Alexan^® (Solution) Instructions for Use

Marketing Authorization Holder

Sandoz, d.d. (Slovenia)

Manufactured By

Fareva Unterach, GmbH (Austria)

ATC Code

L01BC01 (Cytarabine)

Active Substance

Cytarabine (Rec.INN registered by WHO)

Dosage Forms

	Alexan®	Solution for injection 1 g/20 ml: vial 1 pc.
		Solution for injection 2 g/40 ml: vial 1 pc.
		Solution for injection 100 mg/5 ml: vial 1 pc.
		Solution for injection 500 mg/10 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

Solution for injection as a colorless, transparent liquid.

Excipients: sodium chloride – 6 mg, sodium lactate 60% solution – 4.16 mg, lactic acid – 0.027 mg*, water for injection – 981.813 mg.

5 ml – glass vials (1) – cardboard packs.

Solution for injection as a colorless, transparent liquid.

Excipients: sodium lactate 60% solution – 10.4 mg, lactic acid – 0.066 mg*, water for injection – 961.534 mg.

10 ml – glass vials (1) – cardboard packs.

Solution for injection as a colorless, transparent liquid.

Excipients: sodium lactate 60% solution – 10.4 mg, lactic acid – 0.066 mg*, water for injection – 961.534 mg.

20 ml – glass vials (1) – cardboard packs.

Solution for injection as a colorless, transparent liquid.

Excipients: sodium lactate 60% solution – 10.4 mg, lactic acid – 0.066 mg*, water for injection – 961.534 mg.

40 ml – glass vials (1) – cardboard packs.

* Lactic acid is used to adjust the pH of the initial solution, therefore its amount may vary. These fluctuations are compensated by water for injection to achieve the final mass. The average amount of lactic acid is indicated.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antineoplastic drug. It belongs to the group of pyrimidine metabolism antimetabolites and is an S-phase-specific drug. It inhibits DNA synthesis. As a result of phosphorylation, it is converted into arabinosyl cytosine triphosphate (Ara-CTP), which competitively inhibits DNA polymerase. Furthermore, there is evidence that DNA synthesis is also inhibited due to the incorporation of cytarabine into the DNA and RNA molecule.

The possible development of resistance to cytarabine is associated with inhibition of membrane transport, deficiency of phosphorylating enzymes, increased activity of inactivating enzymes, reduced affinity of DNA polymerase, or an increased deoxy-CTP pool. Cytotoxic action is achieved by creating sustained high intracellular concentrations of Ara-CTP.

Pharmacokinetics

Absorption and Distribution

With continuous IV infusion of cytarabine at a conventional dose (100-200 mg/m² body surface area), concentrations of 0.04-0.6 µmol/L are achieved. With SC administration, C_max in plasma is reached within 20-60 minutes, followed by a biphasic decrease in concentration.

Cytarabine penetrates the blood-brain barrier. After continuous infusion, a concentration is achieved in the cerebrospinal fluid, constituting 10-40% of the plasma concentration.

Plasma protein binding is 15%.

Metabolism

After IV administration, Cytarabine is rapidly and almost completely biotransformed in the liver and other tissues under the action of cytidine deaminase into the inactive uracil metabolite (Ara-U). A small portion of cytarabine undergoes phosphorylation under the action of kinases at the intracellular level, resulting in the formation of the active metabolite Ara-CTP.

Excretion

T_1/2 in the initial (α-phase) phase is 10 minutes, in the terminal (β-phase) phase it is approximately 1-3 hours.

Due to minimal deaminase activity in the CNS, the elimination of cytarabine from the cerebrospinal fluid is slow, with a T_1/2 of 2-11 hours.

4-10% of the administered dose is excreted unchanged by the kidneys. Within the first 24 hours, 71-96% of the administered drug is detected in the urine as Ara-U.

Indications

• Acute non-lymphoblastic and/or lymphoblastic leukemia (for remission induction, as well as for maintenance therapy);
• Prevention and treatment of neuroleukemia (intrathecal administration both as monotherapy and in combination with other antineoplastic drugs);
• Treatment of non-Hodgkin’s lymphomas;
• Treatment of blast crises in chronic myeloid leukemia.

High-dose cytarabine therapy

• Therapy-refractory non-Hodgkin’s lymphomas;
• Therapy-refractory acute lymphoblastic and/or non-lymphoblastic leukemia, as well as variants with an unfavorable prognosis;
• Relapses of acute leukemias;
• Secondary leukemias after prior chemotherapy and/or radiation therapy;
• Overt leukemia after transformation of preleukemias;
• Acute non-lymphoblastic leukemia in patients under 60 years of age (for consolidation of remission);
• Blast crises in chronic myeloid leukemia.

ICD codes

Dosage Regimen

The regimen and method of administration of Alexan^® vary when using different chemotherapy regimens. Before prescribing the drug, one should refer to specialized literature. Alexan^® can be administered IV bolus or drip, SC, IM (usually used only during maintenance therapy), as well as intrathecally. The average daily dose is 100-200 mg/m² body surface area, for elderly patients or patients with reduced hematopoietic reserves – 50-70 mg/m² body surface area.

For remission induction in acute leukemias in combination with other antineoplastic drugs, 100 mg/m² body surface area/day is prescribed as a continuous IV infusion for 7 days or 100 mg/m² body surface area IV every 12 hours for 7 consecutive days. A total of 4-7 treatment courses are conducted. Intervals between courses are at least 14 days.

For high-dose therapy for the treatment of leukemias with poor prognosis, as well as refractory leukemias and relapses, Alexan^® is prescribed at a dose of 2-3 g/m² body surface area as an IV infusion lasting 1-3 hours with a 12-hour interval for 2-6 days as monotherapy or in combination with other antineoplastic drugs.

For intrathecal administration in acute leukemia, the dose of Alexan^® is 5-75 mg/m² body surface area. The frequency of administration can range from once/day for 4 days to once every 4 days. Most often, Alexan^® is prescribed at 30 mg/m² body surface area every 4 days until parameters normalize, followed by one additional administration. However, doses and intervals between administrations depend on the clinical situation. Since the doses and administration regimen of Alexan^® depend on specially developed polychemotherapy regimens, in each individual case, one should refer to specialized literature.

In renal and hepatic impairment, there is no need to reduce the drug dose in case of using Alexan^® at conventional doses. If high-dose therapy is conducted, the increased risk of CNS complications should be taken into account when selecting the dose.

Rules for preparation of infusion solution

Alexan^® at the required dose is diluted in 0.9% sodium chloride solution or in 5% dextrose solution.

The concentration of cytarabine should not exceed 100 mg/ml.

For perfusion, Alexan^® can be used undiluted.

For intrathecal, lumbar, and intraventricular administration, the original solution can be used. First, 5-8 ml of cerebrospinal fluid should be withdrawn, mixed with the Alexan^® solution in a syringe, and then slow reverse administration of the resulting solution should be performed. The use of this route of administration is not associated with the risk of systemic toxic action.

Adverse Reactions

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

From the hematopoietic system: leukopenia, thrombocytopenia, anemia, megaloblastosis, reticulocytopenia. The decrease in leukocyte count is biphasic, with the first maximum decrease reached by days 7-9. This is followed by a short-term rise with a maximum on day 12. During the second and deeper decrease, the minimum leukocyte count is noted on days 15-24. In the following 10 days, the leukocyte count rapidly increases. The decrease in platelet count is noted by day 5, with the minimum noted between days 12-15. In the following 10 days, a rapid increase in platelet count to the initial level is noted. The severity of these reactions depends on the dose and administration regimen.

From the digestive system: nausea, vomiting, loss of appetite, abdominal pain, diarrhea, inflammation or ulceration of the gastrointestinal mucosa (including oral cavity, rectum, less commonly – esophagus). Nausea and vomiting most often occur following rapid IV administration. During high-dose therapy (2-3 g/m²), gastrointestinal ulcerations can be severe, possibly developing necrotic colitis, small intestine necrosis, cystic pneumatosis of the intestine leading to peritonitis.

From the liver and pancreas: impaired liver function, jaundice. With high-dose therapy – impaired liver function with hyperbilirubinemia, sepsis, liver abscess. Isolated cases of hepatic vein thrombosis (Budd-Chiari syndrome), as well as pancreatitis during high-dose therapy in combination with other antineoplastic drugs, have also been reported.

From the nervous system: neuritis, neurotoxicity, headache, dizziness. CNS disorders are mainly noted during high-dose therapy (primarily disorders of brain and cerebellar function) – nystagmus, dysarthria, ataxia, confusion, personality changes, drowsiness, coma. CNS disorders are reversible. Cases of peripheral motor and sensory neuropathy and late progressive ascending paralysis have also been reported. In isolated cases after intrathecal administration, nausea, vomiting, dizziness, fever were noted, possibly related to the lumbar puncture procedure. Cumulative neurotoxicity may also manifest, especially with short intervals between dose administrations. With intrathecal administration of the drug, isolated cases of necrotizing leukoencephalopathy, paraplegia, and blindness have been described.

From the sensory organs: conjunctivitis (photophobia, burning in the eyes, pronounced lacrimation), keratitis; with high-dose therapy – reversible ulcerative keratitis, hemorrhagic conjunctivitis, visual disturbances.

From the musculoskeletal system: with high-dose therapy – myalgias and/or arthralgias in the neck and lower extremities. A single case of rhabdomyolysis has been described.

From the respiratory system: sore throat, shortness of breath, pneumonia, diffuse interstitial pneumonitis (with the use of medium doses of 1 g/m²), progressive respiratory distress syndrome leading to pulmonary edema and cardiomegaly with possible fatal outcome (with the use of high-dose therapy).

From the cardiovascular system: cardiomyopathy (including fatal when using cytarabine in high doses in combination with cyclophosphamide), pericarditis, transient arrhythmia.

From the urinary system: impaired renal function, urinary retention, hyperuricemia or urate nephropathy.

Dermatological reactions: itching, maculopapular or urticarial rash, appearance of skin pigmentation spots, skin ulceration, alopecia; rarely – severe skin rash leading to desquamation.

Allergic reactions: urticaria, anaphylaxis, edema.

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

Infectious complications: viral, bacterial, fungal, parasitic, or saprophytic flora-induced infections of any localization (including sepsis), usually mild or moderate in severity, but can be severe and sometimes fatal (their development is due to decreased immunity).

Other: fever, thrombophlebitis; in isolated cases – syndrome of inappropriate ADH secretion.

6-12 hours after administration of Alexan^®, a cytarabine syndrome may develop: fever, muscle pain, bone pain, sometimes chest pain, maculopapular rash, conjunctivitis, malaise (the effectiveness of corticosteroids has been established).

Contraindications

• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to cytarabine and other components of the drug.

With caution the drug should be prescribed for hepatic and/or renal impairment (due to the increased risk of neurotoxicity, especially during high-dose therapy), for drug-induced hematopoietic suppression, infiltration of the bone marrow with tumor cells, acute infectious diseases of viral (including chickenpox, herpes zoster), fungal or bacterial etiology (risk of developing severe complications and generalization of the process), diseases in which there is an increased risk of hyperuricemia (gout or urate nephrolithiasis).

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation. During therapy with Alexan^®, and for 6 months after the end of therapy, women and men of reproductive age must use reliable methods of contraception.

Use in Hepatic Impairment

Patients with impaired liver function should be prescribed the drug with caution and possibly at a reduced dose.

With caution the drug should be prescribed for hepatic impairment (due to the increased risk of neurotoxicity, especially during high-dose therapy).

Use in Renal Impairment

Patients with impaired renal function should be prescribed the drug with caution and possibly at a reduced dose.

With caution the drug should be prescribed for renal impairment (due to the increased risk of neurotoxicity, especially during high-dose therapy).

Geriatric Use

The average daily dose for elderly patients is 50-70 mg/m² body surface area.

Special Precautions

When working with the drug, precautions developed for handling cytostatics should be observed. Contact of the drug with the skin and mucous membranes, especially the mucous membrane of the eyes, should be avoided.

Induction and consolidation therapy using Alexan^® for acute leukemias should be carried out in a specialized hospital setting, under the supervision of experienced oncologists and with careful monitoring.

It is necessary to regularly determine the count of blood cells, bone marrow, liver and kidney function, as well as the level of uric acid in the serum. In patients with a high content of blast cells or with large tumors (in non-Hodgkin’s lymphomas), prophylaxis of hyperuricemia is recommended.

If platelets fall below 50,000/µl or polymorphonuclear granulocytes below 1000/µl, therapy should be interrupted or modified. The count of peripheral blood cells may continue to fall after drug discontinuation and reach a minimum level after 12-24 days. If indicated, therapy can be resumed upon the appearance of clear signs of hematopoietic recovery according to bone marrow examination results.

When conducting high-dose therapy and intrathecal therapy, solutions containing benzyl alcohol should not be used.

When conducting high-dose therapy, constant monitoring of CNS and lung function should be carried out.

When conducting high-dose therapy and in case of impaired liver and kidney function, the likelihood of CNS toxicity may increase.

Patients with impaired liver and kidney function should be prescribed the drug with caution and possibly at a reduced dose.

Patients receiving high-dose therapy with Alexan^® should be monitored for the possibility of developing neuropathy, as dose or regimen changes may be required to prevent irreversible neurological disorders. If symptoms of CNS toxic influence appear, a benefit-risk assessment should be performed; the same actions are necessary upon the appearance of the first symptoms of allergy.

When using Alexan^®, hyperuricemia may develop due to tumor cell breakdown. Prophylaxis of hyperuricemia is recommended in patients with a high content of blast cells or with large tumors (e.g., non-Hodgkin’s lymphomas).

Vaccination of patients undergoing therapy with Alexan^® should be carried out with extreme caution, after a thorough assessment of the hematological status and with the consent of the oncologist. The interval between the end of immunosuppressive therapy and vaccination depends on the type of immunosuppressant, the underlying disease, and other factors and ranges from 3 months to 1 year.

Patients on hemodialysis should not be administered Alexan^® immediately before and during dialysis, because Cytarabine is eliminated by hemodialysis.

Administration of corticosteroids allows for the prevention or reduction of manifestations of the cytarabine syndrome.

Effect on the ability to drive vehicles and operate machinery

There are no data on the effect of Alexan^® on the ability to drive vehicles and operate machinery; however, since nausea and vomiting may occur during therapy, this may indirectly affect the ability to drive vehicles and operate machinery. Therefore, careful attention should be paid to the individual effect of the drug in the situations mentioned above.

Overdose

Symptoms chronic overdose may lead to severe impairment of bone marrow hematopoiesis, which may be accompanied by massive bleeding, the development of life-threatening infections, as well as the manifestation of neurotoxic effects.

Treatment since there are no effective antidotes for cytarabine, each administration of the drug should be carried out with caution. In case of overdose, supportive therapy (blood transfusion, antibiotic therapy) is indicated. In case of a severe overdose occurring during intrathecal administration, repeated lumbar punctures should be performed to ensure drainage of the cerebrospinal fluid; neurosurgical intervention with ventriculolumbar perfusion is possible.

Cytarabine can be removed by hemodialysis; however, information on the effectiveness of hemodialysis for cytarabine overdose is not available.

Drug Interactions

With the simultaneous use of Alexan^® with other myelosuppressive antitumor drugs or radiation therapy, the cytostatic and immunosuppressive activity of these drugs is enhanced.

When using polychemotherapy including cytarabine, a reversible decrease in the equilibrium plasma concentration of digoxin is observed due to reduced absorption (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 the use of digitoxin, the equilibrium plasma concentration of which does not change.

In vitro studies of the interaction between gentamicin and cytarabine revealed the existence of antagonism, which may lead to a decrease in the sensitivity of Klebsiella pneumoniae strains to gentamicin.

With the simultaneous use of Alexan^® with flucytosine, a decrease in the effectiveness of the latter is possible.

Immunosuppressants (azathioprine, chlorambucil, corticosteroids, cyclophosphamide, cyclosporine, mercaptopurine, tacrolimus) increase the risk of infectious complications when used concomitantly with Alexan^®.

With the simultaneous use of Alexan^® with killed viral vaccines, a decrease in antibody formation is possible due to the suppression of normal defense mechanisms by cytarabine.

With the simultaneous use of Alexan^® with live viral vaccines, a decrease in antibody formation, potentiation of virus replication, and an increase in side effects are possible due to the suppression of normal defense mechanisms by cytarabine.

Pharmaceutical interactions

Alexan^® should not be mixed in the same syringe or infusion set with other drugs. It is pharmaceutically incompatible with heparin, insulin, methotrexate, 5-fluorouracil, oxacillin, benzylpenicillin, and methylprednisolone.

Storage Conditions

List B. The drug should be stored in a place protected from light, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.