(and dosage form):
Sterile lyophilised solid cake for solution
Each vial contains 50 mg fludarabine phosphate as a lyophilised solid cake (equivalent to 39,05 mg fludarabine per vial).
A. 26 Cytostatic agents.
Fludara contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-beta-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase.
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A which is taken up by cells and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite has been shown to inhibit ribonucleotide reductase, DNA polymerase alpha/delta and epsilon, DNA primase and DNA ligase thereby inhibiting DNA synthesis. Furthermore, partial inhibition of RNA polymerase II and consequent reduction in protein synthesis occurs.
While some aspects of the mechanism of action of 2-fluoro-ara-ATP are as yet unclear, it is assumed that effects on DNA, RNA and protein synthesis all contribute to inhibition of cell growth with inhibition of DNA synthesis being the dominant factor.
In addition, in vitro studies have shown that exposure of chronic lymphocytic leukaemia lymphocytes to 2F-ara-A triggers extensive DNA fragmentation and cell death characteristic of apoptosis.
Plasma and urinary pharmacokinetics of fludarabine (2F-ara-A)
The pharmacokinetics of fludarabine (2F-ara-A) has been studied after intravenous administration by rapid bolus injection, short-term infusion and following continuous infusion of fludarabine phosphate (Fludara, 2F-ara-AMP). 2F-ara-A demonstrated a similar pharmacokinetic profile in chronic lymphocytic leukaemia.
No clear correlation was found between 2F-ara-A pharmacokinetics and treatment efficacy in cancer patients. However, occurrence of neutropenia and hematocrit changes indicated that the cytotoxicity of fludarabine phosphate depresses hematopoiesis in a dose-dependent manner.
Distribution and metabolism
After single dose infusion of 25 mg 2F-ara-AMP per m² to chronic lymphocytic leukaemia patients for 30 minutes, 2F-ara-A reached mean maximum concentrations in the plasma of 3,5 to 3,7 microM at the end of the infusion. Corresponding 2F-ara-A levels after the fifth dose showed a moderate accumulation with mean maximum levels of 4,4 to 4,8 microM at the end of infusion. During a 5 day treatment schedule, 2F-ara-A plasma trough levels increased by a factor of about 2. An accumulation of 2F-ara-A over several treatment cycles can be excluded. Postmaximum levels decayed in three disposition phases with an initial half-life of approximately 5 minutes, an intermediate half-life of 1 to 2 hours and a terminal half-life of approximately 20 hours.
An interstudy comparison of 2F-ara-A pharmacokinetics resulted in a mean total plasma clearance (CL) of 79 mL/min/m² (2,2 mL/min/kg) and a mean volume of distribution (Vss) of 83 L/m² (2,4 L/kg). Data showed a high interindividual variability. After intravenous administration of fludarabine phosphate plasma levels of 2F-ara-A and areas under the plasma level time curves increased linearly with the dose, whereas half-lives, plasma clearance and volumes of distribution remained constant independent of the dose indicating a dose linear behaviour.
2F-ara-A elimination is largely by renal excretion, 40 to 60% of the administered intravenous dose was excreted in the urine.
Characteristics in patients
Individuals with impaired renal function exhibited a reduced total body clearance, indicating the need for a dose reduction. In vitro investigations with human plasma proteins revealed no pronounced tendency of 2F-ara-A protein binding.
Cellular pharmacokinetics of fludarabine triphosphate
2F-ara-A is actively transported into leukaemic cells, whereupon it is rephosphorylated to the monophosphate and subsequently to the di- and triphosphate. The triphosphate 2F-ara-ATP is the major intracellular metabolite and the only metabolite known to have cytotoxic activity. Maximum 2F-ara-ATP levels in leukaemic lymphocytes of chronic lymphocytic leukaemia patients were observed at a median of 4 hours and exhibited a considerable variation with a median peak concentration of approximately 20 microM, 2F-ara-ATP levels in leukaemic cells were always considerably higher than maximum 2F-ara-A levels in the plasma indicating an accumulation at the target sites. In vitro incubation of leukaemic lymphocytes showed a linear relationship between extracellular 2F-ara-A exposure (product of 2F-ara-A concentration and duration of incubation) and intracellular 2F-ara-ATP enrichment, 2F-ara-ATP elimination from target cells showed median half-life values of 15 and 23 hours.
Fludara is indicated for the treatment of patients with B-cell chronic lymphocytic leukaemia who have not responded to or have not progressed during treatment with at least one standard alkylating-agent containing regimen.
Fludara is contra-indicated in those patients who are hypersensitive to fludarabine or its components and in renally impaired patients with creatinine clearance <30 mL/minute and in patients with haemolytic anaemia.
The safety and effectiveness of Fludara in children has not been established.
Fludara should not be used during pregnancy.
Embryotoxicity studies in animals demonstrated an embryotoxic and/or teratogenic potential posing a relevant risk to humans at the envisaged therapeutic dose. Preclinical data in rats demonstrated a transfer of fludarabine phosphate and/or metabolites through the feto-placental barrier.
One case of fludarabine phosphate use during early pregnancy leading to skeletal and cardiac malformation in the newborn has been reported.
Women of childbearing potential should be advised to avoid becoming pregnant and to inform the treating physician immediately should this occur.
It is not known whether this drug is excreted in human milk.
However, there is evidence from preclinical data that fludarabine phosphate and/or metabolites transfer from maternal blood to milk.
Therefore, breastfeeding should be discontinued for the duration of Fludara therapy.
DOSAGE AND DIRECTIONS FOR USE
Reduced kidney function
Doses should be adjusted for patients with reduced kidney function. If creatinine clearance is between 30 and 70 mL/min, the dose should be reduced by up to 50% and close haematological monitoring should be used to assess toxicity. For further information see Special precautions. Fludara treatment is contra-indicated if creatinine clearance is <30 mL/min.
Fludara should be prepared for parenteral use by aseptically adding sterile water for injection.
When reconstituted with 2 mL of sterile water for injection, the solid cake should fully dissolve in 15 seconds or less.
Each mL of the resulting solution will contain 25 mg of fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7,7. The pH range for the final product is 7,2 to 8,2.
Discard within 8 hours of reconstitution.
Fludara should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.
It is strongly recommended that Fludara should be only administered intravenously. No cases have been reported in which paravenously administered Fludara led to severe local adverse reactions. However, unintentional paravenous administration must be avoided.
The recommended dose is 25 mg/m² body surface given daily for 5 consecutive days every 28 days by the intravenous route. Each vial is to be made up in 2 mL water for injection. Each mL of the resulting solution will contain 25 mg fludarabine phosphate. The dose should not be exceeded as severe neurotoxicity may occur.
The required dose (calculated on the basis of the patient's body surface) is drawn up into a syringe. For intravenous bolus injection this dose is further diluted into 10 mL of physiological saline. Alternatively, the required dose drawn up in a syringe may be diluted into 100 mL physiological saline and infused over approximately 30 minutes.
Depending on the treatment success and the tolerability of the drug, Fludara should be administered in chronic lymphocytic leukaemia patients up to the achievement of best response (complete or partial remission, usually 6 cycles) and then the drug should be discontinued.
Handling and disposal
Fludara should not be handled by pregnant staff.
Procedures for proper handling and disposal should be observed. Consideration should be given to handling and disposal according to guidelines used for cytotoxic medicine. Any spillage or waste material may be disposed of by incineration.
Caution should be exercised in the handling and preparation of the Fludara solution. The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution comes into contact with the skin or mucous membranes, the area should be washed thoroughly with soap and water. In the event of contact with the eyes, rinse them thoroughly with copious amounts of water. Exposure by inhalation should be avoided.
SIDE EFFECTS AND SPECIAL PRECAUTIONS
The most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anaemia), fever, chills and infection including pneumonia. Other commonly reported events include oedema, malaise, fatigue, weakness, peripheral neuropathy, visual disturbances, anorexia, nausea, vomiting, diarrhoea, stomatitis and skin rashes. Serious opportunistic infections have occurred in patients treated with Fludara. Fatalities as a consequence of serious adverse events have been reported.
The most frequently reported adverse events and those reactions which are more clearly related to the drug are arranged below according to body system. Their frequencies (common >1%, uncommon >0,1% and <1%) are based on clinical trial data regardless of the causal relationship with Fludara. The rare events (<0,1%) were mainly identified from post-marketing experience.
Body as a whole
Fever, chills, infection, malaise, weakness and fatigue have been commonly reported.
Haemic and lymphatic system
Haematologic events (neutropenia, thrombocytopenia, and anaemia) have been reported in the majority of patients treated with Fludara. Myelosuppression may be severe and cumulative. Fludaras prolonged effect on the decrease in the number of T-lymphocytes may lead to increased risk for opportunistic infections, including those due to latent viral reactivation, eg progressive multifocal leucoencephalopathy.
Clinically significant autoimmune phenomena are uncommon in patients receiving Fludara (see Special precautions).
Metabolic and nutritional disorders
Tumour lysis syndrome has been reported in patients treated with Fludara. This complication may include hyperuricaemia, hyperphosphataemia, hypocalcaemia, metabolic acidosis, hyperkalaemia, haematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and haematuria.
Oedema has been commonly reported.
Changes in hepatic and pancreatic enzyme levels are uncommon.
Coma, seizures and agitation occur rarely and confusion uncommonly. Peripheral neuropathy has been commonly observed.
Visual disturbances are commonly reported events in patients treated with Fludara. In rare cases, optic neuritis, optic neuropathy and blindness have occurred.
Pneumonia commonly occurs in association with Fludara treatment. Pulmonary hypersensitivity reactions to Fludara (pulmonary infiltrates/pneumonitis/fibrosis) associated with dyspnoea and cough are uncommon.
Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhoea and stomatitis are common events. Gastrointestinal bleeding, mainly related to thrombocytopenia, has been reported in patients treated with Fludara.
In rare cases, heart failure and arrhythmia have been reported in patients treated with Fludara.
Rare cases of haemorrhagic cystitis have been reported in patients treated with Fludara.
Skin and appendages
Skin rashes have been commonly reported in patients treated with Fludara.
In rare cases a Stevens-Johnson syndrome or a toxic epidermal necrolysis (Lyell's syndrome) may develop.
When used at high doses in dose-ranging studies in patients with acute leukaemia, Fludara was associated with severe neurologic effects, including blindness, coma and death. This severe central nervous system toxicity occurred in 36% of patients treated intravenously with doses approximately four times greater (96 mg/m²/day for 5 to 7 days) than the dose recommended for treatment of chronic lymphocytic leukaemia. In patients treated at doses in the range of the dose recommended for chronic lymphocytic leukaemia severe central nervous system toxicity occurred rarely (coma, seizures and agitation) or uncommonly (confusion). Patients should be closely observed for signs of neurologic side effects.
The effect of chronic administration of Fludara on the central nervous system is unknown. However, patients tolerated the recommended dose, in some studies for relatively long treatment times, whereby up to 26 courses of therapy were administered.
Impaired state of health
In patients with impaired state of health, Fludara should not be given. This applies especially for patients with severe impairment of bone marrow function (thrombocytopenia, anaemia, and/or granulocytopenia), immunodeficiency or with a history of opportunistic infection.
Severe bone marrow suppression, notably anaemia, thrombocytopenia and neutropenia, has been reported in patients treated with Fludara. In a Phase I study in solid tumour patients, the median time to nadir counts was 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days ) for platelets. Most patients had haematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of fludarabine phosphate requires careful haematologic monitoring.
Fludara is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of haematologic and non-haematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of anaemia, neutropenia and thrombocytopenia.
Transfusion of blood products
Transfusion-associated graft-versus-host disease (reaction by the transfused immunocompetent lymphocytes to the host) has been observed rarely after transfusion of non-irradiated blood in Fludara treated patients. Fatal outcome as a consequence of this disease has been reported with a high frequency. Therefore patients who require blood transfusion and who are undergoing, or who have received, treatment with Fludara should receive irradiated blood only.
Skin cancer lesions
Reversible worsening or flare up of pre-existing skin cancer lesions has been reported in some patients during or after Fludara therapy.
Tumour lysis syndrome
Tumour lysis syndrome associated with Fludara treatment has been reported in patients with large tumour burdens. Since Fludara can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.
Irrespective of any previous history of autoimmune processes or Coombs test status, life-threatening and sometimes fatal autoimmune phenomena (eg autoimmune haemolytic anaemia, autoimmune thrombocytopenia, thrombocytopenic purpora, pemphigus, Evans syndrome) have been reported to occur during or after treatment with Fludara. The majority of patients experiencing haemolytic anaemia developed a recurrence in the haemolytic process after rechallenge with Fludara.
Patients undergoing treatment with Fludara should be closely monitored for signs of autoimmune haemolytic anaemia (decline in haemoglobin linked with haemolysis and positive Coombs test). Discontinuation of therapy with Fludara is recommended in case of haemolysis. Blood transfusion (irradiated, see above) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia.
Reduced renal function
The total body clearance of the principal plasma metabolite 2-F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced renal function demonstrated an increased total body exposure (AUC of 2F-ara-A). Limited clinical data are available in patients with impairment of renal function (creatinine clearance below 70 mL/minute).
Therefore, if renal impairment is clinically suspected, or in patients over the age of 70 years, creatinine clearance should be measured. If creatinine clearance is between 30 and 70 mL/min, the dose should be reduced by up to 50% and close haematological monitoring should be used to assess toxicity. Fludara treatment is contra-indicated, if creatinine clearance is <30 mL/minute.
Since there are limited data for the use of Fludara in elderly persons (>75 years), caution should be exercised with the administration of Fludara in these patients.
Females of child-bearing potential and males must take contraceptive measures during and at least for 6 months after cessation of therapy.
During and after treatment with Fludara, vaccination with live vaccines should be avoided.
Interaction with other medicines and other forms of interaction
In clinical investigation using Fludara in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukaemia there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludara in combination with pentostatin is not recommended.
The therapeutic efficacy of Fludara may be reduced by dipyridamole and other inhibitors of adenosine uptake.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
High doses of Fludara have been associated with an irreversible central nervous system toxicity characterised by delayed blindness, coma, and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for Fludara overdosage. Treatment consists of discontinuation of treatment and supportive therapy.
Sterile white lyophilised solid cake or powder supplied in clear glass single dose vials of 6 mL capacity.
1 vial containing 50 mg.
5 vials containing 50 mg each.
Store below 30°C. Keep out of reach of children. For shelf-life refer to the imprint on the pack.
NAME AND BUSINESS ADDRESS OF THE APPLICANT
Schering (Pty) Ltd
(Reg No: 1964/009072/07)
106 Sixteenth Road
P O Box 5278
Halfway House 1685
DATE OF PUBLICATION OF THIS PACKAGE INSERT
20 September 2002
SCHERING (PTY) LTD
(Reg No: 1964/009072/07)
Schering AG Germany
Updated on this site: January 2005
Source: Pharmaceutical Industry
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