Fludarabine-Teva, 25 mg/ml concentrate 2 ml

Pharmacodynamics

Antitumor drug. Fludarabine phosphate, a component of the drug, is a water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A), relatively resistant to the action of adenosine deaminase. Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ar-A, which is taken up by the cells and then phosphorylated intracellularly by deoxycytidine kinase to active triphosphate (2-fluoro-ar-AATP). This metabolite inhibits ribonucleotide reductase, DNA polymerase, DNA primase, and DNA ligase, which inhibits DNA synthesis. In addition, RNA polymerase II is partially inhibited with a subsequent decrease in protein synthesis. In vitro studies have shown that exposure of lymphocytes of patients with chronic lympholeukemia to 2-fluoroar-A activates the mechanism of intense DNA fragmentation and apoptosis.

Pharmacokinetics

Fludarabine phosphate (2-fluoroura-A-MP) is a water-soluble precursor of fludarabine (2-fluoroura-A). In humans, 2-fluoroar-ar-AMP is rapidly and completely dephosphorylated to the nucleoside 2-fluoroar-ar-A.

Intake

After a single infusion in patients with chronic lympholeukemia of 2-fluoroura-ar-AMP at a dose of 25 mg/m2 for 30 min, the Cmax of 2-fluoroura-A is 3.5-3.7 μmol and is reached by the end of the infusion. Determinations of the corresponding 2-fluoroura-A levels after 5 administrations of the drug showed moderate cumulation with a mean Cmax of 4.4-4.8 μmol by the end of the infusion. During 5 days of treatment, plasma levels of 2-fluoroar-A increased 2-fold. However, cumulation of 2-Fluoro-Ara-A after several cycles of therapy may be insignificant.

Distribution

The binding of 2-Fluoro-Ara-A to plasma proteins is insignificant.

The Cmax of 2-fluoroura-AATP in leukemia lymphocytes of patients with CLL was observed an average of 4 h after infusion and was characterized by a significant variation in the mean value of approximately 20 μmol. The concentration of 2-fluoroar-ATP in leukemia cells was always significantly higher than its maximum concentration in plasma, indicating cumulation of the substance in target cells. A comparison of the pharmacokinetics of 2-fluoroura-A showed an average total plasma clearance of 79±40 ml/min/m2 (2.2±1.2 ml/min/kg) and an average Vd of 83±55 l/m2 (2.4±1.61 l/kg). The findings indicate high individual variability. After IV administration, the plasma concentration of 2-fluoroar-A and AUC increase in a linear dose-dependent manner, whereas T1/2,plasma clearance and Vd remain constant regardless of dose.

Metabolism and excretion

2-Fluoro-Ara-A is delivered to leukemia cells by active transport, where it is rephosphorylated to monophosphate and partially to di- and triphosphate. Triphosphate (2-fluoroura-ATP) is the major intracellular metabolite and is the only known metabolite with cytotoxic activity. The T1/2 of 2-fluoroura-ATP from target cells averaged 15 and 23 h.

After reaching Cmax in plasma, levels of 2-fluoroura-ATP decrease in three phases: the T1/2 in the alpha phase is approximately 5 min, the beta phase 1-2 h and in the terminal phase about 20 h.

2-Fluoro-Ara-A is excreted primarily by the kidneys (40-60% of the IV dose administered).

Pharmacokinetics in Special Clinical Cases

No clear correlation between the pharmacokinetics of 2-fluoro-ar-A and the therapeutic effect of the drug in cancer patients has been found; however, the frequency of neutropenia and changes in hematocrit indicate a dose-dependent nature of the cytotoxic action of fludarabine phosphate in the form of suppression of hematopoiesis.

In persons with decreased renal function, a decrease in total clearance of the drug was observed, indicating the need to reduce the dose.

Indications

Active ingredient

Composition

1 ml (1 vial) contains:

Active substances:

fludarabine phosphate 25 mg (50 mg).

Associates:

Mannitol – 25 mg,

Sodium hydroxide – 3.3 mg,

water d/i – q.s. to 1 ml.

The bottle contains 2 ml of concentrate.

There is 1 vial in the carton pack.

How to take, the dosage

Injection of fludarabine only by injection is allowed, and accidental extravascular ingestion should be avoided.

The recommended dose of fludarabine phosphate for adults is 25 mg/m2 body surface area by IV once daily for 5 days every 28 days. The required dose (calculated according to the patient’s body surface area) is drawn into a syringe. For intravenous administration by injection, the above dose is diluted in 10 ml of 0.9% sodium chloride solution, or the required dose can be diluted in 100 ml of 0.9% sodium chloride solution and given by drip for 30 minutes. There are no clear data on the optimal duration of treatment. The course of treatment depends on the observed effect and tolerability of the drug.

The treatment with fludarabine is recommended until a therapeutic response is achieved (usually 6 cycles), after which the drug is stopped.

The data on efficacy and safety of fludarabine in patients with hepatic impairment are limited. In patients in this group fludarabine is administered with caution after careful assessment of the risk/benefit ratio. Treatment of these patients should be carried out under close supervision. If necessary, the drug dose should be reduced or treatment should be stopped.

In patients with possible renal dysfunction and in patients older than 70 years, CK determinations are necessary. If CKD is within 30-70 ml/min, the drug dose should be reduced up to 50% and the treatment should be monitored by blood tests to assess toxicity. Treatment with fludarabine is contraindicated if the CK is less than 30 ml/min.

Interaction

The use of fludarabine in combination with pentostatin (deoxycoformicin) for the treatment of chronic lympholeukemia has often been fatal because of high pulmonary toxicity.

The therapeutic efficacy of fludarabine may be reduced by adenosine reuptake inhibitors and dipyridamole.

In treatment with a combination of fludarabine and cytarabine a pharmacokinetic interaction has been observed in patients with chronic lympholeukemia and acute myeloid leukemia.

The co-administration of cytarabine with fludarabine showed higher intracellular peak concentrations and intracellular AUC of the cytarabine metabolite arabinosyl cytosine triphosphate. Plasma concentrations of cytarabine and excretion of arabinosyl cytosine triphosphate were not altered.

Fludarabine solution for intravenous administration should not be mixed with other drugs.

Special Instructions

Treatment with fludarabine should be performed under the supervision of a physician experienced in the use of cytotoxic agents.

In therapy with fludarabine, periodic peripheral blood counts are recommended to detect anemia, neutropenia and thrombocytopenia, serum creatinine concentration and creatinine clearance should be closely monitored, and CNS function should be closely monitored to detect possible neurological disorders in a timely manner.

The bone marrow depression is usually reversible. During fludarabine therapy, the greatest decrease in neutrophil counts is observed on average on day 13 (day 3-25) from the start of treatment, and in platelets – on average on day 16 (day 2-32). Myelosuppression can be pronounced and cumulative. Several cases of bone marrow hypoplasia or aplasia in adults have been described, manifesting as pancytopenia, sometimes with fatal outcome. The duration of clinically significant pancytopenia ranged from 2 months to 1 year. These episodes were detected in both pretreated and untreated patients.

Patients at increased risk of opportunistic infections are recommended for prophylactic therapy. Serious opportunistic infections have been reported with fludarabine therapy, in some cases leading to death.

If future hematopoietic stem cell transplantation is contemplated, caution should be exercised when prescribing fludarabine, which is a cytotoxic agent.

In transfusions of unexposed blood in patients treated with fludarabine, a graft vs. host reaction (a reaction of transfused immunocompetent lymphocytes against the host) has been observed, which is associated with a high mortality rate. Patients needing hemotransfusions and receiving or having received fludarabine should be transfused only with irradiated blood.

Tumor decay syndrome, which occurs with fludarabine treatment, has been observed in patients with CLL who have a large tumor mass. Because fludarabine can have a therapeutic effect as early as the first week of therapy, precautions should be taken in patients who are at likely risk of developing this complication.

Whether or not there is a history of autoimmune processes and the results of the Coombs test, there is a risk of life-threatening autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, bulla, Evans syndrome) during or after fludarabine treatment. Recurrent hemolytic process after resumption of fludarabine treatment is possible. Patients receiving fludarabine should be closely monitored for hemolysis. If hemolysis develops, discontinuation of therapy is recommended. The most common therapeutic measures used to treat autoimmune hemolytic anemia are blood transfusion (irradiated) and GCS.

Vaccination with live vaccines should be avoided during and after treatment with fludarabine.

Most patients who are insensitive to fludarabine are also insensitive to chlorambucil.

Please use only a clear and colorless solution containing no visible solid particles. If the container is damaged, the drug should not be used.

The chemical and physical stability of the solution prepared for injection or infusion is maintained for 3 days at 25°C or in the refrigerator (2°C to 8°C) when diluting the concentrate with 0.9% sodium chloride solution for infusion or 5% dextrose solution for infusion. In terms of microbiological purity the diluted solution should be used immediately, it is allowed to store the diluted solution in refrigerator (2° to 8°C) for not more than 24 hours.

When working with fludarabine, follow the rules for handling cytotoxic drugs, avoid contact with the solution! If the solution comes into contact with the skin, mucous membranes or eyes, rinse them thoroughly with plenty of water.

Impact on the ability to drive vehicles and other mechanisms requiring high concentration

Some side effects of the drug, such as increased fatigue, weakness, visual impairment, may adversely affect the ability to drive vehicles and engage in potentially dangerous activities requiring increased concentration and rapid psychomotor reactions.

Contraindications

With caution and after careful evaluation: risk/benefit ratio, fludarabine should be used in frail patients, with marked decreased bone marrow function (thrombocytopenia, anemia and/or granulocytopenia), renal or liver failure, immunodeficiency, opportunistic infections in the history, in patients over 75 years.

Side effects

The frequency of adverse reactions is based on data from clinical studies, regardless of causal relationship to fludarabine use, according to the following frequency gradation:

Hematopoietic system: very common – neutropenia, thrombocytopenia and anemia; often – myelosuppression.

Immune system disorders: infrequent – autoimmune disorders (including autoimmune hemolytic anemia, thrombocytopenic purpura, pemic ulcer, Evans syndrome, acquired hemophilia), allergic reactions.

In the digestive system: very frequently – nausea, vomiting, diarrhea; frequently – anorexia, stomatitis, mucositis; infrequently – gastrointestinal bleeding, changes of liver and pancreatic enzyme activity.

Mechanical disorders: infrequent – hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria may develop as a result of lysis of tumor.

Nervous system disorders: often – peripheral neuropathy; infrequent – mental confusion; rarely – agitation, convulsions, coma.

An organ of vision: often – visual disturbances; rarely – optic neuritis, optic neuropathy and blindness.

Respiratory system: very common – cough; infrequent – dyspnea, pulmonary fibrosis, pneumonitis.

Cardiovascular system: rarely – heart failure, arrhythmia.

Urinary system disorders: rarely – hemorrhagic cystitis.

Skin and appendages: often – skin rash; rarely – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome). Rare cases of increased growth of existing skin cancer and development of skin cancer during or after treatment with fludarabine have been reported.

Others: very common – increase in body temperature, increased fatigue, weakness, accession of secondary infections; common – chills, malaise, peripheral edema; rare – lymphoproliferative disorders (associated with Epstein-Barr virus). In patients who received fludarabine before, after or simultaneously with alkylating cytotoxic agents or radiotherapy, myelodysplastic syndrome/acute myeloid leukemia was observed in rare cases.

Overdose

Symptoms: when using fludarabine in high doses, irreversible CNS changes, vision loss, coma and death are possible, as well as the development of severe thrombocytopenia and neutropenia due to suppression of bone marrow function.

Treatment: In case of threatening symptoms the drug should be immediately withdrawn and supportive therapy should be carried out. A specific antidote is not known.