Fludarabine Phosphate for Injection USP 50mg/2ml Taj Pharma

1. Name of the medicinal product

Fludarabine Phosphate for Injection USP 25mg/ml Taj Pharma
Fludarabine Phosphate for Injection USP 50mg/2ml Taj Pharma

2. Qualitative and quantitative composition

a) Fludarabine Phosphate for Injection USP 25mg/ml Taj Pharma
Each ml Lyophised vial contains:
Fludarabine Phosphate USP 25mg
Excipients: Q.S.

b) Fludarabine Phosphate for Injection USP 50mg/2ml Taj Pharma
Each 2ml Lyophised vial contains:
Fludarabine Phosphate USP 50mg
Excipients: Q.S.

Each 1ml of reconstituted solution contains 25mg fludarabine phosphate and 2ml of reconstituted solution contains 50mg

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder for solution for injection or infusion.

White or almost white lyophilisate.

4. Clinical particulars

• Therapeutic indications

Treatment of B-cell chronic lymphocytic leukaemia (CLL) in patients with sufficient bone marrow reserves.

First line treatment with Fludarabine Taj Pharma should only be initiated in patients with advanced disease, Rai stages III/IV (Binet stage C), or Rai stages I/II (Binet stage A/B) where the patient has disease related symptoms or evidence of progressive disease.

• Posology and method of administration

Posology

The recommended dose is 25mg fludarabine phosphate/m² body surface area given daily for 5 consecutive days every 28 days by intravenous route. Each vial is to be made up in 2 ml water for injection. Each ml of the resulting solution will contain 25mg Fludarabine Taj Pharma Phosphate Taj Pharma (see section 6.6).

The required dose (calculated on the basis of the patient’s body surface area) of the reconstituted solution is drawn up into a syringe. For intravenous bolus injection this dose is further diluted in 10 ml sodium chloride 9mg/ml (0.9%). Alternatively, for infusion, the required dose drawn up in a syringe may be diluted in 100 ml sodium chloride 9mg/ml (0.9%) and infused over approximately 30 minutes.

The duration of treatment depends on the treatment success and the tolerability of the drug.

In CLL patients, Fludarabine Taj Pharma should be administered up to the achievement of best response (complete or partial remission, usually 6 cycles) and then the drug should be discontinued.

Patients with renal impairment

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 (see section 4.4).

Fludarabine Taj Pharma treatment is contraindicated, if creatinine clearance is < 30 ml/min (see section 4.3).

Patients with hepatic impairment

No data are available concerning the use of Fludarabine Taj Pharma in patients with hepatic impairment. In this group of patients, Fludarabine Taj Pharma should be used with caution.

Pediatric population

The safety and efficacy of Fludarabine Taj Pharma in children below the age of 18 years have not been established. Therefore, Fludarabine Taj Pharma is not recommended for use in children.

Older people

Since there are limited data for the use of Fludarabine Taj Pharma in older people (> 75 years), caution should be exercised with the administration of Fludarabine Taj Pharma in these patients.

In patients over the age of 65 years, creatinine clearance should be measured (see “Patients with renal impairment” and section 4.4).

Method of administration

Fludarabine Taj Pharma should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

It is strongly recommended that Fludarabine Taj Pharma should be only administered intravenously. No cases have been reported in which paravenously administered Fludarabine Taj Pharma led to severe local adverse reactions. However, unintentional paravenous administration must be avoided.

Precautions to be taken before handling the medicinal product

For instructions on handling and reconstitution of the medicinal product before administration, see section 6.6.

• Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Renal impairment with creatinine clearance < 30 ml/min.
• Decompensated haemolytic anaemia.
  • Special warnings and precautions for use

Myelosuppression

Severe bone marrow suppression, notably anaemia, thrombocytopenia and neutropenia, has been reported in patients treated with Fludarabine Taj Pharma. In a Phase I intravenous study in adult solid tumour patients, the median time to nadir counts was 13 days (range, 3-25 days) for granulocytes and 16 days (range, 2-32 days) for platelets. Most patients had haematological 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 Taj Pharma Phosphate Taj Pharma requires careful haematological monitoring.

Fludarabine Taj Pharma Phosphate Taj Pharma 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.

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients.

As with other cytotoxics, caution should be exercised with fludarabine phosphate, when further haematopoietic stem cell sampling is considered.

Autoimmune disorders

Irrespective of any previous history of autoimmune processes or Coombs test status, life-threatening and sometimes fatal autoimmune phenomena (see section 4.8) have been reported to occur during or after treatment with Fludarabine Taj Pharma. The majority of patients experiencing haemolytic anaemia developed a recurrence in the haemolytic process after rechallenge with Fludarabine Taj Pharma . Patients treated with Fludarabine Taj Pharma should be closely monitored for signs of haemolysis.

Discontinuation of therapy with Fludarabine Taj Pharma is recommended in case of haemolysis. Blood transfusion (irradiated, see below) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia.

Neurotoxicity

The effect of chronic administration of Fludarabine Taj Pharma on the central nervous system is unknown. However, patients tolerated the recommended dose in some studies for relatively long term treatment times (for up to 26 courses of therapy). Patients should be closely observed for signs of neurologic effects.

When used at high doses in dose-ranging studies in patients with acute leukaemia, intravenous Fludarabine Taj Pharma was associated with severe neurological effects, including blindness, coma and death. Symptoms appeared from 21 to 60 days from last dose. This severe central nervous system toxicity occurred in 36 % of patients treated intravenously with doses approximately four times greater (96mg/m²/day for 5 –7 days) than the recommended dose. In patients treated at doses in the range of the dose recommended for CLL (chronic lymphocytic leukaemia), severe central nervous system toxicity occurred rarely (coma, seizures and agitation) or uncommonly (confusion) (see section 4.8).

In post-marketing experience neurotoxicity has been reported to occur earlier or later than in clinical trials.

Administration of Fludarabine Taj Pharma can be associated with leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL) or reversible posterior leukoencephalopathy syndrome (RPLS).

These may occur:

• at the recommended dose
• when Fludarabine Taj Pharma is given following, or in combination with, medications known to be associated with LE, ATL or RPLS,
• or when Fludarabine Taj Pharma is given in patients with other risk factors such as cranial or total body irradiation, Hematopoietic Cell Transplantation, Graft versus Host Disease, renal impairment, or hepatic encephalopathy.
• at doses higher than the recommended dose

LE, ATL or RPLS symptoms may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, altered sensorium, and focal neurological deficits. Additional effects may include optic neuritis, and papillitis, confusion, somnolence, agitation, paraparesis/ quadriparesis, muscle spasticity and incontinence.

LE/ ATL/ RPLS may be irreversible, life-threatening, or fatal.

Whenever LE, ATL or RPLS is suspected, fludarabine treatment should be stopped. Patients should be monitored and should undergo brain imaging, preferably utilizing MRI. If the diagnosis is confirmed, fludarabine therapy should be permanently discontinued.

Tumour lysis syndrome

Tumour lysis syndrome has been reported in CLL patients with large tumour burdens. Since Fludarabine Taj Pharma 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, and hospitalisation may be recommended for these patients during the first course of treatment.

Transfusion-associated graft-versus-host disease

Transfusion-associated graft-versus-host disease (reaction by the transfused immunocompetent lymphocytes to the host) has been observed after transfusion of non-irradiated blood in patients treated with Fludarabine Taj Pharma. Fatal outcome as a consequence of this disease has been reported with a high frequency. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received treatment with Fludarabine Taj Pharma should receive irradiated blood only.

Skin cancer

The worsening or flare up of pre-existing skin cancer lesions as well as new onset of skin cancer have been reported in some patients to occur during or after Fludarabine Taj Pharma therapy.

Impaired state of health

In patients with impaired state of health, Fludarabine Taj Pharma should be given with caution and after careful risk/benefit consideration. 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.

Renal impairment

The total body clearance of the principle 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). There are limited clinical data available in patients with impairment of renal function (creatinine clearance <70 ml/min).

Fludarabine Taj Pharma must be administered cautiously in patients with renal insufficiency. In patients with moderate impairment of renal function (creatinine clearance between 30 and 70 ml/min.) the dose should be reduced by up to 50% and the patient should be monitored closely (see section 4.2). Fludarabine Taj Pharma treatment is contraindicated if creatinine clearance is <30 ml/min. (see section 4.3).

Older peopleSince there are limited data for the use of Fludarabine Taj Pharma in elderly persons > 75 years), caution should be exercised with the administration of Fludarabine Taj Pharma in these patients (see also section 4.2).

In patients aged 65 years or older, creatinine clearance should be measured before start of treatment, see “Renal impairment” and section 4.2.

Paediatric population

No data are available concerning the use of Fludarabine Taj Pharma Phosphate Taj Pharma in the paediatric population. Therefore, treatment with Fludarabine Taj Pharma in children and adolescents below age 18 is not recommended.

Pregnancy

Fludarabine Taj Pharma should not be used during pregnancy unless clearly necessary (e.g. life-threatening situation, no alternative safer treatment available without compromising the therapeutic benefit, treatment cannot be avoided). It has the potential to cause foetal harm (see sections 4.6 and 5.3). Prescribers may only consider the use of Fludarabine Taj Pharma , if the potential benefits justify the potential risks to the foetus.

Women should avoid becoming pregnant while on Fludarabine Taj Pharma therapy.

Women of childbearing potential must be apprised of the potential hazard to the foetus.

Contraception

Females of child-bearing potential or fertile males must take effective contraceptive measures during and at least for 6 months after cessation of therapy (see section 4.6).

Vaccination

During and after treatment with Fludarabine Taj Pharma vaccination with live vaccines should be avoided.

Retreatment options after initial Fludarabine Taj Pharma treatment

A crossover from initial treatment with Fludarabine Taj Pharma to chlorambucil for non responders to Fludarabine Taj Pharma should be avoided because most patients who have been resistant to Fludarabine Taj Pharma have shown resistance to chlorambucil.

Excipients

This medicinal product contains less than 1 mmol sodium (23mg) per ml after reconstitution, i.e. essentially sodium free.

• Interaction with other medicinal products and other forms of interaction

In a clinical investigation using Fludarabine Taj Pharma Phosphate Taj Pharma in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukaemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludarabine Taj Pharma in combination with pentostatin is not recommended.

Dipyridamole and other inhibitors of adenosine uptake may reduce the therapeutic efficacy of fludarabine phosphate.

Clinical studies and in vitro experiments showed that during use of fludarabine in combination with cytarabine the intracellular peak concentration and intracellular exposure of Ara-CTP (active metabolite of cytarabine) increased in leukemic cells. Plasma concentrations of Ara-C and the elimination rate of Ara-CTP were not affected.

• Fertility, pregnancy and lactation

Fertility

Women of childbearing potential must be apprised of the potential hazard to the foetus.

Both sexually active men and women of childbearing potential must take effective contraceptive measures during and at least for 6 months after cessation of therapy (see section 4.4).

Pregnancy

Pre-clinical data in rats demonstrated a transfer of fludarabine and/or metabolites through the placenta. The results from intravenous embryotoxicity studies in rats and rabbits indicated an embryolethal and teratogenic potential at the therapeutic doses (see section 5.3).

There are very limited data of fludarabine use in pregnant women in the first trimester.

Fludarabine Taj Pharma should not be used during pregnancy unless clearly necessary (e.g. life-threatening situation, no alternative safer treatment available without compromising the therapeutic benefit, treatment cannot be avoided). Fludarabine Taj Pharma has the potential to cause foetal harm. Prescribers may only consider the use of Fludarabine Taj Pharma if the potential benefits justify the potential risks to the foetus.

Lactation

It is not known whether this drug or its metabolites are excreted in human milk.

However, there is evidence from preclinical data that Fludarabine Taj Pharma Phosphate Taj Pharma and/or metabolites transfer from maternal blood to milk.

Because of the potential for serious adverse reactions to Fludarabine Taj Pharma in breast-fed infants, Fludarabine Taj Pharma is contraindicated in nursing mothers (see section 4.3).

• Effects on ability to drive and use machines

Fludarabine Taj Pharma may reduce the ability to drive and use machines, since e.g. fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.

• Undesirable effects

Summary of safety profile

Based on the experience with the use of Fludarabine Taj Pharma, the most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anaemia), infection including pneumonia, cough, fever, fatigue, weakness, nausea, vomiting and diarrhoea. Other commonly reported events include chills, oedema, malaise, peripheral neuropathy, visual disturbance, anorexia, mucositis, stomatitis and skin rash. Serious opportunistic infections have occurred in patients treated with Fludarabine Taj Pharma. Fatalities as a consequence of serious adverse events have been reported.

Tabulated list of adverse reactions

The table below reports adverse events by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data regardless of the causal relationship with Fludarabine Taj Pharma. The rare adverse reactions were mainly identified from the post-marketing experience.

The most appropriate MedDRA term to describe a certain adverse event is listed. Synonyms or related conditions are not listed, but should be taken into account as well. Adverse event term representation is based on MedDRA version 12.0.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Postmarketing experience with frequency unknown

• Nervous system disorders
  • Cerebral haemorrhage
  • Leukoencephalopathy (see section 4.4)
  • Acute toxic leukoencephalopathy (see section 4.4)
  • Reversible posterior leukoencephalopathy syndrome (RPLS) (see section 4.4)
• Respiratory, thoracic and mediastinal disorders
  • Pulmonary haemorrhage
• Renal and urinary disorder
  • Haemorrhagic cystitis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

• Overdose

High doses of Fludarabine Taj Pharma have been associated with leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome (RPLS). Symptoms may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, altered sensorium, and focal neurological deficits. Additional effects may include optic neuritis, and papillitis, confusion, somnolence, agitation, paraparesis/ quadriparesis, muscle spasticity, incontinence, 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 Fludarabine Taj Pharma overdosage. Treatment consists of drug discontinuation and supportive therapy.

5. Pharmacological properties
   • Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, purine analogues

Mechanism of action

Fludarabine Taj Pharma contains fludarabine phosphate, a water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine, 9 ß-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase.

Fludarabine Taj Pharma Phosphate Taj Pharma is rapidly dephosphorylated to 2F-ara-A which is taken up by cells and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2F-ara-ATP. This metabolite has been shown to inhibit ribonucleotide reductase, DNA polymerase α/δ and ε, DNA primase and DNA ligase thereby inhibiting DNA synthesis. Furthermore, partial inhibition of RNA polymerase II and consequent reduction in protein synthesis occur.

While some aspects of the mechanism of action of 2F-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 CLL lymphocytes to 2F-ara-A triggers extensive DNA fragmentation and cell death characteristic of apoptosis.

Clinical efficacy and safety

A phase III trial in patients with previously untreated B-chronic lymphocytic leukaemia comparing treatment with Fludarabine Taj Pharma Phosphate Taj Pharma vs. chlorambucil (40mg / m² q4 weeks) in 195 and 199 patients respectively showed the following outcome: statistically significant higher overall response rates and complete response rates after 1st line treatment with Fludarabine Taj Pharma Phosphate Taj Pharma compared to chlorambucil (61.1% vs. 37.6% and 14.9% vs. 3.4%, respectively); statistically significant longer duration of response (19 vs. 12.2 months) and time to progression (17 vs. 13.2 months) for the patients in the Fludarabine Taj Pharma Phosphate Taj Pharma group. The median survival of the two patient groups was 56.1 months for fludarabine phsophate and 55.1 months for chlorambucil, a non-significant difference was also shown with performance status. The proportion of patients reported to have toxicities were comparable between Fludarabine Taj Pharma Phosphate Taj Pharma patients (89.7%) and chlorambucil patients (89.9%). While the difference in the overall incidence of haematological toxicities was not significant between the two treatment groups, significantly greater proportions of Fludarabine Taj Pharma Phosphate Taj Pharma patients experienced white blood cell (p=0.0054) and lymphocyte (p=0.0240) toxicities than chlorambucil patients. The proportions of patients who experienced nausea, vomiting, and diarrhoea were significantly lower for Fludarabine Taj Pharma Phosphate Taj Pharma patients (p<0.0001, p<0.0001, and p=0.0489, respectively) than chlorambucil patients. Toxicities of the liver were also reported for significantly (p=0.0487) less proportions of patients in the Fludarabine Taj Pharma Phosphate Taj Pharma group than in the chlorambucil group.

Patients who initially respond to Fludarabine Taj Pharma Phosphate Taj Pharma have a chance of responding again to Fludarabine Taj Pharma Phosphate Taj Pharma monotherapy.

A randomised trial of Fludarabine Taj Pharma Phosphate Taj Pharma vs. cyclophosphamide, adriamycin and prednisone (CAP) in 208 patients with CLL Binet stage B or C revealed the following results in the subgroup of 103 previously treated patients: the overall response rate and the complete response rate were higher with Fludarabine Taj Pharma Phosphate Taj Pharma compared to CAP (45% vs. 26% and 13% vs. 6%, respectively); response duration and overall survival were similar with Fludarabine Taj Pharma Phosphate Taj Pharma and CAP. Within the stipulated treatment period of 6 months the number of deaths was 9 (fludarabine phosphate) vs. 4 (CAP).

Post-hoc analyses using only data of up to 6 months after start of treatment revealed a difference between survival curves of Fludarabine Taj Pharma Phosphate Taj Pharma and CAP in favour of CAP in the subgroup of pretreated Binet stage C patients.

• Pharmacokinetic properties

Plasma and urinary pharmacokinetics of fludarabine (2F-ara-A)

The pharmacokinetics of fludarabine (2F-ara-A) have been studied after intravenous administration by rapid bolus injection and short-term infusion as well as following continuous infusion and after peroral dosing of Fludarabine Taj Pharma Phosphate Taj Pharma (Fludara, 2F-ara-AMP).

No clear correlation was found between 2F-ara-A pharmacokinetics and treatment efficacy in cancer patients.

However, occurrence of neutropenia and haematocrit changes indicated that the cytotoxicity of Fludarabine Taj Pharma Phosphate Taj Pharma depresses the haematopoiesis in a dose-dependent manner.

Distribution and metabolism

2F-ara-AMP is a water-soluble prodrug of fludarabine (2F-ara-A), which is rapidly and quantitatively dephosphorylated in the human organism to the nucleoside fludarabine (2F-ara-A).

Another metabolite, 2F-ara-hypoxanthine, which represents the major metabolite in the dog, was observed in humans only to a minor extent.

After single dose infusion of 25mg 2F-ara-AMP per m² to CLL patients for 30 minutes 2F-ara-A reached mean maximum concentrations in the plasma of 3.5 – 3.7 μM 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 – 4.8 µM 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 – 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 ± 40 ml/min/m² (2.2 ± 1.2 ml/min/kg) and a mean volume of distribution (Vss) of 83 ± 55 l/m² (2.4 ± 1.6 l/kg). Data showed a high interindividual variability. After intravenous and peroral administration of Fludarabine Taj Pharma Phosphate Taj Pharma 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.

Elimination

2F-ara-A elimination is largely by renal excretion. 40 to 60 % of the administered intravenous dose was excreted in the urine. Mass balance studies in laboratory animals with ³H-2F-ara-AMP showed a complete recovery of radio-labelled substances 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 CLL patients were observed at a median of 4 hours and exhibited a considerable variation with a median peak concentration of approximately 20 µM. 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.

• Preclinical safety data

Systemic toxicity

In acute toxicity studies, single doses of Fludarabine Taj Pharma Phosphate Taj Pharma produced severe intoxication symptoms or death at dosages about two orders of magnitude above the therapeutic dose. As expected for a cytotoxic compound, the bone marrow, lymphoid organs, gastrointestinal mucosa, kidneys and male gonads were affected. In patients, severe side effects were observed closer to the recommended therapeutic dose (factor 3 to 4) and included severe neurotoxicity partly with lethal outcome (see section 4.9).

Systemic toxicity studies following repeated administration of Fludarabine Taj Pharma Phosphate Taj Pharma showed also the expected effects on rapidly proliferating tissues above a threshold dose. The severity of morphological manifestations increased with dose levels and duration of dosing and the observed changes were generally considered to be reversible. In principle, the available experience from the therapeutic use of Fludarabine Taj Pharma Phosphate Taj Pharma points to a comparable toxicological profile in humans, although additional undesirable effects such as neurotoxicity were observed in patients (see section 4.8).

Embryotoxicity

The results from intravenous animal embryotoxicity studies in rats and rabbits indicated an embryolethal and teratogenic potential of Fludarabine Taj Pharma Phosphate Taj Pharma as manifested in skeletal malformations, foetal weight loss and post implantation loss. In view of the small safety margin between the teratogenic doses in animals and the human therapeutic dose as well as in analogy to other antimetabolites which are assumed to interfere with the process of differentiation, the therapeutic use of Fludarabine Taj Pharma is associated with a relevant risk of teratogenic effects in humans (see section 4.6).

Genotoxic potential, tumorigenicity

Fludarabine Taj Pharma Phosphate Taj Pharma has been shown, to cause DNA-damage in a sister chromatid exchange test, to induce chromosomal aberrations in an in vitro cytogenetic assay and to increase the rate of micronuclei in the mouse micronucleus test in vivo, but was negative in gene mutation assays and in the dominant lethal test in male mice. Thus, the mutagenic potential was demonstrated in somatic cells but could not be shown in germ cells.

The known activity of Fludarabine Taj Pharma Phosphate Taj Pharma at the DNA-level and the mutagenicity test results form the basis for the suspicion of a tumorigenic potential. No animal studies which directly address the question of tumorigenicity have been conducted, because the suspicion of an increased risk of second tumours due to Fludarabine Taj Pharma Phosphate Taj Pharma therapy can exclusively be verified by epidemiological data.

Local tolerance

According to the results from animal experiments following intravenous administration of fludarabine phosphate, no remarkable local irritation has to be expected at the injection site. Even in case of misplaced injections, no relevant local irritation was observed after paravenous, intraarterial, and intramuscular administration of an aqueous solution containing 7.5mg fludarabine phosphate/ml.

The similarity in nature of the observed lesions in the gastrointestinal tract after intravenous or intragastric dosing in animal experiments supports the assumption that the Fludarabine Taj Pharma Phosphate Taj Pharma induced enteritis is a systemic effect.

6. Pharmaceutical particulars
   • List of excipients

Mannitol

Sodium hydroxide (for pH adjustment).

• Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

• Shelf life

Vial before opening:

4 years.

After reconstitution:

The physicochemical stability of the drug product after reconstitution in water for injections has been demonstrated for 8 hours at 25°C and for 7 days at 2-8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

• Special precautions for storage

Store below 25°C.

For storage after reconstitution or dilution, see Section 6.3.

• Nature and contents of container

Colourless glass vial (type I) with bromobutylic rubber stopper and metallic cap (aluminium) with polypropylene disk. Vial will be packed with or without a protective plastic overwrap.

Pack sizes

1x25mg vial
5x25mg vial
1 x 50mg vial
5 x 50mg vial

Not all pack sizes may be marketed.

• Special precautions for disposal and other handling

Reconstitution

Fludarabine Taj Pharma should be prepared for parenteral use by aseptically adding sterile water for injection. When reconstituted with 2 ml of sterile water for injection, the powder should fully dissolve in 15 seconds or less. Each ml of the resulting solution will contain 25mg of fludarabine phosphate, 25mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2 – 8.2.

Dilution

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 in 10 ml of 0.9 % sodium chloride. Alternatively, for infusion, the required dose may be diluted in 100 ml of 0.9 % sodium chloride (see section 4.2).

Inspection prior to use

The reconstituted solution is clear and colourless. It should be visually inspected before use.

Only clear and colourless solutions without particles should be used. Fludarabine Taj Pharma should not be used in case of a defective container.

Handling and disposal

Fludarabine Taj Pharma should not be handled by pregnant staff.

Procedures for proper handling should be followed according to local requirements for cytotoxic drugs. Caution should be exercised in the handling and preparation of the Fludarabine Taj Pharma 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.

The medicinal product is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.

Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
At SURVEY NO.188/1 TO 189/1,190/1 TO 4, ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)

Fludarabine Phosphate for Injection USP 50mg/2ml Taj Pharma

PACKAGE LEAFLET FOR PATIENT INFORMATION:
Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Fludarabine Taj Pharma is and what it is used for
2. What you need to know before you use Fludarabine Taj Pharma
3. How to use Fludarabine Taj Pharma
4. Possible side effects
5. How to store Fludarabine Taj Pharma
6. Contents of the pack and other information

1.What Fludarabine Taj Pharma is and what it is used for

Fludarabine Taj Pharma is an anti-cancer drug.
Fludarabine Taj Pharma is used to treat chronic B-cell lymphocytic leukaemia (B-CLL) in patients with sufficient healthy blood cell production.
This is a type of cancer of white blood cells (the cells are called lymphocytes).
First treatment for chronic lymphocytic leukaemia with Fludarabine Taj Pharma should only be started in patients with advanced disease having disease related symptoms or evidence of disease progression.

All cells of the body produce new cells like themselves by dividing. For this purpose, the cells’ genetic material (DNA) must be copied and reproduced. Fludarabine Taj Pharma works by hindering the production of new DNA.

Therefore, when Fludarabine Taj Pharma is taken up by the cancer cells, it stops the growth of new cancer cells.

In cancers of the white blood cells (as chronic lymphocytic leukaemia) many abnormal lymphocytes are produced. The abnormal lymphocytes either do not work properly or are too young (immature) to carry out the normal disease fighting functions of white blood cells. If there are too many of these abnormal lymphocytes, they push aside healthy blood cells in the bone marrow where most of the new blood cells are formed. Without enough healthy blood cells, infections, anaemia, bruising, excessive bleeding or even organ failure can result.

2. What you need to know before you use Fludarabine Taj Pharma

Do not use Fludarabine Taj Pharma

• if you are allergic to Fludarabine Taj Pharma phosphate or any of the other ingredients of this medicine (listed in section 6).
• if you are breast-feeding
• if you have severe kidney problems.
• if your red blood cell count is low, because of a type of anaemia (decompensated haemolytic anaemia).

Your doctor will have told you if you have this condition

Tell your doctor if you think any of these may apply to you.

Warnings and precautions

Talk to your doctor before using Fludarabine Taj Pharma
Take special care with Fludarabine Taj Pharma:

• if your bone marrow is not working properly or if you have a poorly functioning or depressed immune system or a history of serious infections.

• Your doctor may decide to not give you this medicine, or may take precautions.
• if you feel very unwell, notice any unusual bruising, more bleeding than usual after injury, or if you seem to be catching a lot of infections.
• if during treatment you have a red to brownish urine, or have a rash or any blisters on your skin.
• Tell your doctor immediately

These may be signs of a reduction in the number of blood cells, which may be caused either by the disease itself or the therapy.

It can last for up to a year, independent of whether or not you had treatment with

Fludarabine Taj Pharma before. During treatment with Fludarabine Taj Pharma your immune system may attack different parts of your body, or your red blood cells (called ‘autoimmune disorders’).

These conditions can be life-threatening.

If this occurs your doctor will stop your treatment and you may receive further medication such as transfusion of irradiated blood (see below) and adrenocorticoids.

You will have regular blood tests during treatment and you will be closely monitored while you are being treated with Fludarabine Taj Pharma.

• if you notice any unusual symptoms of your nervous system such as disturbed vision, headache, confusion, seizures.

If Fludarabine Taj Pharma is used for a long time, its effects on the central nervous system are not known. However, patients treated with the recommended dose for up to 26 courses of therapy were able to tolerate it.

When Fludarabine Taj Pharma is used at the recommended dose, following the treatment with some other medications or at the same time as some other medications, the following adverse events have been reported: neurological disorders manifested by headache, feeling sick (nausea) and vomiting, seizures, visual disturbances including vision loss, changes in mental status (thinking abnormal, confusion, altered consciousness) and occasionally neuromuscular disorders manifested by muscle weakness in your limbs (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy or reversible posterior leukoencephalopathy syndrome (RPLS)).

In patients on doses four times greater than recommended, blindness, coma and death have been reported.

Some of these symptoms appeared delayed around 60 days or more after treatment had been stopped. In some patients receiving Fludarabine Taj Pharma doses higher than the recommended dose, leukoencephalopathy

(LE), acute toxic leukoencephalopathy (ATL) or reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported.

Same symptoms of LE, ATL or RPLS as above described could occur.

LE, ATL, and RPLS may be irreversible, lifethreatening, or fatal.

Whenever LE, ATL or RPLS is suspected, your treatment with Fludarabine Taj Pharma will be stopped for further investigations.

If the diagnosis of LE, ATL, or RPLS is confirmed, you doctor will permanently discontinue your treatment with Fludarabine Taj Pharma.

• if you notice any pain in your side, blood in your urine or reduced amount of urine.

When your disease is very severe, your body may not be able to clear all the waste products from the cells destroyed by Fludarabine Taj Pharma. This is called tumour lysis syndrome and can cause kidney failure and heart problems from the first week of treatment. Your doctor will be aware of this and may give you other medicines to help prevent it.

• if you need to have stem cells collected and you are being treated with Fludarabine Taj Pharma (or have been).
• if you need a blood transfusion and you are being treated with Fludarabine Taj Pharma (or have been).

• In case you need a blood transfusion your doctor will ensure that you only receive blood that has been treated by irradiation.
• There have been severe complications and even death, from transfusions of nonirradiated blood.
• if you notice any changes to your skin either while you are receiving this medicine or after you have finished the therapy.
• if you have or have had skin cancer it may worsen or flare up again during

Fludarabine Taj Pharma therapy or afterwards. You may develop skin cancer during or after

Fludarabine Taj Pharma therapy.

Other things to consider while you are treated with Fludarabine Taj Pharma:

• Men and women who are fertile must use effective contraception during treatment and for at least 6 months afterwards. It cannot be ruled out that Fludarabine Taj Pharma may harm an unborn baby.

Your doctor will carefully weigh the benefit of your treatment against a possible risk for an unborn child and, if you are pregnant, will only treat you with Fludarabine Taj Pharma if clearly necessary.

• if you consider or are breastfeeding you should not start it or continue while on treatment with Fludarabine Taj Pharma.
• if you need a vaccination, check with your doctor, because live vaccinations should be avoided during and after treatment with Fludarabine Taj Pharma.
• if you have kidney problems or if you are over 65, you will have regular blood and/ or laboratory tests to check your kidney function. If your kidney problems are severe, you will not be given this medicine at all (see sections 2 and 3).

Children and adolescents

The safety and effectiveness of Fludarabine Taj Pharma in children below the age of 18 years has not been established. Therefore, Fludarabine Taj Pharma is not recommended for use in children.

Older patients and Fludarabine Taj Pharma:

People over 65 will have regular tests for kidney function (see also section 3. How to use

Fludarabine Taj Pharma).

People over 75 will be monitored especially closely.

Other medicines and Fludarabine Taj Pharma

Tell your doctor if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

It is especially important to tell your doctor about:

• pentostatin (deoxycoformycin), also used to treat B-CLL. Taking these two drugs together can lead to severe lung problems.
• dipyridamole, used to prevent excessive blood clotting or other similar drugs.

They may reduce the effectiveness of

Fludarabine Taj Pharma.

• cytarabine (Ara-C) used to treat chronic lymphocytic leukaemia. If Fludarabine Taj Pharma is combined with cytarabine, levels of the active form of Fludarabine Taj Pharma in Ieukaemic cells may rise. However, the overall levels in the blood and its elimination from the blood were not shown to have changed.

Pregnancy, breast-feeding and fertility

Pregnancy

Fludarabine Taj Pharma should not be given to women who are pregnant because animal studies and very limited experience in humans have shown a possible risk of abnormalities in the unborn baby as well as early pregnancy loss or premature delivery.

If you are pregnant or you think you may be pregnant, tell your doctor immediately. Your doctor will carefully weigh the benefit of your treatment against a possible risk for an unborn child and, if you are pregnant, will only prescribe Fludarabine Taj Pharma if clearly necessary.

Breast-feeding

You must not start or continue breast feeding during your treatment with Fludarabine Taj Pharma, as this medicine may interfere with the growth and development of your baby.

Fertility

Men and women, who are fertile, must use effective contraception during treatment and for at least 6 months afterwards

Driving and using machines

Some people get tired, feel weak, have disturbed vision, become confused, or agitated or have seizures while they are treated with Fludarabine Taj Pharma. Do not try to drive or operate machines until you are sure that you are not affected.

3. How to use Fludarabine Taj Pharma

Fludarabine Taj Pharma should be administered under the supervision of a qualified doctor experienced in the use of anti-cancer therapy.

How much Fludarabine Taj Pharma is given

The dose you are given depends on your body surface area. This is measured in square metres (m2) and is worked out by the doctor from your height and weight.

The recommended dose is 25 mg Fludarabine Taj Pharma phosphate/m2 body surface area.

How Fludarabine Taj Pharma is given Fludarabine Taj Pharma is given in the form of a solution as an injection or mostly as an infusion.

An infusion means that the medicine is given directly into the blood stream by a drip through a vein. One infusion takes approximately 30 minutes.

Your doctor will make sure that Fludarabine Taj Pharma is not given beside the vein (paravenously).

However, if this happens, no severe local adverse events have been reported.

For how long Fludarabine Taj Pharma is given

The dose will be given once a day for 5 consecutive days.

This 5-day course of treatment will be repeated every 28 days until your doctor has decided that the best effect has been achieved (usually after 6 courses).

How long the treatment lasts depends on how successful your treatment is and how well you tolerate Fludarabine Taj Pharma. The repeat course may be delayed if side effects are a problem.

You will have regular blood tests during your treatment. Your individual dose will be carefully adjusted according to the number of your blood cells and your response to the therapy. The dosage may be decreased if side effects are a problem.

If you have kidney problems or if you are over the age of 65, you will have regular tests to check your kidney function. If your kidneys do not work properly you may be given this medicine at a lower dose. If your kidney function is severely reduced you will not be given this medicine at all (see section 2).

If any Fludarabine Taj Pharma solution is accidentally spilt

If any of the Fludarabine Taj Pharma solution comes into contact with your skin or the lining of your nose or mouth, wash the area thoroughly with soap and water. If the solution gets into your eyes, rinse them thoroughly with plenty of tap water. Avoid any exposure by inhalation.

If more Fludarabine Taj Pharma is given than it should

If you may have received an overdose your doctor will stop the therapy and treat the symptoms.

High doses can lead to a severely reduced number of blood cells.

For Fludarabine Taj Pharma given intravenously it has been reported, that overdose can cause delayed blindness, coma and even death.

If a dose of Fludarabine Taj Pharma is forgotten

Your doctor will set the times at which you are to receive this medicine. Talk to your doctor as soon as possible, if you think you may have missed a dose.

If you stop using Fludarabine Taj Pharma

You and your doctor may decide to stop your treatment with Fludarabine Taj Pharma if the side effects are becoming too severe.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you are not sure what the side effects below are, ask your doctor to explain them to you.

Some side effects can be life-threatening.

Tell your doctor immediately:

• if you have difficulty breathing, have a cough, or have chest pain with or without fever. These may be signs of an infection of the lungs.
• if you notice any unusual bruising, more bleeding than usual after injury or if you seem to be catching a lot of infections.
• These may be caused by a reduced number of blood cells. This may also lead to an increased risk of (serious) infections, caused by organisms, that usually do not cause disease in healthy persons (opportunistic infections) including a late reactivation of viruses, for example herpes zoster.
• if you notice any pain in your side, blood in your urine, or reduced amount of urine. These may be signs of tumour lysis syndrome (see section 2).
• if you notice any skin and /or mucous coat reaction with redness, inflammation, blistering and tissue break down. These may be signs of a severe allergic reaction
• (Lyell’s syndrome, Stevens-Johnson syndrome).
• if you have palpitations (if you suddenly become aware of your heart beat) or chest pain. These may be signs of heart problems.
• Below are possible side effects by how common they are.
• Very common side effects (may affect more than 1 in 10 people)
• infections (some serious)
• infections due to depressed immune system (opportunistic infections)
• infection of the lungs (pneumonia) with possible symptoms like breathing
• difficulties and / or cough with or without
• fever
• reduction in the number of blood platelets (thrombocytopenia) with the possibility of bruising and bleeding
• lowered white blood cell count (neutropenia)
• lowered red blood cell count (anaemia)
• cough
• vomiting, diarrhoea, feeling sick (nausea)
• fever
• feeling tired (fatigue)
• weakness

Common side effects (may affect up to 1 in 10 people)

• other blood related cancers (myelodysplastic syndrome, acute myeloid leukaemia). Most patients with these conditions were previously, or at the same time or later treated with other cancer drugs (alkylating agents, topoisomerase inhibitors) or radiation therapy.
• bone marrow depression (myelosuppression)
• severe loss of appetite leading to weight loss (anorexia)
• numbness or weakness in limbs (peripheral neuropathy)
• disturbed vision
• inflammation of the inside of the mouth (stomatitis)
• skin rash
• swelling due to excessive fluid retention
• (oedema)
• inflammation of the mucous coat of the digestive system from the mouth to the anus (mucositis)
• chills
• generally feeling unwell

Uncommon side effects (may affect up to 1 in 100 people)

• autoimmune disorder (see section 2)
• tumour lysis syndrome (see section 2)
• confusion
• lung toxicity, scarring throughout the lungs (pulmonary fibrosis), inflammation of the lungs (pneumonitis), shortness of breath
• (dyspnoea)
• bleeding in the stomach or intestines
• abnormal levels of the liver or pancreas enzymes
• Rare side effects (may affect up to 1 in 1,000 people)
• disorders of the lymph system due to a viral infection (EBV-associated
• Iymphoproliferative disorder)
• coma
• seizures
• agitation
• blindness
• inflammation or damage of the nerve of the eyes (optic neuritis; optic neuropathy)
• heart failure
• irregular heart beat (arrhythmia)
• skin cancer
• skin and/or mucous coat reaction with redness, inflammation, blistering and tissue

break down (Lyell‘s syndrome, StevensJohnson syndrome)
Not known (frequency cannot be estimated from available data)

• bleeding in the brain
• neurological disorders manifested by headache, feeling sick (nausea) and vomiting, seizures, visual disturbances including vision loss, changes in mental status (thinking abnormal, confusion, altered consciousness), and occasionally neuromuscular disorders manifested by muscle weakness in your limbs (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy or reversible posterior leukoencephalopathy syndrome (RPLS)).
• bleeding in the lungs
• inflammation of the bladder, which can cause pain when passing urine, and can lead to blood in the urine (haemorrhagic cystitis)

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

By reporting side effects you can help provide more information on the safety of this medicine.

5.  How to store Fludarabine Taj Pharma

Keep this medicine out of the sight and reach of children.

Store below 25°C.

Do not use this medicine after the expiry date which is stated on the carton and vial after EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Fludarabine Taj Pharma contains

• The active substance is Fludarabine Taj Pharma phosphate
• The other ingredients are mannitol and sodium hydroxide.

What Fludarabine Taj Pharma looks like and contents of the pack

Each vial contains 50mg Fludarabine Taj Pharma phosphate as a powder for injection or infusion. The powder will be made up into a solution before it is given to you. 1 ml of reconstituted solution contains 25mg Fludarabine Taj Pharma phosphate.

Pack sizes:

1x25mg
5x25mg
1 x 50mg vial
5 x 50mg vial

Not all pack sizes may be marketed.

Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
At SURVEY NO.188/1 TO 189/1,190/1 TO 4, ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)