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fludarabine phosphate for injection, USP Adverse Reactions

ADVERSE REACTIONS

The most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in CLL patients treated with fludarabine phosphate, USP. 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, USP. During fludarabine phosphate, USP treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm3 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, USP.

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in postmarketing 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), Evan's syndrome, and acquired hemophilia have been reported to occur in patients receiving fludarabine phosphate, USP (see WARNINGS section). The majority of patients rechallenged with fludarabine phosphate, USP 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, USP.

Rare cases of Epstein Barr Virus (EBV) associated lymphoproliferative disorders have been reported in patients treated with fludarabine phosphate, USP.

Metabolic: Tumor lysis syndrome has been reported in CLL patients treated with fludarabine phosphate, USP. 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, USP at the recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine phosphate, USP and one case of wrist-drop was reported.

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.

Pulmonary System: Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16%, and 22% of those treated with fludarabine phosphate, USP in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to fludarabine phosphate, USP 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 use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, 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 have been reported in patients treated with fludarabine phosphate, USP.

Cardiovascular: Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine phosphate, USP. 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, USP.

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

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and pemphigus have been reported, with fatal outcomes in some cases.

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, USP.

Data in the following table are derived from the 133 patients with CLL who received fludarabine phosphate, USP in the MDAH and SWOG studies.

PERCENT OF CLL PATIENTS REPORTING NON-HEMATOLOGIC 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

72

60

11

10

33

20

8

1

0

1

1

1

1

84

69

19

38

44

22

6

13

3

0

0

6

0

NEUROLOGICAL

      WEAKNESS

      PARESTHESIA

      HEADACHE

      VISUAL DISTURBANCE

      HEARING LOSS

      SLEEP DISORDER

      DEPRESSION

      CEREBELLAR SYNDROME

      IMPAIRED MENTATION

21

9

4

3

3

2

1

1

1

1

69

65

12

0

15

6

3

0

0

0

PULMONARY

      COUGH

      PNEUMONIA

      DYSPNEA

      SINUSITIS

      PHARYNGITIS

      UPPER RESPIRATORY INFECTION

      ALLERGIC PNEUMONITIS

      EPISTAXIS

      HEMOPTYSIS

      BRONCHITIS

      HYPOXIA

35

10

16

9

5

0

2

0

1

1

1

1

69

44

22

22

0

9

16

6

0

6

0

0

GASTROINTESTINAL

      NAUSEA/VOMITING

      DIARRHEA

      ANOREXIA

      STOMATITIS

      GI BLEEDING

      ESOPHAGITIS

      MUCOSITIS

      LIVER FAILURE

      ABNORMAL LIVER FUNCTION TEST

      CHOLELITHIASIS

      CONSTIPATION

      DYSPHAGIA

46

36

15

7

9

3

3

2

1

1

0

1

1

63

31

13

34

0

13

0

0

0

3

3

3

0

CUTANEOUS

      RASH

      PRURITUS

      SEBORRHEA

17

15

1

1

18

15

3

0

GENITOURINARY

      DYSURIA

      URINARY INFECTION

      HEMATURIA

      RENAL FAILURE

      ABNORMAL RENAL FUNCTION TEST

      PROTEINURIA

      HESITANCY

12

4

2

2

1

1

1

0

22

3

15

3

0

0

0

3

CARDIOVASCULAR

      EDEMA

      ANGINA

      CONGESTIVE HEART FAILURE

      ARRHYTHMIA

      SUPRAVENTRICULAR TACHYCARDIA

      MYOCARDIAL INFARCTION

      DEEP VENOUS THROMBOSIS

      PHLEBITIS

      TRANSIENT ISCHEMIC ATTACK

      ANEURYSM

      CEREBROVASCULAR ACCIDENT

12

8

0

0

0

0

0

1

1

1

1

0

38

19

6

3

3

3

3

3

3

0

0

3

MUSCULOSKELETAL

      MYALGIA

      OSTEOPOROSIS

      ARTHRALGIA

7

4

2

1

16

16

0

0

TUMOR LYSIS SYNDROME

1

0

More than 3000 adult patients received fludarabine phosphate, USP 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.

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