FLUDARABINE PHOSPHATE injection

United States - English - NLM (National Library of Medicine)

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Active ingredient:
FLUDARABINE PHOSPHATE (UNII: 1X9VK9O1SC) (FLUDARABINE - UNII:P2K93U8740)
Available from:
Mylan Institutional LLC
INN (International Name):
FLUDARABINE PHOSPHATE
Composition:
FLUDARABINE PHOSPHATE 25 mg in 1 mL
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

FLUDARABINE PHOSPHATE- fludarabine phosphate injection

Mylan Institutional LLC

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Fludarabine Phosphate Injection, USP

Rx only

FOR INTRAVENOUS USE ONLY

WARNING

Fludarabine Phosphate Injection should be administered under the supervision of a qualified

physician experienced in the use of antineoplastic therapy. Fludarabine Phosphate Injection can

severely suppress bone marrow function. When used at high doses in dose-ranging studies in

patients with acute leukemia, fludarabine phosphate injection was associated with severe

neurologic effects, including blindness, coma, and death. This severe central nervous system

toxicity occurred in 36% of patients treated with doses approximately four times greater (96

mg/m /day for 5–7 days) than the recommended dose. Similar severe central nervous system

toxicity, including coma, seizures, agitation and confusion, has been reported in patients treated at

doses in the range of the dose recommended for chronic lymphocytic leukemia.

Instances of life-threatening and sometimes fatal autoimmune phenomena such as hemolytic

anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and

acquired hemophilia have been reported to occur after one or more cycles of treatment with

fludarabine phosphate injection. Patients undergoing treatment with fludarabine phosphate

injection should be evaluated and closely monitored for hemolysis.

In a clinical investigation using fludarabine phosphate injection in combination with pentostatin

(deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL), there

was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine

phosphate injection in combination with pentostatin is not recommended.

DESCRIPTION

Fludarabine Phosphate Injection contains fludarabine phosphate, a fluorinated nucleotide analog of the

antiviral agent vidarabine, 9-ß D-arabinofuranosyladenine (ara-A) that is relatively resistant to

deamination by adenosine deaminase. Each mL contains 25 mg of the active ingredient fludarabine

phosphate, 25 mg of mannitol, water for injection, qs; and sodium hydroxide to adjust pH to 6.8. The pH

range for the final product is 6.0–7.1. Fludarabine Phosphate Injection, USP is a sterile solution

intended for intravenous administration.

The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2fluoro-9-(5-O-phosphono-ß-D-

arabinofuranosyl) (2-fluoro-ara- AMP).

The molecular formula of fludarabine phosphate is C

H FN O P (MW 365.2) and the structure is:

CLINICAL PHARMACOLOGY

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. The mechanism of action of this antimetabolite is not completely

characterized and may be multi-faceted.

Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the

active metabolite, 2-fluoro-ara- A, within minutes after intravenous infusion. Consequently, clinical

pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of

25 mg 2-fluoro-ara-AMP/m to cancer patients infused over 30 minutes, 2-fluoro-ara- A concentrations

show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels

increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as

approximately 20 hours. In vitro, plasma protein binding of fludarabine ranged between 19% and 29%.

A correlation was noted between the degree of absolute granulocyte count nadir and increased area

under the concentration x time curve (AUC).

Special Populations

Pediatric Patients

Limited pharmacokinetic data for fludarabine phosphate injection are available from a published study

of children (ages 1– 21 years) with refractory acute leukemias or solid tumors (Children’s Cancer

Group Study 097). When fludarabine phosphate injection was administered as a loading dose over 10

minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached

early.

Patients with Renal Impairment

The total body clearance of the principal metabolite 2-fluoro-ara-A correlated with the creatinine

clearance, indicating the importance of the renal excretion pathway for the elimination of the drug.

Renal clearance represents approximately 40% of the total body clearance. Patients with creatinine

clearance 30-79 mL/min should have their Fludarabine Phosphate Injection dose reduced and be

monitored closely for excessive toxicity. Due to insufficient data, Fludarabine Phosphate Injection

should not be administered to patients with creatinine clearance less than 30 mL/min. (See DOSAGE

AND ADMINISTRATION section).

CLINICAL STUDIES

Two single-arm open-label studies of fludarabine phosphate injection have been conducted in adult

patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In a study

conducted by M.D. Anderson Cancer Center (MDAH), 48 patients were treated with a dose of 22–40

mg/m daily for 5 days every 28 days. Another study conducted by the Southwest Oncology Group

(SWOG) involved 31 patients treated with a dose of 15–25 mg/m daily for 5 days every 28 days. The

overall objective response rates were 48% and 32% in the MDAH and SWOG studies, respectively.

The complete response rate in both studies was 13%; the partial response rate was 35% in the MDAH

study and 19% in the SWOG study. These response rates were obtained using standardized response

criteria developed by the National Cancer Institute CLL Working Group and were achieved in heavily

pretreated patients. The ability of fludarabine phosphate injection to induce a significant rate of

response in refractory patients suggests minimal cross-resistance with commonly used anti-CLL agents.

The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks)

and 21 weeks (range of 1 to 53 weeks) respectively. The median duration of disease control was 91

weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with

fludarabine phosphate injection was 43 weeks and 52 weeks in the MDAH and SWOG studies,

respectively.

Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG

responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin

concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of

anemic patients. Similarly, average platelet count improved from 63,500/mm to 103,300/mm at the time

of response in a subgroup of patients who were thrombocytopenic at baseline.

INDICATIONS AND USAGE

Fludarabine Phosphate Injection 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

fludarabine phosphate injection in previously untreated or non-refractory patients with CLL have not

been established.

CONTRAINDICATIONS

Fludarabine Phosphate Injection is contraindicated in those patients who are hypersensitive to this drug

or its components.

WARNINGS

(See boxed warning)

Dose Dependent Neurologic Toxicities

There are clear dose-dependent toxic effects seen with fludarabine phosphate injection. Dose levels

approximately 4 times greater (96 mg/m /day for 5 to 7 days) than that recommended for CLL (25

mg/m /day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and

death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients (36%)

who received fludarabine phosphate injection at high doses (96 mg/m /day for 5 to 7 days) developed

this severe neurotoxicity. Similar severe central nervous system toxicity, including coma, seizures,

agitation and confusion, has been reported in patients treated at doses in the range of the dose

recommended for chronic lymphocytic leukemia.

In postmarketing experience neurotoxicity has been reported to occur either earlier or later than in

clinical trials (range 7 to 225 days).

The effect of chronic administration of fludarabine phosphate injection on the central nervous system is

unknown, however, patients have received the recommended dose for up to 15 courses of therapy.

Bone Marrow Suppression

Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported

in patients treated with fludarabine phosphate injection. In a Phase I study in adult solid tumor patients,

the median time to nadir counts was 13 days (range, 3–25 days) for granulocytes and 16 days (range, 2–

32) for platelets. Most patients had hematologic 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 phosphate

injection requires careful hematologic monitoring.

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.

Autoimmune Reactions

Instances of life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia,

autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired

hemophilia have been reported to occur after one or more cycles of treatment with fludarabine

phosphate injection in patients with or without a previous history of autoimmune hemolytic anemia or a

positive Coombs’ test and who may or may not be in remission from their disease. Steroids may or may

not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with

fludarabine phosphate injection developed a recurrence in the hemolytic process. The mechanism(s)

which predispose patients to the development of this complication has not been identified. Patients

undergoing treatment with fludarabine phosphate injection should be evaluated and closely monitored

for hemolysis. Discontinuation of therapy with fludarabine phosphate injection is recommended in case

of hemolysis.

Transfusion Associated Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated

blood in fludarabine phosphate injection treated patients. Fatal outcome as a consequence of this disease

has been reported. 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 phosphate injection should receive irradiated blood only.

Pulmonary Toxicity

In a clinical investigation using fludarabine phosphate injection in combination with pentostatin

(deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there

was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine

phosphate injection in combination with pentostatin is not recommended.

Pregnancy Category D

Based on its mechanism of action, fludarabine phosphate can cause fetal harm when administered to a

pregnant woman. There are no adequate and well-controlled studies of fludarabine phosphate injection

in pregnant women. Fludarabine administered to rats and rabbits during organogenesis caused an

increase in resorptions, skeletal and visceral malformations and decreased fetal body weights. If

fludarabine phosphate injection is used during pregnancy, or if the patient becomes pregnant while

taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of

childbearing potential should be advised to avoid becoming pregnant.

Male Fertility and Reproductive Outcomes

Males with female sexual partners of childbearing potential should use contraception during and after

cessation of fludarabine phosphate injection therapy. Fludarabine may damage testicular tissue and

spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic

abnormalities in fetuses. The duration of this effect is uncertain. [See PRECAUTIONS, Impairment

of Fertility]

PRECAUTIONS

General

Fludarabine Phosphate Injection is a potent antineoplastic agent with potentially significant toxic side

effects. Patients undergoing therapy should be closely observed for signs of hematologic and

nonhematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the

development of anemia, neutropenia and thrombocytopenia.

In patients with impaired state of health, fludarabine phosphate injection should be given with caution

and after careful risk/benefit consideration. This applies especially for patients with severe impairment

of bone marrow function (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency or

with a history of opportunistic infection. Prophylactic treatment should be considered in patients at

increased risk of developing opportunistic infections.

Fludarabine Phosphate Injection may reduce the ability to drive or use machines, since fatigue,

weakness, visual disturbances, confusion, agitation and seizures have been observed.

Tumor Cell Lysis

Tumor lysis syndrome has been associated with fludarabine phosphate injection treatment. This

syndrome has been reported in CLL patients with large tumor burden. Since fludarabine phosphate

injection 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.

Renal Impairment

Fludarabine Phosphate Injection must be administered cautiously in patients with renal impairment. The

total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine

clearance. Patients with creatinine clearance 30-79 mL/min should have their fludarabine phosphate

injection dose reduced and be monitored closely for excessive toxicity. Fludarabine Phosphate

Injection should not be administered to patients with creatinine clearance less than 30 mL/min. (See

DOSAGE AND ADMINISTRATION section).

In patients aged 65 years or older, creatinine clearance should be measured before start of treatment.

Laboratory Tests

During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be

monitored regularly to determine the degree of hematopoietic suppression.

Drug Interactions

The use of fludarabine phosphate injection in combination with pentostatin is not recommended due to

the risk of severe pulmonary toxicity (see WARNINGS section).

Carcinogenes is

No animal carcinogenicity studies with fludarabine phosphate injection have been conducted.

Mutagenes is

Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells (HGRPT assay in

Chinese hamster ovary cells) either in the presence or absence of metabolic activation. Fludarabine

phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberrations in the

presence of metabolic activation) and induced sister chromatid exchanges both with and without

metabolic activation. In addition, fludarabine phosphate was clastogenic in vivo (mouse micronucleus

assay) but was not mutagenic to germ cells (dominant lethal test in male mice).

Impairment of Fertility

Studies in mice, rats and dogs have demonstrated dose-related adverse effects on the male reproductive

system. Observations consisted of a decrease in mean testicular weights in mice and rats with a trend

toward decreased testicular weights in dogs and degeneration and necrosis of spermatogenic epithelium

of the testes in mice, rats and dogs. The possible adverse effects on fertility in humans have not been

adequately evaluated.

Pregnancy

Pregnancy Category D

(See WARNINGS section).

Based on its mechanism of action, fludarabine phosphate can cause fetal harm when administered to a

pregnant woman. There are not adequate and well-controlled studies of fludarabine phosphate in

pregnant women. Fludarabine phosphate was embryolethal and teratogenic in rats and rabbits. If

fludarabine phosphate injection is used during pregnancy, or if the patient becomes pregnant while

taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of

childbearing potential should be advised to avoid becoming pregnant.

In rats, repeated intravenous doses of fludarabine phosphate at 2.4 times and 7.2 times the recommended

human IV dose (25 mg/m ) administered during organogenesis caused an increase in resorptions,

skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and

decreased fetal body weights. Maternal toxicity was not apparent at 2.4 times the human IV dose, and

was limited to slight body weight decreases at 7.2 times the human IV dose. In rabbits, repeated

intravenous doses of fludarabine phosphate at 3.8 times the human IV dose administered during

organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease

in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly,

brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib

anomalies were seen in all dose levels (≥ 0.5 times the human IV dose).

Nursing Mothers

It is not known whether fludarabine phosphate is excreted in human milk. Because many drugs are

excreted in human milk and because of the potential for serious adverse reactions including

tumorigenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the

drug, taking into account the importance of the drug to the mother.

Pediatric Use

Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy.

Fludarabine Phosphate Injection was evaluated in 62 pediatric patients (median age 10, range 1–21) with

refractory acute leukemia (45 patients) or solid tumors (17 patients). The fludarabine phosphate injection

regimen tested for pediatric acute lymphocytic leukemia (ALL) patients was a loading bolus of 10.5

mg/m /day followed by a continuous infusion of 30.5 mg/m2/day for 5 days. In 12 pediatric patients with

solid tumors, dose-limiting myelosuppression was observed with a loading dose of 8 mg/m /day

followed by a continuous infusion of 23.5 mg/m /day for 5 days. The maximum tolerated dose was a

loading dose of 7 mg/m /day followed by a continuous infusion of 20 mg/m /day for 5 days. Treatment

toxicity included bone marrow suppression. Platelet counts appeared to be more sensitive to the effects

of fludarabine phosphate injection than hemoglobin and white blood cell counts. Other adverse events

included fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection. There were no reported

occurrences of peripheral neuropathy or pulmonary hypersensitivity reaction.

Vaccination

During and after treatment with Fludarabine Phosphate Injection vaccination with live vaccines should

be avoided.

Disease Progression

Richter's syndrome has been reported in CLL patients.

ADVERSE REACTIONS

Very common adverse events include myelosuppression (neutropenia, thrombocytopenia and anemia),

fever and chills, fatigue, weakness, infection, pneumonia, cough, nausea, vomiting, and diarrhea. Other

commonly reported events include malaise, mucositis and anorexia. Serious opportunistic infections

(such as latent viral reactivation, herpes zoster virus, Epstein- Barr virus, and progressive multifocal

leukoencephalopathy) have occurred in CLL patients treated with fludarabine phosphate injection.

Adverse events and those reactions which are more clearly related to the drug are arranged below

according to body system.

Hematopoietic Systems

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of

CLL patients treated with fludarabine phosphate injection. During fludarabine phosphate injection

treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm in

59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%,

and platelet count decreased from pretreatment values by at least 50% in 55%. Myelosuppression may

be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL

patient treated with fludarabine phosphate injection.

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes

resulting in death, have been reported in post-marketing surveillance. 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.

Life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia, autoimmune

thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have

been reported to occur in patients receiving fludarabine phosphate injection (see WARNINGS

section). The majority of patients rechallenged with fludarabine phosphate injection developed a

recurrence in the hemolytic process.

In post-marketing experience, cases of myelodysplastic syndrome and acute myeloid leukemia, mainly

associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomerase

inhibitors, or irradiation have been reported.

Infections

Serious, and sometimes fatal infections, including opportunistic infections and reactivations of latent

viral infections such as VZV (herpes zoster), Epstein-Barr virus and JC virus (progressive multifocal

leukoencephalopathy)) have been reported in patients treated with fludarabine phosphate injection.

Rare cases of Epstein Barr Virus (EBV) associated lymphoproliferative disorders have been reported

in patients treated with fludarabine phosphate injection.

In post-marketing experience, cases of progressive multifocal leukoencephalopathy have been

reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or

concurrent chemotherapy. The time to onset has ranged from a few weeks to approximately one year

after initiating treatment.

Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study, approximately 50%

of which were due to infection.

Metabolic

Tumor lysis syndrome has been reported in CLL patients treated with fludarabine phosphate injection.

This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis,

hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be

heralded by flank pain and hematuria.

Nervous System

(See WARNINGS section)

Objective weakness, agitation, confusion, seizures visual disturbances, optic neuritis, optic neuropathy,

blindness and coma have occurred in CLL patients treated with fludarabine phosphate injection at the

recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine

phosphate injection and one case of wrist-drop was reported. There have been additional reports of

cerebral hemorrhage though the frequency is not known.

Pulmonary System

Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16% and 22% of those

treated with fludarabine phosphate injection in the MDAH and SWOG studies, respectively. Pulmonary

hypersensitivity reactions to fludarabine phosphate injection characterized by dyspnea, cough and

interstitial pulmonary infiltrate have been observed.

In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine

phosphate injection use which resulted in ARDS, respiratory distress, pulmonary hemorrhage,

pulmonary fibrosis, pneumonitis and respiratory failure. After an infectious origin has been excluded,

some patients experienced symptom improvement with corticosteroids.

Gastrointestinal System

Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis, and

gastrointestinal bleeding and hemorrhage have been reported in patients treated with fludarabine

phosphate injection. Elevations of pancreatic enzyme levels have also been reported.

Cardiovas cular

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to

treatment with fludarabine phosphate injection. There have been additional reports of heart failure and

arrhythmia though the frequency is rare. No other severe cardiovascular events were considered to be

drug related.

Genitourinary System

Rare cases of hemorrhagic cystitis have been reported in patients treated with fludarabine phosphate

injection.

Skin

Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with fludarabine

phosphate injection. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and

pemphigus have been reported, with fatal outcomes in some cases.

Neoplas ms

Worsening or flare-up of pre-existing skin cancer lesions, as well as new onset of skin cancer, has been

reported in patients during or after treatment with fludarabine phosphate injection.

Hepatobiliary Disorders

Elevations of hepatic enzyme levels have been reported.

Data in the following table are derived from the 133 patients with CLL who received fludarabine

phosphate injection in the MDAH and SWOG studies.

PERCENT OF CLL PATIENTS REPORTING NONHEMATOLOGIC ADVERSE EVENTS

ADVERSE EVENTS

MDAH (N=101)

SWOG (N=32)

ANY ADVERSE EVENT

88 %

91 %

BODY AS A WHOLE

FEVER

CHILLS

FATIGUE

INFECTION

PAIN

MALAISE

DIAPHORESIS

ALOPECIA

ANAPHYLAXIS

HEMORRHAGE

HYPERGLYCEMIA

DEHYDRATION

NEUROLOGICAL

WEAKNESS

PARESTHESIA

HEADACHE

VISUAL DISTURBANCE

HEARING LOSS

SLEEP DISORDER

DEPRESSION

CEREBELLAR SYNDROME

IMPAIRED MENTATION

PULMONARY

COUGH

PNEUMONIA

DYSPENIA

SINUSITIS

PHARYNGITIS

UPPER RESPIRATORY INFECTION

ALLERGIC PNEUMONITIS

EPISTAXIS

HEMOPTYSIS

BRONCHITIS

HYPOXIA

GASTROINTESTINAL

NAUSEA/VOMITING

DIARRHEA

ANOREXIA

STOMATITIS

GI BLEEDING

ESOPHAGITIS

MUCOSITIS

LIVER FAILURE

ABNORMAL LIVER FUNCTION TEST

CHOLELITHIASIS

CONSTIPATION

DYSPHAGIA

CUTANEOUS

RASH

PRURITUS

SEBORRHEA

GENITOURINARY

DYSURIA

URINARY INFECTION

HEMATURIA

RENAL FAILURE

ABNORMAL RENAL FUNCTION TEST

PROTEINURIA

HESITANCY

CARDIOVASCULAR

EDEMA

ANGINA

CONGESTIVE HEART FAILURE

ARRHYTHMIA

SUPRAVENTRICULAR TACHYCARDIA

MYOCARDIAL INFARCTION

DEEP VENOUS THROMBOSIS

PHLEBITIS

TRANSIENT ISCHEMIC ATTACK

ANEURYSM

CEREBROVASCULAR ACCIDENT

MUSCULOSKELETAL

MYALGIA

OSTEOPOROSIS

ARTHRALGIA

TUMOR LYSIS SYNDROME

More than 3000 adult patients received fludarabine phosphate injection in studies of other leukemias,

lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was

consistent with the data presented above.

OVERDOSAGE

High doses of fludarabine phosphate injection (see WARNINGS section) have been associated with an

irreversible central nervous system toxicity characterized 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 phosphate injection overdosage.

Treatment consists of drug discontinuation and supportive therapy.

DOSAGE AND ADMINISTRATION

Usual Dose

The recommended adult dose of fludarabine phosphate injection is 25 mg/m administered intravenously

over a period of approximately 30 minutes daily for five consecutive days. Each 5 day course of

treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of

hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug

if neurotoxicity occurs.

A number of clinical settings may predispose to increased toxicity from fludarabine phosphate injection.

These include advanced age, renal impairment, and bone marrow impairment. Such patients should be

monitored closely for excessive toxicity and the dose modified accordingly.

The optimal duration of treatment has not been clearly established. It is recommended that three

additional cycles of fludarabine phosphate injection be administered following the achievement of a

maximal response and then the drug should be discontinued.

Renal Impairment

Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with

creatinine clearance 30-79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are

based on a pharmacokinetic study in patients with renal impairment. Fludarabine Phosphate Injection,

should not be administered to patients with creatinine clearance less than 30 mL/min.

Starting Dose Adjustment for Renal Impairment

Creatinine Clearance

Starting Dose

≥ 80 mL/min

25 mg/m (full dose)

50 - 79 mL/min

20 mg/m

30 - 49 mL/min

15 mg/m

< 30 mL/min

do not administer

Renally impaired patients should be monitored closely for excessive toxicity and the dose modified

accordingly.

Preparation of Solutions

Fludarabine Phosphate Injection; Each mL contains 25 mg fludarabine phosphate, 25 mg mannitol, water

for injection, qs; and sodium hydroxide to adjust the pH to 6.8. The pH range for the final product is

6.0–7.1. In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% dextrose injection

USP, or 0.9% sodium chloride USP.

Fludarabine Phosphate Injection, contains no antimicrobial preservative and thus should be used within 8

hours of initial entry. Care must be taken to assure the sterility of prepared solutions. Parenteral drug

products should be inspected visually for particulate matter and discoloration prior to administration.

Fludarabine Phosphate Injection, should not be mixed with other drugs.

Handling and Disposal

Procedures for proper handling and disposal should be considered. Consideration should be given to

handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this

subject have been published.

Caution should be exercised in the handling of fludarabine phosphate injection. 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 contacts the skin or mucous membranes, wash thoroughly with soap and water;

rinse eyes thoroughly with plain water. Avoid exposure by inhalation or by direct contact of the skin or

mucous membranes.

HOW SUPPLIED

Fludarabine Phosphate Injection is supplied as a clear, sterile solution. Each mL contains 25 mg of

fludarabine phosphate, 25 mg of mannitol, water for injection, qs; and sodium hydroxide to adjust pH to

6.8. The pH range for the final product is 6.0–7.1. Store under refrigeration, between 2°–8°C (36°–

46°F).

Fludarabine Phosphate Injection is supplied in a single dose vial and packaged in a unit carton.

NDC Number Fludarabine Phosphate Injection, USP

67457-495-21 50 mg/2 mL (25 mg/mL)

Single Dose vial packaged individually

REFERENCES

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care

Settings. NIOSH Alert 2004-165.

2. OSHA Technical Manual, TED 1-0.. 15A, Section VI: Chapter 2. Controlling Occupational

Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi_2.html

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs.

Am j Health-Syst Pharm. 2006: 63: 1172-1193.

4. Polvich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines

and recommendations for practice (2

ed.). Pittsburgh, PA: Oncology Nursing Society.

Manufactured for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Manufactured by:

Agila Specialties Pvt. Ltd.

Bangalore, India

December 2013

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FLUDARABINE PHOSPHATE

fludarabine phosphate injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 7457-49 5

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

FLUDARABINE PHO SPHATE (UNII: 1X9 VK9 O1SC) (FLUDARABINE -

UNII:P2K9 3U8 740 )

FLUDARABINE

PHOSPHATE

25 mg

in 1 mL

Mylan Institutional LLC

Inactive Ingredients

Ingredient Name

Stre ng th

MANNITO L (UNII: 3OWL53L36 A)

SO DIUM HYDRO XIDE (UNII: 55X0 4QC32I)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 7457-49 5-21

1 in 1 CARTON

1

2 mL in 1 VIAL

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 0 6 47

12/22/20 11

Labeler -

Mylan Institutional LLC (790384502)

Registrant -

Onco T herapies Limited (676159830)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Onco Therapies

Limite d

6 76 159 8 30

Analysis(6 7457-49 5) , Manufacture(6 7457-49 5) , Sterilize(6 7457-49 5) , Label(6 7457-49 5) ,

Pa c k(6 7457-49 5)

Revised: 2/2014

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