fludarabine

floo-DAR-a-been

Therapeutic Classification: antineoplastics

Pharmacologic Classification: antimetabolites

High Alert

B-cell chronic lymphocytic leukemia (CLL) (in combination with cyclophosphamide and rituximab).
B-cell CLL in patients who have not responded to or whose disease has progressed during treatment with ≥1 regimen containing an alkylating agent (as monotherapy).

Converted intracellularly to an active phosphorylated metabolite that inhibits DNA synthesis.

Therapeutic effects:

Death of rapidly replicating cells, particularly malignant ones.

Absorption: IV administration results in complete bioavailability.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Following administration, rapidly converted to an active metabolite (2-fluoro-ara-A), which, when phosphorylated intracellularly, exerts antineoplastic activity; 40% of initial active metabolite excreted unchanged by the kidneys.

Half-Life: 20 hr (for initial active metabolite).

(effects on blood counts)

ROUTE	ONSET	PEAK	DURATION
IV	7 wk‡	13–16 days	unknown

‡Median time to response.

Contraindicated in:

Hypersensitivity to fludarabine, mannitol, or sodium hydroxide;
Severe renal impairment (CCr <30 mL/min);
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Moderate renal impairment (↓ dose);
Bone marrow depression;
OB: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: edema

Derm: rash

EENT: hearing loss, sinusitis, visual disturbances

Endo: gonadal suppression

GI: diarrhea, nausea, vomiting, anorexia, esophagitis, GI BLEEDING, mucositis, stomatitis

GU: dysuria, hematuria, urinary tract infection

Hemat: anemia, neutropenia, thrombocytopenia, HEMOLYTIC ANEMIA, IDIOPATHIC THROMBOCYTOPENIC PURPURA, TRANSFUSION-ASSOCIATED GRAFT-VERSUS-HOST DISEASE

MS: myalgia

Neuro: fatigue, agitation, coma, confusion, headache, malaise, peripheral neuropathy, SEIZURES, weakness

Resp: cough, pneumonia, dyspnea, PULMONARY HYPERSENSITIVITY

Misc: fever, tumor lysis syndrome

Drug-drug:

↑bone marrow suppression with other antineoplastics or radiation therapy.
Concurrent use with pentostatin↑ risk of potentially fatal pulmonary toxicity; concurrent use not recommended.
May ↓ antibody response to or ↑ risk of adverse reactions to live vaccines; avoid concurrent use.

In Combination With Cyclophosphamide and Rituximab

IV (Adults ): 25 mg/m² once daily for 1st 3 days (Days 1–3) of each 28-day cycle for 6 cycles or until disease progression or unacceptable toxicity.

Renal Impairment

IV (Adults ): CCr 50–79 mL/min: 25 mg/m² once daily for 1st 3 days (Days 1–3) of each 28-day cycle for 6 cycles or until disease progression or unacceptable toxicity. CCr 30–49 mL/min: 15 mg/m² once daily for 1st 3 days (Days 1–3) of each 28-day cycle for 6 cycles or until disease progression or unacceptable toxicity.

As Monotherapy

IV (Adults ): 25 mg/m² daily for 5 days; repeat course every 28 days.

Renal Impairment

IV (Adults ): CCr 50–79 mL/min: 25 mg/m² once daily for 1st 3 days (Days 1–3) of each 28-day cycle for 6 cycles or until disease progression or unacceptable toxicity. CCr 30–49 mL/min: 15 mg/m² once daily for 1st 3 days (Days 1–3) of each 28-day cycle for 6 cycles or until disease progression or unacceptable toxicity.

(Generic available)

Powder for injection: 50 mg/vial
Solution for injection: 25 mg/mL

Assess patient for visual changes, weakness, confusion, and changes in level of consciousness during and for 60 days following therapy, as neurologic effects resulting in blindness, coma, and death have been reported. Therapy may be delayed or discontinued if neurotoxicity occurs.
Monitor for seizure activity. Institute seizure precautions as indicated.
Monitor for bone marrow depression. Assess for bleeding (bleeding gums; bruising; petechiae; guaiac stools, urine, and emesis) and avoid IM injections and rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for ↑ fatigue, dyspnea, and orthostatic hypotension.
Monitor for signs and symptoms of graft-versus-host disease (fatigue, rash, pruritus, nausea, vomiting, diarrhea, jaundice, scleral icterus, xerostomia, arthralgias).
Monitor for signs and symptoms of hemolytic anemia (weakness, dizziness, pallor, jaundice, splenomegaly, abdominal pain) and autoimmune thrombocytopenia purpura (fatigue, ecchymosis, petechiae, epistaxis, bleeding gums, hematuria, hematochezia); more likely to occur after one or more cycles of treatment.
Monitor respiratory status, intake and output, and daily weights. Report significant changes or symptoms of pulmonary hypersensitivity (cough, fever, shortness of breath).
Assess nutritional status. Administering an antiemetic prior to and periodically during therapy and adjusting diet as tolerated may help maintain fluid and electrolyte balance and nutritional status.
Assess for signs and symptoms of tumor lysis syndrome (malaise, tachycardia, hypotension, confusion, delirium, arthralgia, myalgia, muscle spasms or twitches, paresthesia, headache, dizziness, nausea, vomiting, dark urine) in patients with advanced stage disease and/or with high tumor burden. Supportive therapy may be necessary based on severity. Tumor lysis syndrome may lead to hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. Monitor for flank pain and hematuria.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
Monitor CBC with differential prior to and frequently during therapy. The nadir for leukopenia occurs in 13 days (range 3–25 days) and for thrombocytopenia in 16 days (range 2–32 days) after administration.
- Monitor serum uric acid concentrations periodically during therapy; may be ↑ as part of tumor lysis in patients with large tumor burdens. Uric acid nephropathy may be prevented by adequate oral hydration. Allopurinol and alkalization of the urine may also be used to treat ↑ uric acid concentrations.
- Monitor CCr prior to treatment in patients with renal impairment.
- May ↑ AST and serum alkaline phosphatase.

High Alert: Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order, calculations, and infusion pump settings.

IV Administration:

Use double gloves and a protective gown to prepare and administer. If possible, prepare in a biologic safety cabinet or a compounding aseptic containment isolator; eye, face, and respiratory protection may be needed. Prepare and administer in a closed-system drug transfer device. During administration, if there is a potential that the substance could splash or if the patient may resist, use eye and face protection. Discard IV equipment in specially designated containers.
Unopened vials should be refrigerated. The 5-day course of therapy is continued every 28 days until patient is in complete remission or until neurotoxicity develops.
IV: Reconstitute each vial with 2 mL of sterile water for injection; solid cake should dissolve in <15 sec. Concentration: 25 mg/mL. Reconstituted solution is stable for 8 hr.
Intermittent Infusion: Diluent: Dilute appropriate volume of reconstituted solution in 100–125 mL of 0.9% NaCl or D5W.
Rate: Infuse over 30 min.
Y-Site Compatibility:
- alemtuzumab
- allopurinol
- amifostine
- amikacin
- aminocaproic acid
- aminophylline
- amphotericin B lipid complex
- amphotericin B liposomal
- ampicillin
- ampicillin/sulbactam
- anidulafungin
- argatroban
- atracurium
- aztreonam
- bivalirudin
- bleomycin
- bumetanide
- buprenorphine
- butorphanol
- calcium acetate
- calcium chloride
- calcium gluconate
- carboplatin
- carmustine
- caspofungin
- cefazolin
- cefepime
- cefotaxime
- cefotetan
- cefoxitin
- ceftazidime
- ceftriaxone
- cefuroxime
- chloramphenicol
- ciprofloxacin
- cisatracurium
- cisplatin
- clindamycin
- cyclophosphamide
- cyclosporine
- cytarabine
- dacarbazine
- dactinomycin
- daptomycin
- dexamethasone
- dexmedetomidine
- dexrazoxane
- digoxin
- diltiazem
- diphenhydramine
- dobutamine
- docetaxel
- dopamine
- doxorubicin hydrochloride
- doxycycline
- droperidol
- enalaprilat
- ephedrine
- epinephrine
- ertapenem
- erythromycin
- esmolol
- etoposide
- etoposide phosphate
- famotidine
- fentanyl
- filgrastim
- floxuridine
- fluconazole
- fluorouracil
- foscarnet
- fosphenytoin
- furosemide
- gemcitabine
- gentamicin
- glycopyrrolate
- granisetron
- haloperidol
- heparin
- hetastarch
- hydralazine
- hydrocortisone
- hydromorphone
- ifosfamide
- imipenem/cilastatin
- insulin regular
- isoproterenol
- ketorolac
- labetalol
- leucovorin
- levofloxacin
- lidocaine
- linezolid
- lorazepam
- magnesium sulfate
- mannitol
- melphalan
- meperidine
- meropenem
- mesna
- methohexital
- methotrexate
- methylprednisolone
- metoclopramide
- metoprolol
- metronidazole
- midazolam
- milrinone
- mitomycin
- mitoxantrone
- morphine
- multivitamins
- nafcillin
- nalbuphine
- naloxone
- nitroglycerin
- nitroprusside
- norepinephrine
- octreotide
- ondansetron
- oxaliplatin
- paclitaxel
- palonosetron
- pamidronate
- pemetrexed
- pentamidine
- pentobarbital
- phenobarbital
- phentolamine
- phenylephrine
- piperacillin/tazobactam
- potassium acetate
- potassium chloride
- potassium phosphates
- procainamide
- promethazine
- propranolol
- remifentanil
- rituximab
- rocuronium
- sodium acetate
- sodium bicarbonate
- sodium phosphates
- succinylcholine
- sufentanil
- tacrolimus
- theophylline
- thiopental
- thiotepa
- tigecycline
- tirofiban
- tobramycin
- topotecan
- trimethoprim/sulfamethoxazole
- vancomycin
- vasopressin
- vecuronium
- verapamil
- vinblastine
- vincristine
- vinorelbine
- voriconazole
- zidovudine
- zoledronic acid
Y-Site Incompatibility:
- acyclovir
- amiodarone
- amphotericin B deoxycholate
- chlorpromazine
- dantrolene
- daunorubicin hydrochloride
- diazepam
- ganciclovir
- gemtuzumab ozogamicin
- hydroxyzine
- idarubicin
- nicardipine
- pantoprazole
- phenytoin
- prochlorperazine
- trastuzumab

Explain the purpose and side effects of fludarabine.
Emphasize the need for periodic lab tests to monitor for side effects.
Caution patient to avoid crowds and persons with known infections. Health care professional should be informed immediately if symptoms of infection (chills, cough, or burning pain on urination) occur.
Instruct patient to report unusual bleeding. Advise patient of thrombocytopenia precautions (use soft toothbrush and electric razor; avoid contact sports and other situations in which injury might occur). Do not drink alcoholic beverages or take medication containing aspirin or NSAIDs; may precipitate gastric bleeding.
Instruct patient to inspect oral mucosa for redness and ulceration. If mouth sores occur, advise patient to use sponge brush and rinse mouth with water after eating and drinking. Consult health care professional if pain interferes with eating. Stomatitis pain treatment may require opioid analgesics.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
Rep: May cause fetal harm; advise women of reproductive potential to use effective contraception during therapy and for ≥6 mo after last dose. Advise patient to avoid breastfeeding during therapy and 1 wk after last dose Advise men with female partners of reproductive potential to use effective contraception during therapy and for 3 mo after last dose. May cause male infertility.

Improvement of hematopoietic values in leukemias.

~~Fludara,~~ ~~Oforta~~

NDC Code

0480- Teva Pharmaceuticals, Inc.
- 0480-9772- Fludarabine Phosphate
  - 0480-9772-01- 1 VIAL, SINGLE-DOSE in 1 CARTON (0480-9772-01) / 2 mL in 1 VIAL, SINGLE-DOSE

0527- Lannett Company, Inc.
- 0527-1242- Fludarabine Phosphate
  - 0527-1242-02- 1 VIAL, SINGLE-DOSE in 1 CARTON (0527-1242-02) / 2 mL in 1 VIAL, SINGLE-DOSE

25021- Sagent Pharmaceuticals
- 25021-242- Fludarabine Phosphate
  - 25021-242-02- 1 VIAL in 1 CARTON (25021-242-02) / 2 mL in 1 VIAL

33656- Chongqing Biocare Pharmaceutical Ltd.
- 33656-0015-
  - 33656-0015-1- 1 g in 1 POUCH (33656-0015-1)

45963- Actavis Pharma, Inc.
- 45963-609- Fludarabine phosphate
  - 45963-609-55- 1 VIAL, GLASS in 1 CARTON (45963-609-55) / 2 mL in 1 VIAL, GLASS

51916- Wuhan Biocause Pharmaceutical Development Co., Ltd
- 51916-310-
  - 51916-310-01- 100 g in 1 BOTTLE, GLASS (51916-310-01)

53183- Sicor S.r.l.
- 53183-7841-
  - 53183-7841-1- 1 kg in 1 CARTON (53183-7841-1)

58623- Zhejiang Hisun Pharmaceutical Co., Ltd.
- 58623-0043-
  58623-0043-1- 1 kg in 1 DRUM (58623-0043-1)

59923- Areva Pharmaceuticals
- 59923-604- Fludarabine Phosphate
  59923-604-02- 1 VIAL, SINGLE-DOSE in 1 CARTON (59923-604-02) / 2 mL in 1 VIAL, SINGLE-DOSE

63323- Fresenius Kabi USA, LLC
- 63323-192- Fludarabine
  - 63323-192-02- 1 VIAL in 1 BOX (63323-192-02) / 2 mL in 1 VIAL

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