Fludarabine Phosphate

Pronunciation: (floo-DAYR-a-been FOS-fate)
Class: Purine antimetabolite

Trade Names

Fludara
- Injection, lyophilized cake for solution 50 mg

Fludarabine Phosphate
- Injection, solution 25 mg/mL

Oforta
- Tablets, oral 10 mg

Pharmacology

Fludarabine is a fluorinated nucleotide analog of the antiviral agent vidarabine. Fludarabine's metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis.

Pharmacokinetics

Absorption

T _max is 1 to 2 h (oral). Oral bioavailability is 50% to 65%. Administration with a high-fat meal delays T _max from 1.3 to 2.2 h.

Distribution

Plasma protein binding ranged between 19% and 29%.

Metabolism

Fludarabine is dephosphorylated to 2-fluoro-ara-A and then phosphorylated by deoxycytidine kinase to the active triphosphate 2-fluoro-ara-adenosine triphosphate.

Elimination

The terminal half-life of 2-fluoroaraA is approximately 20 h. Plasma Cl is 117 to 145 mL/min (IV). Renal Cl represents approximately 40% of the total body Cl.

Special Populations

Renal Function Impairment

Total body Cl of the principal metabolite correlates with CrCl. Mean body Cl is 124 mL/min for patients with moderate renal impairment and 71 mL/min for patients with severe renal impairment. In 2 patients with a median CrCl of 22 mL/min/m ² , Cl was reduced by 56%.

Children

Pharmacokinetic data are limited. Steady-state conditions were reached early in children who received a loading dose over 10 min followed by a 5-day continuous infusion.

Indications and Usage

Treatment of B-cell chronic lymphocytic leukemia (CLL) in patients whose disease has not responded or has progressed during or after treatment with at least 1 standard alkylating agent.

Unlabeled Uses

Leukemias, non-Hodgkin lymphoma, solid tumors, Waldenstrom macroglobulinemia.

Contraindications

Hypersensitivity to fludarabine or any of its components.

Dosage and Administration

B-cell Chronic Lymphocytic Leukemia
Adults

IV 25 mg/m ² per day over approximately 30 min daily for 5 consecutive days. Each 5day course should commence every 28 days. PO 40 mg/m ² once daily for 5 consecutive days. Each 5-day course of treatment should commence every 28 days.

Renal Function Impairment
Adults IV

Solution for injection Reduce dose by 20% in patients with moderate renal impairment (CrCl 30 to 70 mL/min per 1.73 m ² ). Do not administer in patients with severely impaired renal function (CrCl less than 30 mL/min per 1.73 m ² ).

Lyophilized cake Reduce dose to 20 mg/m ² in patients with CrCl 50 to 79 mL/min, and to 15 mg/m ² in patients with CrCl 30 to 49 mL/min. Do not administer in patients with CrCl less than 30 mL/min.

PO Reduce dose by 20% in patients with mild to moderate renal impairment (CrCl 30 to 69 mL/min per 1.73 m ² ). Reduce dose by 50% in patients with severe renal impairment (CrCl 29 mL/min per 1.73 m ² or less).

General Advice

• Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Consider delaying or discontinuing therapy if neurotoxicity develops.
• Optimal duration is unknown. In general, an additional 3 cycles of fludarabine are recommended following achievement of maximal response.

• Injection
• Administer IV over a period of approximately 30 min.
• Do not mix with other drugs.
• Reconstitute lyophilized cake with 2 mL of sterile water for injection; each mL of the resulting solution contains fludarabine 25 mg.
• Further dilute reconstituted lyophilized cake solution and solution for injection in 100 or 125 mL of dextrose 5% injection or sodium chloride 0.9%.
• If solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.

• Tablet
• May be taken with or without food.
• Tablets should be swallowed whole with water. Tablets should not be broken or chewed.
• Do not remove tablets from blister packs until immediately prior to taking a dose.
• If powder from the tablets contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water for 15 min.

Storage/Stability

Store injection refrigerated between 36° and 46°F. Injection should be used within 8 h of reconstitution. Store tablets between 59° and 86°F.

Drug Interactions

Digoxin

Pharmacologic effect of digoxin (oral) may be decreased because of decreased GI absorption caused by fludarabine. Monitor serum digoxin concentrations and the patient for evidence of clinical deterioration and adjust dosage accordingly.

Pentostatin

Concomitant therapy may cause severe or fatal pulmonary toxicity. Coadministration is not recommended.

Palifermin

Coadministration within the same 24-h time period may increase the severity and duration of oral mucositis. Do not administer palifermin within 24 h before, during, or after administration of fludarabine.

Vaccination

Avoid vaccination with live vaccines during and after treatment.

Adverse Reactions

Cardiovascular

Angina (6%); arrhythmia, cerebrovascular accident, CHF, deep vein thrombosis, MI, phlebitis, supraventricular tachycardia (3%); aneurysm, transient ischemic attack (1%); arrhythmia, heart failure, pericardial effusion (rare).

CNS

Weakness (65%); fatigue (38%); asthenia (31%); paresthesia (12%); headache (9%); malaise (8%); sleep disorder (3%); cerebellar syndrome, depression, impaired mentation (1%); agitation, cerebral hemorrhage, coma, confusion, peripheral neuropathy, seizure; progressive multifocal leukoencephalopathy.

Dermatologic

Rash (15%); sweating increased (14%); diaphoresis (13%); herpes simplex (8%); skin disorder (6%); alopecia, pruritus (3%); seborrhea (1%); erythema multiforme, new onset of skin cancer, pemphigus, Stevens-Johnson syndrome, TEN, worsening or flare-up of preexisting skin cancer lesions.

EENT

Visual disturbances (15%); rhinitis (11%); pharyngitis (9%); hearing loss (6%); blindness, optic neuritis, optic neuropathy.

GI

Nausea/vomiting (38%); anorexia (34%); diarrhea (15%); GI bleeding (13%); abdominal pain (10%); stomatitis (9%); constipation, esophagitis (3%); mucositis (2%); dysphagia (1%).

Genitourinary

Urinary infection (15%); dysuria (4%); hematuria, urinary hesitancy (3%); abnormal renal function tests, proteinuria, renal failure (1%); hemorrhagic cystitis.

Hematologic-Lymphatic

Anemia (60%); neutropenia (59%); thrombocytopenia (55%); hemorrhage (1%); acquired hemophilia, autoimmune thrombocytopenia/thrombocytopenic purpura, bone marrow fibrosis, Evan syndrome, hemolytic anemia; acute myeloid leukemia, bone marrow hypoplasia or aplasia, myelodysplastic syndrome, pancytopenia (postmarketing).

Hepatic

Abnormal LFTs, cholelithiasis (3%); liver failure (1%); elevation of pancreatic enzymes.

Hypersensitivity

Anaphylaxis (1%).

Metabolic-Nutritional

Peripheral edema (7%); hyperglycemia, lactic dehydrogenase increase, weight decreased (6%); dehydration, tumor lysis syndrome (1%).

Musculoskeletal

Myalgia (16%); back pain (9%); osteoporosis (2%); arthralgia (1%).

Respiratory

Cough (44%); dyspnea, pneumonia (22%); upper respiratory tract infection (16%); bronchitis (9%); allergic pneumonitis, cough increased, hemoptysis (6%); sinusitis (5%); epistaxis, hypoxia (1%); pulmonary hypersensitivity; acute respiratory distress syndrome, pulmonary fibrosis, pulmonary hemorrhage, respiratory distress, respiratory failure (postmarketing).

Miscellaneous

Fever (69%); infection (44%); pain (22%); chills, edema (19%); flu syndrome (8%); chest pain (5%); opportunistic infections and reactivation of latent viral infections (herpes zoster, Epstein-Barr, JC virus); tumor lysis syndrome (1%); Epstein-Barr virus–associated lymphoproliferative disorders (rare).

Precautions

Warnings Severe depression of bone marrow function can occur. Life-threatening and sometimes fatal autoimmune phenomena, such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura, Evan syndrome, and acquired hemophilia, have occurred after 1 or more cycles of treatment. Closely evaluate and monitor patients for hemolysis. When used in high doses in dose-ranging studies in patients with acute leukemia, severe neurologic effects, including blindness, coma, and death, have occurred. Severe CNS toxicity occurred in 36% of patients treated with doses 4 times more than the recommended dose. Similar CNS toxicity, including coma, seizures, agitation, and confusion, has rarely (0.2%) been reported in patients treated at doses in the recommended dose range for CLL. Coadministration with pentostatin is not recommended because of the high incidence of fatal pulmonary toxicity.

Monitor Closely observe patients for signs of hematologic and nonhematologic toxicity. Regular assessment of peripheral blood cell counts is recommended to detect anemia, neutropenia, thrombocytopenia, and hemolysis. Periodic neurologic assessment is recommended. Monitor for signs and symptoms of infection. Monitor patients with advanced age, renal impairment, and bone marrow impairment closely for excessive toxicity.

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Advanced age may predispose patients to increased toxicity.

Renal Function

Administer cautiously and at reduced dosages. Fludarabine injection is not recommended in patients with severe renal impairment (CrCl less than 30 mL/min).

Special Risk Patients

Use with caution in patients with severe impairment of bone marrow function, immunodeficiency, or a history of opportunistic infection.

Disease progression

Disease progression and transformation (eg, Richter syndrome) have been reported in patients with CLL.

Dose-dependent toxicity

There are clear dose-dependent toxic effects seen with fludarabine.

Fatalities

Of fatalities in clinical studies, 50% with IV fludarabine and 15% with oral fludarabine were attributed to infection.

Transfusion

Transfusion-associated graft-versus-host disease may occur after transfusion of nonirradiated blood.

Tumor lysis syndrome

Has occurred.

Overdosage

Symptoms

Irreversible CNS toxicity characterized by delayed blindness, coma, and death; severe thrombocytopenia and neutropenia.

Patient Information

• Review the treatment regimen, including dosing schedule, duration of treatment, and monitoring that will be required.
• Advise patient, family, or caregiver that medication may be used in combination with other agents to achieve max benefit possible.
• Advise patient, family, or caregiver to immediately report any of the following to health care provider: bleeding or unusual bruising; dark urine; difficulty breathing; fever, chills, or other signs of infection; hives; pain, redness, or swelling at injection site; rash; sores in mouth; yellowing of the skin or eyes.
• Inform patient of the importance of periodic assessment of their blood count to detect the development of anemia, neutropenia, and thrombocytopenia.
• Advise patient, family, or caregiver to report any of the following to health care provider: persistent nausea, vomiting, diarrhea, or appetite loss; persistent or worsening general body weakness.
• Caution patients that drug may reduce the ability to drive or use machinery.
• Caution women of childbearing potential to avoid becoming pregnant during therapy. Advise women of childbearing potential and fertile men to take contraceptive measures during and for at least 6 mo after stopping therapy with fludarabine.
• Advise patient not to crush the tablets and to avoid exposure by direct contact of the skin or mucous membranes or by inhalation. If contact occurs, advise patient to wash the contact area thoroughly with soap and water or wash out the eyes immediately with water for at least 15 min.

Copyright © 2009 Wolters Kluwer Health.