6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Very common adverse reactions 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 have occurred in CLL patients treated with fludarabine phosphate. The most frequently reported adverse reactions and those reactions which are more clearly related to the drug are arranged below according to body system.
Most common adverse reactions (incidence > 30%) include myelosuppression (neutropenia, thrombocytopenia and anemia), fever, infection, nausea and vomiting, fatigue, anorexia, cough and weakness ( 6 ). gov/medwatch. 1 Hematopoietic Systems Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with fludarabine phosphate.
During fludarabine phosphate treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm 3 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. 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. 3 )]. The majority of patients rechallenged with fludarabine phosphate 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.
2 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.
Rare cases of Epstein-Barr (EBV) associated lymphoproliferative disorders have been reported in patients treated with fludarabine phosphate. 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 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.
3 Metabolic Tumor lysis syndrome has been reported in CLL patients treated with fludarabine phosphate. 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. 4 Nervous System Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with fludarabine phosphate at the recommended dose.
Peripheral neuropathy has been observed in patients treated with fludarabine phosphate and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known [see Warnings and Precautions ( 5 )].
5 Pulmonary System Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16%, and 22% of those treated with fludarabine phosphate in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to fludarabine phosphate 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 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. 6 Gastrointestinal System Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis, and hemorrhage have been reported in patients treated with fludarabine phosphate.
Elevations of pancreatic enzyme levels have also been reported. 7 Cardiovascular Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine phosphate. There have been reports of heart failure and arrhythmia.
No other severe cardiovascular events were considered to be drug related. 8 Genitourinary System Hemorrhagic cystitis has been reported in patients treated with fludarabine phosphate. 9 Skin Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with fludarabine phosphate.
Erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis and pemphigus have been reported, with fatal outcomes in some cases. 10 Neoplasms Worsening or flare-up of preexisting skin cancer lesions, as well as new onset of skin cancer, has been reported in patients during or after treatment with fludarabine phosphate.
11 Hepatobiliary Disorders Elevations of hepatic enzyme levels have been reported. 12 Adverse Reactions from Clinical Trials Data in Table 1 are derived from the 133 patients with CLL who received fludarabine phosphate in the MDAH and SWOG studies.
TABLE 1:
PERCENT OF CLL PATIENTS REPORTING NON-HEMATOLOGIC ADVERSE REACTIONS ADVERSE REACTIONS MDAH (N=101) SWOG (N=32) ANY ADVERSE REACTION 88% 91% BODY AS A WHOLE 72 84 FEVER 60 69 CHILLS 11 19 FATIGUE 10 38 INFECTION 33 44 PAIN 20 22 MALAISE 8 6 DIAPHORESIS 1 13 ALOPECIA 0 3 ANAPHYLAXIS 1 0 HEMORRHAGE 1 0 HYPERGLYCEMIA 1 6 DEHYDRATION 1 0 NEUROLOGICAL 21 69 WEAKNESS 9 65 PARESTHESIA 4 12 HEADACHE 3 0 VISUAL DISTURBANCE 3 15 HEARING LOSS 2 6 SLEEP DISORDER 1 3 DEPRESSION 1 0 CEREBELLAR SYNDROME 1 0 IMPAIRED MENTATION 1 0 PULMONARY 35 69 COUGH 10 44 PNEUMONIA 16 22 DYSPNEA 9 22 SINUSITIS 5 0 PHARYNGITIS 0 9 UPPER RESPIRATORY INFECTION 2 16 ALLERGIC PNEUMONITIS 0 6 EPISTAXIS 1 0 HEMOPTYSIS 1 6 BRONCHITIS 1 0 HYPOXIA 1 0 GASTROINTESTINAL 46 63 NAUSEA/VOMITING 36 31 DIARRHEA 15 13 ANOREXIA 7 34 STOMATITIS 9 0 GI BLEEDING 3 13 ESOPHAGITIS 3 0 MUCOSITIS 2 0 LIVER FAILURE 1 0 ABNORMAL LIVER FUNCTION TEST 1 3 CHOLELITHIASIS 0 3 CONSTIPATION 1 3 DYSPHAGIA 1 0 CUTANEOUS 17 18 RASH 15 15 PRURITUS 1 3 SEBORRHEA 1 0 GENITOURINARY 12 22 DYSURIA 4 3 URINARY INFECTION 2 15 HEMATURIA 2 3 RENAL FAILURE 1 0 ABNORMAL RENAL FUNCTION TEST 1 0 PROTEINURIA 1 0 HESITANCY 0 3 CARDIOVASCULAR 12 38 EDEMA 8 19 ANGINA 0 6 CONGESTIVE HEART FAILURE 0 3 ARRHYTHMIA 0 3 SUPRAVENTRICULAR TACHYCARDIA 0 3 MYOCARDIAL INFARCTION 0 3 DEEP VENOUS THROMBOSIS 1 3 PHLEBITIS 1 3 TRANSIENT ISCHEMIC ATTACK 1 0 ANEURYSM 1 0 CEREBROVASCULAR ACCIDENT 0 3 MUSCULOSKELETAL 7 16 MYALGIA 4 16 OSTEOPOROSIS 2 0 ARTHRALGIA 1 0 TUMOR LYSIS SYNDROME 1 0 More than 3000 adult patients received fludarabine phosphate 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.