow function, liver and kidneys, as well as the level of uric acid in serum.

Patients with a high content of blast cells or with tumors of large size (nehodzhinskih lymphomas) is recommended to prevent hyperuricemia. By reducing the platelet count below 50 000/mkl or polymorphonuclear granulocytes below 1000/mkl should terminate or modify therapy. The number of formed elements of peripheral blood may continue to fall after the drug withdrawal and reach a minimum level after 12-24 days. If evidence can resume therapy with the appearance of clear signs of recovery of blood on the study of the bone marrow.

In the conduct of high-therapy, and intrathecal therapy can not use solutions containing benzyl alcohol.

In the conduct of high-therapy should continuously monitor the function of the CNS and the lungs.

In the conduct of high-therapy and in violation of liver and kidney function may increase the likelihood of toxicity of the CNS. Patients with impaired liver function and renal drug should be prescribed with caution, and perhaps in a reduced dose. Patients treated by high-Alexan therapy should be observed at the possibility of development of neuropathy, as to prevent the occurrence of irreversible neurological disorders may need to change the dose or treatment regimen.

If you have symptoms of toxic effects on the CNS should be evaluated by the ratio benefit and risk, and the same action is needed and when the first symptoms of allergy.

In the application of Alexan may develop hyperuricemia due to the collapse of tumor cells. It is recommended that prevention of hyperuricemia in patients with a high content of blast cells or tumors bolshgo size (eg, non-Hodgkin's lymphoma).

Vaccination of patients who receive therapy Alexan, should be undertaken with extreme caution, after careful assessment of hematological status, and with the consent of the medical oncologist. The interval between the end of immunosuppressive therapy and vaccination depends on the type immunosupressanta, underlying disease and other factors and varies from 3 months to 1 year. Patients who are on hemodialysis, should not be used Alexan immediately before and during dialysis, because cytarabine appears in hemodialysis. The introduction of SCS to prevent or reduce the manifestations tsitarabinovogo syndrome.

Effects on ability to drive vehicles and management mechanisms

Data on the effect of the drug Alexan on ability to driving and managing mechanisms are available, but because at the time of therapy may have nausea and vomiting, this may indirectly affect the ability to drive vehicles and operate machinery. It should therefore be attentive to the individual action of the drug in the above situations.

Overdose

Symptoms: Chronic overdose can lead to severe disorders of bone marrow hematopoiesis, which may be accompanied by massive bleeding, the development of life-threatening infections, as well as the manifestation of neurotoxic action.

Treatment: as for cytarabine no effective antidotes, each of the drug should be pursued with caution.

In case of overdose shows supportive treatment (blood transfusions, antibiotics). In cases of severe overdose, emerged during intrathecal administration, should be repeated lumbar puncture for drainage of cerebrospinal fluid, possibly neurosurgical intervention ventrikulolyumbalnoy perfusion. Cytarabine can be displayed with hemodialysis, but information on the effectiveness of hemodialysis in an overdose of cytarabine absent.

Drug Interactions

With simultaneous application of Alexan with other antitumour mielosupressivnymi drugs or radiation therapy increased cytostatic and immunosuppressive activity of these drugs.

When you apply chemotherapy to include cytarabine marked reversible decrease in the equilibrium of plasma digoxin concentration by reducing the absorption (malabsorption due to toxic effects on the intestinal mucosa), as well as reduce the renal excretion of the glycoside. The alternative for these patients can be considered the application of digitoxin, the equilibrium plasma concentration is not changing.

Past in vitro studies of the interaction between gentamicin and cytarabine showed the existence of antagonism, as a result of which may reduce the sensitivity of strains of Klebsiella pneumoniae to gentamicin.

With simultaneous application of Alexan with ftortsitozinom may reduce the effectiveness of the latter. Immunosuppressants (azathioprine, chlorambucil, SCS, cyclophosphamide, cyclosporine, mercaptopurine, tacrolimus) increases the risk of infectious complications after simultaneous application of Alexan.

With simultaneous application of Alexan with killed virus vaccines may reduce the formation of antibodies by the suppression of cytarabine normal defense mechanisms.

With simultaneous application of Alexan with live virus vaccines may reduce the formation of antibodies, the potentiation of viral replication, increased side effects due to the suppression of cytarabine normal defense mechanisms.

Pharmaceutical interactions

You can not mix Alexan in the same syringe or dropper with other drugs. Pharmaceutical incompatible with heparin, insulin, methotrexate, 5-fluorouracil, oxacillin, benzylpenicillin, methylprednisolone.

Terms and Conditions of storage

List B. The drug should be stored protected from light, away from children at or above 25 ° C. Shelf life - 3 years.