Fludarabine

Brand Nativa

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Available since: 2019-09-19

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Clinical Pharmacology

Pharmacodynamics. An anticancer drug containing fludarabina phosphate, which is a water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenin (ara-A), is relatively resistant to the action of adenosine deaminase. Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A, which, being captured by cells, is then intracellularly phosphorylated by deoxycytidine kinase to active triphosphate (2-fluoro-ara-ATP). This metabolite inhibits RNA reductase, DNA polymerase (alpha, delta, and upsilon), DNA primase and DNA ligase, as a result of which DNA synthesis is inhibited. In addition, RNA polymerase II is partially inhibited, followed by a decrease in protein synthesis.

In vitro studies have shown that the effect of 2-fluoro-ara-A on lymphocytes of patients with chronic lymphatic leukemia (CLL) activates a mechanism of intense DNA fragmentation and apoptosis. Toxic. It has teratogenic activity. Mutagenic properties does not possess.

Pharmacokinetics. There was no clear correlation between the pharmacokinetics of fludarabine and its therapeutic effect in cancer patients, and the frequency of detection of neutropenia and changes in hematocrit are dose-dependent.

Absorption: after oral administration, the maximum concentration (Cmax) (20-30% of the concentration determined by the end of intravenous infusion) in the blood is observed after 1-2 hours. Food slightly (less than 10%) increases the area under the concentration-time pharmacokinetic curve (AUC), reduces Tmax (time to reach maximum concentration) and Cmax, does not change the half-life.

Distribution and Metabolism: Fludarabine phosphate (2-fluoro-ara-AMP) is a water-soluble precursor of fludarabine; in the human body, 2-fluoro-ara-AMP is rapidly and completely dephosphorylated to the 2-fluoro-ara-A nucleoside. 2-fluoro-ara-A is actively transported into the leukemic cells, after which it is re-phosphorylated to monophosphate and partially to di- and triphosphate. Triphosphate (2-fluoro-ara-ATP) is the main intracellular metabolite and the only known metabolite with cytotoxic activity. The concentration of 2-fluoro-ara-ATP in leukemic cells is significantly higher than its maximum concentration in plasma, which indicates the accumulation of the substance in tumor cells.

Communication with proteins of a blood plasma insignificant. Bioavailability is 50-65%.

Excretion: 2-fluoro-ara-A is excreted primarily by the kidneys. The half-life of 2-fluoro-ara-ATP from target cells is on average from 15 to 23 hours.

Pharmacokinetics in selected groups of patients: patients with impaired renal function

In chronic renal failure, the clearance of 2-fluoro-ara-A decreases.

Indications

B-cell chronic lymphocytic leukemia (CLL) (as a 1st line therapy). Therapy with Flidarin® as a 1st line therapy can be initiated only in patients with progressive disease (stage C according to the Binet classification or stages III / IV according to the Rai classification) or in stages A / B according to the Binet classification or stages I / II according to the Rai classification, when symptoms and signs of disease progression are observed.
Composition

Active ingredient: 10 mg of fludarabina phosphate.

Ingredients: magnesium alumometasilicate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, ludipress (lactose monohydrate, povidone K30, crospovidone).

Shell: Opadry II white 85F48105 (polyvinyl alcohol - 46.9%, talc - 17.4%, macrogol 3350 - 23.6%, titanium dioxide - 12.1%).

Fludarabine is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Flidarin	Nativa	Russia	pills
Vero-Fludarabine	Veropharm	Russia	bottle
Fludarabina phosphate	Pharmakhemi B.V	Netherlands	solution concentrate

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Dosage and Administration

Fludarabine treatment should be under the supervision of a physician with experience in the use of anticancer therapy. The drug is prescribed only for adults. Reception inside. The drug can be taken on an empty stomach, and at the same time with a meal. pills should be swallowed whole (without chewing or breaking), drinking water.

The recommended oral dose is 40 mg / m2 of body surface area daily for 5 days, every 28 days.

Calculate the number of pills depending on the surface area of the body.

- Body surface area (ППТ), m2: 0.75 - 0.88; the daily dose calculated depending on PPT, mg / day: 30 - 35; number of pills per day: 3 (30 mg).

- Body surface area (ППТ), m2: 0.89 - 1.13; the daily dose calculated depending on PPT, mg / day: 36 - 45; number of pills per day: 4 (40 mg).

- Body surface area (ППТ), m2: 1.14 - 1.38; the daily dose calculated depending on the FPD, mg / day: 46 - 55; number of pills per day: 5 (50 mg).

- Body surface area (ППТ), m2: 1.39 - 1.63; the daily dose calculated depending on the FPD, mg / day: 56 - 65; number of pills per day: 6 (60 mg).

- Body surface area (ППТ), m2: 1.64 - 1.88; the daily dose calculated depending on the FPD, mg / day: 66 - 75; number of pills per day: 7 (70 mg).

- Body surface area (ППТ), m2: 1.89 - 2.13; the daily dose calculated depending on the FPD, mg / day: 76 - 85; number of pills per day: 8 (80 mg).

- Body surface area (ППТ), m2: 2,14 - 2,38; Calculated depending on the PPT daily dose, mg / day: 86 - 95; number of pills per day: 9 (90 mg).

- Body surface area (ППТ), m2: 2.39 - 2.50; calculated daily dose, depending on the FPD, mg / day: 96 - 100; number of pills per day: 10 (100 mg).

The duration of treatment depends on the effectiveness and tolerability of the drug. In CLL, fludarabine should be applied until the maximum response is achieved (complete or partial remission, usually 6 cycles), after which the treatment should be stopped.

In NHL NS, treatment with fludarabine is recommended until a maximum response is achieved (complete or partial remission). After achieving the greatest effect, the need for two consolidation cycles should be considered. The total duration of treatment is usually no more than 8 cycles of therapy. Dose adjustment depending on the number of blood cells

Patients receiving treatment with fludarabine should be regularly examined thoroughly for hematologic toxicity. If the patient has reduced the number of blood cells before the next treatment cycle and there is reason to believe that myelosuppression is associated with treatment, the planned treatment cycle should be postponed until the number of granulocytes is higher than 1.0 x 10 9 / l and the platelets number is higher than 100 x 109 / l . A subsequent cycle of therapy may be delayed for a maximum of two weeks. If the number of granulocytes and platelets has not recovered after these two weeks, the dose of the drug should be reduced according to the scheme suggested below.

- When the number of granulocytes 0.5-1.0 and / or platelet 50-100 [109 / l], the dose should be 30 mg / m2 / day.

- When the number of granulocytes <0.5 and="" or="" platelet="" 50="" 109="" l="" the="" dose="" should="" be="" 20="" mg="" m2="" day="" p="">

Do not reduce the dose of the drug, if thrombocytopenia is associated with the disease. If the patient's condition does not change after 2 weeks of treatment, a very small degree of hematologic toxicity is not revealed, or then a careful dose adjustment with an increase in fludarabine dose in subsequent treatment cycles can be considered.

Patients with impaired renal function. With creatinine clearance from 30 to 70 ml / min, the dose of the drug should be reduced by 50%. When conducting therapy in these patients, constant hematological monitoring is necessary to assess toxicity.When creatinine clearance <30 ml="" min="" fludarabine="" is="" contraindicated="" p="">

Patients with impaired liver function. Data on the use of fludarabine in patients with impaired liver function are not available. Care must be taken when prescribing the drug to this group of patients.

Adverse reactions

The adverse reactions listed below are listed according to the damage to organs and organ systems and the frequency of occurrence. The frequency of adverse reactions is estimated as follows: arising "very often" -> 10%; “Often” -> 1% and <10%, “infrequently” -> 0.1% and <1%, “rarely” -> 0.01% and <0.1%, “very rarely” - <0, 01%, including individual messages, "frequency unknown."

Disorders of the blood and lymphatic system: very often - neutropenia, thrombocytopenia and anemia; often - myelosuppression.

Immune system disorders: infrequently - autoimmune diseases (including autoimmune hemolytic anemia, thrombocytopenic purpura, pemphigus, Evans syndrome, acquired hemophilia).

Metabolic and nutritional disorders: often anorexia; infrequently - hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria (may develop as a result of tumor lysis).

Nervous system disorders: often - peripheral neuropathy; infrequently - confusion; rarely - agitation, convulsions, coma; frequency is unknown - leukoencephalopathy, acute toxic leukoencephalopathy, reversible posterior leukoencephalopathy syndrome (ADHD).

Violations of the organ of vision: often - visual impairment; rarely - optic neuritis, visual neuropathy, blindness.

Heart disorders: seldom - heart failure, arrhythmias.

Vascular disorders: frequency unknown - bleeding (including cerebral hemorrhage, pulmonary hemorrhage).

Disorders of the respiratory system, chest and mediastinal organs: very often - cough; infrequently - pulmonary toxicity (including shortness of breath, pulmonary fibrosis, pneumonitis).

Disorders of the gastrointestinal tract: very often - nausea, vomiting, diarrhea; often - stomatitis, mucositis; infrequently - gastrointestinal bleeding, abnormal activity indicators of pancreatic enzymes.

Disorders of the liver and biliary tract: infrequently - a deviation from the norm indicators of the activity of liver enzymes.

Violations of the skin and subcutaneous tissues: often - skin rash; rarely - skin cancer, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Disturbances from the kidneys and urinary tract: rarely - hemorrhagic cystitis; infrequently - renal failure (may develop as a result of tumor lysis).

Infectious and parasitic diseases: very often - accession of secondary / opportunistic infections (for example, reactivation of latent viral infections, including those caused by the Herpes zoster virus and Epstein-Barr virus, progressive multifocal leukoencephalopathy), pneumonia; rarely, lymphoproliferative disorders (associated with Epstein-Barr virus).

Benign, malignant and unspecified neoplasms (including cysts and polyps): often - myelodysplastic syndrome and acute myeloid leukemia (mainly associated with previous, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors or radiation therapy); infrequently - tumor lysis syndrome.

General disorders and disorders at the injection site: very often - fever, fatigue, weakness; often - chills, malaise, swelling.

Renal impairment with creatinine clearance <30 ml="" min="" h2="">Drug interactions
- With pentostatin.The use of fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of CLL has often been fatal due to its high pulmonary toxicity. Therefore, it is not recommended to prescribe fludarabine in combination with pentostatin.
- With dipyridamole. Dipyridamole or other adenosine reuptake inhibitors may decrease the therapeutic efficacy of fludarabine.
- With cytarabine. When using a combination of fludarabine and cytarabine in patients with CLL, pharmacokinetic interaction was observed. Clinical and in vitro studies have shown that the use of fludarabine in combination with cytarabine can increase the concentration of ara-CTP (active metabolite of cytarabine) in leukemic cells. The concentration of cytarabine in the blood plasma and the rate of its excretion did not change.
Overdosage

When used in doses that exceed the recommended, fludarabine causes the development of leukoencephalopathy, acute toxic leukoencephalopathy or reversible posterior leukoencephalopathy syndrome. Symptoms may include headache, nausea, vomiting, convulsions, visual impairment (such as loss of vision), impaired sensitivity and focal neurological symptoms, as well as lesions of the optic nerve and papillitis, confusion, drowsiness, agitation, paraparesis / quadroparesis, muscular spasticity and incontinence , irreversible changes in the central nervous system, including blindness, coma and death. The use of fludarabine in doses exceeding the recommended doses is also associated with the development of the development of severe thrombocytopenia and neutropenia due to the suppression of bone marrow function. In the event of the appearance of threatening symptoms, the drug should be immediately canceled and maintenance therapy should be carried out. The specific antidote is not known.