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Fludarabine Phosphate

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

Trade Names:
Fludara
- Injection, lyophilized cake for solution 50 mg

Trade Names:
Fludarabine Phosphate
- Injection, solution 25 mg/mL

Pharmacology

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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

Fludarabine is rapidly converted to the active metabolite, 2î“¸fluoroî“¸araî“¸A, within minutes after IV infusion.

Distribution

In vitro, plasma protein binding of fludarabine ranged between 19% and 29%.

Elimination

The terminal half-life of 2î“¸fluoroî“¸araî“¸A is approximately 20 h. 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 172 mL/min in individuals with healthy renal function compared with 124 mL/min for patients with moderate renal function impairment (ie, 17 to 41 mL/min/m ² ).

Indications and Usage

Refractory or progressive B-cell chronic lymphocytic leukemia (CLL).

Unlabeled Uses

Leukemias, non-Hodgkin lymphoma.

Contraindications

Standard considerations.

Dosage and Administration

CLL
Adults

IV 25 mg/m ² /day over approximately 30 min daily for 5 consecutive days. Each 5î“¸day course should commence every 28 days.

Renal Function Impairment
Adults

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

General Advice

Do not mix with other drugs.
Injection should be used within 8 h of reconstitution.
If solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.

Storage/Stability

Store refrigerated between 36° and 46°F.

Drug Interactions

Digoxin

Pharmacologic effect of digoxin (oral) may be decreased because of decreased GI absorption caused by fludarabine.

Pentostatin

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

Vaccination

Avoid vaccination with live vaccines during and after treatment.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

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

CNS

Weakness (65%); fatigue (38%); paresthesia (12%); malaise (8%); headache, sleep disorder (3%); cerebellar syndrome, depression, impaired mentation (1%); multifocal leukoencephalopathy (postmarketing); agitation; coma; confusion; weakness.

Dermatologic

Rash (15%); diaphoresis (13%); alopecia, pruritus (3%); seborrhea (1%); erythema multiforme, new onset of skin cancer, pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis, worsening or flare-up of preexisting skin cancer.

EENT

Visual disturbances (15%); pharyngitis (9%); hearing loss (6%).

GI

Nausea/vomiting (36%); anorexia (34%); diarrhea (15%); GI bleeding (13%); 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%); acute myeloid leukemia, autoimmune hemolytic anemia, myelodysplastic syndrome, pancytopenia (postmarketing).

Hepatic

Abnormal LFTs, cholelithiasis (3%); liver failure (1%).

Hypersensitivity

Anaphylaxis (1%).

Metabolic-Nutritional

Hyperglycemia (6%); dehydration, tumor lysis syndrome (including hematuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, metabolic acidosis, renal failure, urate crystalluria) (1%).

Musculoskeletal

Myalgia (16%); osteoporosis (2%); arthralgia (1%).

Respiratory

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

Miscellaneous

Fever (69%); infection (44%); pain (22%); chills, edema (19%).

Precautions

Warnings

Bone marrow suppression

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 hemolytic anemia.

Neurotoxicity

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 been reported in patients treated at doses in the recommended dose range for CLL.

Pentostatin cotreatment

Coadministration with pentostatin is not recommended because of the high incidence of fatal pulmonary toxicity.

Monitor

Closely evaluate and monitor patients for hemolytic anemia. Closely monitor patients for signs of hematologic and nonhematologic toxicity. Periodic assessment of peripheral blood cell counts is recommended to detect anemia, neutropenia, and thrombocytopenia.

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Renal Function

Administer cautiously.

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.

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 will be prepared and administered by health care provider in a health care setting.
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 skin or eyes.
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 women of childbearing potential to avoid becoming pregnant during therapy.