Fludarabin Hexal IV Infusion

Fludarabin Hexal is indicated for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. The safety and effectiveness of Fludarabin Hexal in previously untreated or non-refractory patients with CLL have not been established.

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis leading to cell death. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

Fludarabine injection: This should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. The recommended dose is 25 mg Fludarabinebine phosphate/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 for injection/infusion will contain 25 mg Fludarabinebine phosphate. 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 0.9% sodium chloride. Alternatively, for infusion, the required dose drawn up in a syringe may be diluted into 100 ml 0.9% sodium chloride 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 should be administered up to the achievement of best response (complete or partial remission, usually 6 cycles) and then the drug should be discontinued. In patients with Lg-NHL, treatment with Fludarabine is recommended up to the achievement of best response (complete or partial remission). Two cycles of consolidation should be considered after best response has been reached. In clinical trials with Lg-NHL, the majority of patients underwent not more than 8 cycles.

Fludarabine tablet: The usual starting dose of Fludarabine tablets is 40 mg/m2 of Fludarabinebine phosphate administered once daily for five consecutive days every 28 days. The duration of treatment depends on the treatment success and the tolerability of the drug. Fludarabine oral should be administered until the achievement of a maximal response (complete or partial remission, usually 6 cycles) and then the drug should be discontinued.

In a clinical investigation, using Fludara in combination with pentostatin (deoxycoformycin) for the treatment of CLL, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludara in combination with pentostatin is not recommended. Dipyridamole and other inhibitors of adenosine uptake may reduce the therapeutic efficacy of Fludara. Clinical studies and in vitro experiments showed that using Fludara in combination with cytarabine may increase the intracellular concentration and intracellular exposure of Ara-CTP (active metabolite of cytarabine) in leukemic cells. Plasma concentrations of Ara-C and the elimination rate of Ara-C were not affected.

• Hypersensitivity to the active substance or to any of the excipients
• Renal impairment with creatinine clearance <30 ml/min
• Decompensated hemolytic anemia

The following are possible serious side effects:

• Decreased production of the blood cells by the bone marrow (bone marrow suppression). The protection against infections, the ability of blood cells to carry oxygen, or blood clotting can be affected. It may result in death.
• Central nervous system problems including blindness, coma, and death at doses four times greater than the recommended dose for CLL. This has been rarely reported at the recommended dose for CLL.
• Low red blood cell count due to a breakdown of red blood cells (hemolytic anemia) may result in death.
• Lung toxicity resulting in death when used in combination with pentostatin (deoxycoformycin).

There are very limited data of Fludarabine use in pregnant women in the first trimester: one newborn has been described with absent bilateral radii and normal thumbs, thrombocytopenia, fossa ovalis aneurysm and a small patent ductus arteriosus. Early pregnancy loss has been reported in Fludarabine monotherapy as well as in combination therapy. Premature delivery has been reported. Breastfeeding should not be initiated during Fludarabine treatment. Nursing women should discontinue breastfeeding. It is not known whether this drug is excreted in human milk. There is evidence from preclinical data that fludarabine phosphate and/or metabolites transfer from maternal blood to milk.

Fludarabin Hexal should be administered under the supervision of, or prescribed by, a qualified physician experienced in the use of antineoplastic therapy. Fludarabin Hexal is associated with:

• Myelosuppression, including fatal cases 
• Irreversible CNS effects, including fatal cases 
• Auto-immune hemolytic anemia, including fatal cases

In a clinical investigation using Fludarabin Hexal in combination with pentostatin (deoxycoformycin) for the treatment of refractory CLL, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludarabin Hexal in combination with pentostatin is contraindicated.

Renal Impairment:

• CrCl 30-70: May reduce the doses by up to 50%
• Severe impairment: Avoid 

Cytotoxic Chemotherapy

Injection should store below 25°C. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2 to 8°C or 8 hours at room temperature. Tablets should store between 15°C and 30°C. Do not freeze. Keep out of reach and sight of children. Leave contents in protective packaging until use.