Fludarabine

Fludarabine phosphate is a water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine (ara-A), and is relatively resistant to deamination by adenosine deaminase. It is a prodrug: in the body it is rapidly dephosphorylated to the nucleoside 2F-ara-A, which enters cells and is converted to the active triphosphate, 2F-ara-ATP.

Mechanism of Action

• Activation: inside the cell, 2F-ara-A is phosphorylated by deoxycytidine kinase and converted, through the monophosphate and the diphosphate, to the active triphosphate 2F-ara-ATP. This is the main intracellular metabolite and the only one known to be cytotoxic.
• Inhibition of DNA synthesis: 2F-ara-ATP inhibits ribonucleotide reductase, DNA polymerases, DNA primase and DNA ligase, and so blocks DNA synthesis. Partial inhibition of RNA polymerase II also reduces protein synthesis.
• Combined effect: effects on DNA, RNA and protein synthesis are thought to act together to inhibit cell growth, with inhibition of DNA synthesis the dominant factor. Some aspects of the mechanism are not fully clarified.
• Apoptosis: in vitro, exposing chronic lymphocytic leukaemia cells to 2F-ara-A caused extensive DNA fragmentation and the cell death typical of apoptosis.

Pharmacokinetics

• Prodrug: fludarabine phosphate (2F-ara-AMP) is rapidly and completely dephosphorylated to 2F-ara-A. A second metabolite, 2F-ara-hypoxanthine (the main one in dogs), is only a minor product in humans.
• Oral absorption: after oral dosing the peak plasma level of 2F-ara-A is about 20–30% of the level at the end of an intravenous infusion and occurs 1–2 hours after the dose. Mean systemic availability is 50–65% after single and repeated doses, and is similar for an oral solution and an immediate-release tablet. Taking the dose with food slightly raised the AUC (by under 10%), slightly lowered and delayed the peak, and did not change the terminal half-life.
• Intravenous dosing: after a 30-minute infusion of 25 mg/m² in patients with chronic lymphocytic leukaemia, the mean peak plasma level of 2F-ara-A was 3.5–3.7 µM at the end of the infusion and 4.4–4.8 µM after the fifth dose. Trough levels about doubled over a 5-day regimen, and accumulation over several cycles can be excluded. After the peak, plasma levels fall in three phases, with half-lives of about 5 minutes, 1–2 hours and about 20 hours (terminal).
• Dose linearity: after intravenous and oral dosing, plasma levels and AUC rise linearly with dose, while half-lives, clearance and volume of distribution stay constant.
• Distribution: mean volume of distribution is 83 ± 55 L/m² and mean total plasma clearance 79 ± 40 mL/min/m², with high variability between patients. Binding to plasma proteins is weak (19–29%).
• Inside leukaemic cells: 2F-ara-A is actively transported into the cells. Peak 2F-ara-ATP concentrations in lymphocytes from patients with chronic lymphocytic leukaemia occur at a median of about 4 hours (median peak about 20 µM), always well above peak plasma 2F-ara-A, which shows accumulation at the target. The median elimination half-life of 2F-ara-ATP from the cells ranged from 15 to 23 hours.
• Elimination: mainly by the kidneys; 40–60% of an intravenous dose is excreted in urine.
• Special populations: patients with reduced renal function have lower total body clearance and higher exposure, which is why the dose is reduced in them.

Both forms (tablets and concentrate) have the same indication:

• B-cell chronic lymphocytic leukaemia (B-CLL): treatment in adults with sufficient bone marrow reserve.
• First-line treatment: should be started only in adults with advanced disease (Rai stage III/IV, Binet stage C), or with Rai stage I/II (Binet stage A/B) if the patient has disease-related symptoms or evidence of progressive disease.

• Hypersensitivity to fludarabine phosphate or to any of the excipients.
• Renal impairment with a creatinine clearance below 30 mL/min.
• Decompensated haemolytic anaemia.
• Breastfeeding.

The most frequent reactions are myelosuppression (neutropenia, thrombocytopenia and anaemia), infections including pneumonia, cough, fever, fatigue, weakness, nausea, vomiting and diarrhoea. Other frequent reactions are chills, oedema, malaise, peripheral neuropathy, visual disturbances, anorexia, mucositis, stomatitis and skin rash. Serious opportunistic infections have occurred and deaths have been reported as a result of serious reactions. Frequencies come from clinical trials regardless of cause; the rare reactions were identified mainly after marketing.

Very common (≥1/10): infections and opportunistic infections (including reactivation of latent viruses, for example progressive multifocal leukoencephalopathy, herpes zoster and Epstein-Barr virus), pneumonia; neutropenia, anaemia, thrombocytopenia; cough; vomiting, diarrhoea, nausea; fever, fatigue, weakness.

Common (≥1/100 to <1/10): myelodysplastic syndromes and acute myeloid leukaemia (associated with previous, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors or irradiation); myelosuppression; anorexia; peripheral neuropathy; visual disorders; stomatitis; rash; oedema, mucositis, chills, malaise.

Uncommon (≥1/1,000 to <1/100): autoimmune disorders (including autoimmune haemolytic anaemia, Evans syndrome, thrombocytopenic purpura, acquired haemophilia, pemphigus); tumour lysis syndrome (including renal failure, metabolic acidosis, hyperkalaemia, hypocalcaemia, hyperuricaemia, haematuria, urate crystalluria, hyperphosphataemia); confusion; pulmonary toxicity (including pulmonary fibrosis, pneumonitis, dyspnoea); gastrointestinal haemorrhage, abnormal pancreatic enzymes; abnormal liver enzymes.

Rare (≥1/10,000 to <1/1,000): Epstein-Barr virus-associated lymphoproliferative disorder; coma, convulsions, agitation; blindness, optic neuritis, optic neuropathy; cardiac failure, arrhythmia; skin cancer, toxic epidermal necrolysis (Lyell type), Stevens-Johnson syndrome.

Not known (reported after marketing): cerebral haemorrhage; leukoencephalopathy, acute toxic leukoencephalopathy, posterior reversible leukoencephalopathy syndrome; pulmonary haemorrhage; haemorrhagic cystitis.

Important serious reactions are severe and sometimes fatal myelosuppression with pancytopenia, life-threatening autoimmune haemolytic anaemia, neurotoxicity (blindness, coma and death at high doses), tumour lysis syndrome and fatal transfusion-associated graft-versus-host disease.

• Pentostatin (deoxycoformycin): the combination is not recommended, because a clinical trial in refractory chronic lymphocytic leukaemia found an unacceptably high incidence of fatal pulmonary toxicity. This applies to intravenous fludarabine as well as to the tablets.
• Dipyridamole and other adenosine uptake inhibitors: may reduce the therapeutic effect of fludarabine.
• Cytarabine: clinical studies and in vitro experiments showed that, with fludarabine, the peak intracellular level and the intracellular exposure of the active cytarabine metabolite Ara-CTP rose in leukaemic cells. Plasma Ara-C levels and the elimination of Ara-CTP were not affected.
• Live vaccines: vaccination with live microorganisms should be avoided during and after treatment.
• Food: taking the tablets with food did not change their pharmacokinetics significantly.

Fludarabine must be prescribed and supervised by a qualified physician experienced in antineoplastic treatment. The tablets and the concentrate are separate products: the oral dose is 1.6 times the intravenous dose. The SmPC refers to its section 6.6 for instructions on handling the medicine.

Tablets (10 mg)

• Dose: 40 mg fludarabine phosphate/m² body surface area, taken orally once daily for 5 consecutive days every 28 days.
• Number of 10 mg tablets per day, by body surface area:
  • 0.75–0.88 m²: 3 tablets (30 mg)
  • 0.89–1.13 m²: 4 tablets (40 mg)
  • 1.14–1.38 m²: 5 tablets (50 mg)
  • 1.39–1.63 m²: 6 tablets (60 mg)
  • 1.64–1.88 m²: 7 tablets (70 mg)
  • 1.89–2.13 m²: 8 tablets (80 mg)
  • 2.14–2.38 m²: 9 tablets (90 mg)
  • 2.39–2.50 m²: 10 tablets (100 mg)
• Method: on an empty stomach or with food; swallowed whole with water, not chewed or broken.

Concentrate (25 mg/mL)

• Dose: 25 mg fludarabine phosphate/m² body surface area, given intravenously once daily for 5 consecutive days every 28 days.
• Preparation: the required dose is drawn into a syringe. For an intravenous bolus it is diluted further with 10 mL of sodium chloride 9 mg/mL (0.9%); for an infusion it is diluted in 100 mL of sodium chloride 0.9% and infused over about 30 minutes.
• Route: intravenous only, under the supervision of a qualified physician experienced in antineoplastic treatment.

Duration and Dose Adjustments

• Duration: depends on response and tolerance. Fludarabine is given until the best response (complete or partial remission, usually reached after 6 cycles) and is then stopped.
• Monitoring (tablet SmPC): response and toxicity are watched closely, and the dose is adjusted carefully to the haematological toxicity seen. No dose adjustment is recommended in the first cycle (except in renal impairment).
• Delaying a cycle (tablet SmPC): if blood counts at the start of the next cycle are too low for the recommended dose and there is evidence of myelosuppression, the cycle is postponed until granulocytes are above 1.0 × 10⁹/L and platelets above 100 × 10⁹/L, for at most two weeks.
• Dose reduction (tablet SmPC): if counts have not recovered after the two-week delay, the dose of fludarabine phosphate is reduced to 30 mg/m² daily when granulocytes are 0.5–1.0 × 10⁹/L and/or platelets 50–100 × 10⁹/L, and to 20 mg/m² daily when granulocytes are below 0.5 × 10⁹/L and/or platelets below 50 × 10⁹/L. The dose is not reduced if the thrombocytopenia is related to the disease.
• Dose increase (tablet SmPC): if a patient has not responded after two cycles and shows little or no haematological toxicity, a careful increase in later cycles may be considered.

Special Populations

• Renal impairment: the dose is reduced by up to 50% when creatinine clearance is 30–70 mL/min, with careful haematological monitoring. Treatment is contraindicated below 30 mL/min.
• Hepatic impairment: there are no data; use with caution.
• Elderly: data above 75 years of age are limited, so caution is needed. Creatinine clearance should be determined in patients over 65 years.
• Children and adolescents: safety and efficacy under 18 years have not been established, and use is not recommended.

Bone Marrow Suppression

Severe myelosuppression, especially anaemia, thrombocytopenia and neutropenia, has been reported. In a phase I intravenous study in adults with solid tumours, the lowest counts occurred at a median of 13 days (range 3–25) for granulocytes and 16 days (range 2–32) for platelets; most patients already had blood-count impairment from the disease or earlier treatment. Myelosuppression can be cumulative. Several cases of trilineage bone marrow hypoplasia or aplasia with pancytopenia, sometimes fatal, have been reported; clinically significant cytopenia lasted from about 2 months to about 1 year, in previously treated and untreated patients. Peripheral blood counts are checked regularly, and caution is needed if collection of haematopoietic progenitor cells is planned.

Autoimmune Disorders

Life-threatening and sometimes fatal autoimmune phenomena, including autoimmune haemolytic anaemia, have been reported during or after treatment, whatever the patient’s autoimmune history or Coombs’ test result. Most patients with haemolytic anaemia who were given fludarabine again had a recurrence. Patients are monitored closely for signs and symptoms of haemolysis, and treatment is recommended to be stopped if haemolysis occurs. Usual management of autoimmune haemolytic anaemia is blood transfusion (irradiated blood) and corticosteroids.

Neurotoxicity and Leukoencephalopathy

• The effect of long-term use on the central nervous system is unknown, although patients tolerated the recommended dose for up to 26 cycles in some studies. Patients are examined carefully for neurological signs.
• High intravenous doses in dose-escalation studies in acute leukaemia caused severe neurological effects, including blindness, coma and death, with symptoms 21–60 days after the last dose. Severe central nervous system toxicity occurred in 36% of patients given about four times the recommended dose (96 mg/m² daily for 5–7 days). At recommended doses for chronic lymphocytic leukaemia, it occurred rarely (coma, convulsions, agitation) or uncommonly (confusion).
• Leukoencephalopathy, acute toxic leukoencephalopathy or posterior reversible leukoencephalopathy syndrome can occur at the recommended dose, after or together with medicines known to be associated with them, in patients with other risk factors (cranial or total body irradiation, haematopoietic cell transplantation, graft-versus-host disease, renal impairment, hepatic encephalopathy), or at higher doses. Symptoms can include headache, nausea and vomiting, seizures, visual disturbances such as loss of vision, altered sensorium and focal neurological deficits. They can be irreversible, life-threatening or fatal.
• If one of these conditions is suspected, treatment is stopped, the patient is monitored and brain imaging (preferably MRI) is done. If the diagnosis is confirmed, fludarabine is stopped permanently.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported in patients with chronic lymphocytic leukaemia and a large tumour burden. Because fludarabine can produce a response in the first week, precautions are needed in patients at risk, and hospitalisation may be advised during the first cycle.

Transfusions

Transfusion-associated graft-versus-host disease (a reaction of transfused immunocompetent lymphocytes against the host) has been seen after non-irradiated blood in patients treated with fludarabine, very often with a fatal outcome. Patients who need blood and are being or have been treated with fludarabine should receive only irradiated blood.

Skin Cancer

Worsening or reactivation of existing skin cancer lesions, and new skin cancer, have been reported during or after treatment.

Patients in Poor General Condition

Fludarabine is given with caution and after careful weighing of risk and benefit in patients in poor health, especially those with severe bone marrow impairment (thrombocytopenia, anaemia and/or granulocytopenia), immunodeficiency or a history of opportunistic infections.

Renal Impairment

The total body clearance of 2F-ara-A correlates with creatinine clearance, and patients with reduced renal function had higher total exposure (AUC). Clinical data in patients with a creatinine clearance below 70 mL/min are limited. Fludarabine is given with care in renal impairment, with a dose reduction of up to 50% and close monitoring at 30–70 mL/min.

Vaccination, Switching and Re-treatment

• Vaccination: vaccination with live microorganisms should be avoided during and after treatment.
• Chlorambucil: switching to chlorambucil in patients who do not respond to fludarabine should be avoided, because most fludarabine-resistant patients were also resistant to chlorambucil.
• Oral to intravenous: nausea and vomiting were reported more often with the oral than with the intravenous form. If this remains a clinical problem, a switch to the intravenous form is recommended.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: because of the genotoxic risk, women of childbearing potential must use effective contraception during treatment and for at least 6 months afterwards. Men must use effective contraception and be advised not to father a child during treatment and for at least 3 months afterwards.
• Pregnancy: fludarabine phosphate is genotoxic, and was embryotoxic and foetotoxic in rabbits and rats. It can cause foetal harm and is not used in pregnancy unless the potential benefit to the mother outweighs the risk to the foetus. Women of childbearing potential are advised to avoid pregnancy and to tell their doctor at once if it occurs.
• Breastfeeding: contraindicated. Preclinical data show that fludarabine phosphate or its metabolites pass from blood into milk, with a potential for serious reactions in the breast-fed child.
• Fertility: fludarabine affects fertility in both men and women.

Excipients

• Lactose: each 10 mg tablet contains 74.75 mg of lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it.
• Sodium: the tablets contain less than 1 mmol sodium (23 mg) per tablet, that is, they are essentially sodium-free. The concentrate contains less than 1 mmol of sodium per mL.

Effect on Driving

Fludarabine can reduce the ability to drive and use machines, because fatigue, weakness, visual disturbances, confusion, agitation and convulsions have been observed.

• Tablets: keep in the original package to protect from moisture. Do not store above 25 °C and do not refrigerate. The tablets come in blisters of 5, packed in a bottle with a child-resistant cap (15 or 20 tablets).
• Concentrate: store in a refrigerator at 2–8 °C and do not freeze. Handle it as a cold-chain product during transport and storage.
• For storage after dilution of the concentrate, see Shelf Life.

• Tablets: 3 years.
• Concentrate: 2 years as packaged for sale. After dilution to 0.2–6.0 mg/mL with sodium chloride 0.9% or glucose 5%, chemical and physical stability was shown for 7 days at 2–8 °C and for 5 days at 20–25 °C in non-PVC bags and glass bottles. From a microbiological point of view the product should be used immediately; otherwise in-use storage times are the responsibility of the user and should normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx), prescribed by a qualified physician experienced in antineoplastic treatment. The 10 mg tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription. The 25 mg/mL concentrate is given intravenously, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.