Fludarabine Side Effects

Brand Names: Fludara, Oforta

Please note - some side effects for Fludarabine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Fludarabine - for the Consumer

Fludarabine

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Fludarabine:

Diarrhea; general body discomfort; loss of appetite; muscle pain; nausea; tiredness; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Fludarabine:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; black, tarry, or bloody stools; bloody or dark urine; changes in strength or the way you walk; chest pain; confusion; coughing or vomiting blood; difficult, decreased, or painful urination; fainting; hearing loss; irregular heartbeat; lower back or side pain; mental or mood changes (eg, agitation); muscle weakness or cramps; numbness or tingling in the hands or feet; red, swollen, blistered, or peeling skin; seizures; severe or persistent tiredness or weakness; shortness of breath; signs of infection (eg, fever, chills, cough, or sore throat); skin changes; swelling of the fingers, hands, or feet; swelling or sores of the mouth, lips, or tongue; unusual bruising or bleeding; vision changes or blindness; vomit that looks like coffee grounds; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Fludarabine Tablets

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Fludarabine Tablets:

Diarrhea; general body discomfort; increased sweating; loss of appetite; muscle pain; nausea; sinus inflammation; stuffy nose; tiredness; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Fludarabine Tablets:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; black, tarry, or bloody stools; blood in the urine; changes in strength or the way you walk; chest pain; confusion; coughing or vomiting blood; dark urine; difficult or painful urination; fainting; hearing loss; irregular heartbeat; lower back or side pain; mental or mood changes (eg, agitation, confusion); muscle weakness or cramps; numbness or tingling in the hands or feet; red, swollen, blistered, or peeling skin; seizures; severe or persistent tiredness or weakness; shortness of breath; signs of infection (eg, fever, chills, cough, or sore throat); skin changes; sores on the mouth or lips; swelling of the fingers, hands, or feet; unusual bruising or bleeding; vision changes or blindness; vomit that looks like coffee grounds; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Fludarabine Side Effects - for the Professional

Fludarabine

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 for 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 for injection. During Fludarabine phosphate for injection 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 for injection.

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), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving Fludarabine phosphate for injection. The majority of patients rechallenged with Fludarabine phosphate for 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 for injection.

Rare cases of Epstein-Barr Virus (EBV) associated lymphoproliferative disorders have been reported in patients treated with Fludarabine phosphate for injection.

In postmarketing 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 for 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

Objective weakness, agitation, confusion, seizures, [visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with Fludarabine phosphate for injection at the recommended dose. Peripheral neuropathy has been observed in patients treated with Fludarabine phosphate for 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 for injection in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to Fludarabine phosphate for 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 for injection 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 for injection. Elevations of pancreatic enzyme levels have also been reported.

Cardiovascular

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with Fludarabine phosphate for 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 for injection.

Skin

Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with Fludarabine phosphate for injection.

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

Neoplasms

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 for 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 for injection 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	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 for 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.

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Side Effects by Body System - for Healthcare Professionals

General

In general, the most common dose-limiting toxicities have been myelosuppression (60%), fever and chills (11% to 60%, sometimes without infection), infection (33%, including serious opportunistic infections), and nausea and vomiting (36%).

General side effects including pain (up to 19%), flu syndrome (up to 8%), and decreased weight (up to 6%) have been reported.

Hematologic

Hematologic toxicity has been reported to have occurred in the majority of patients. It presents as either neutropenia, thrombocytopenia, anemia, or a combination. Fifty-nine percent of patients develop an absolute neutrophil count of less than 500/mm3, 60% develop a hemoglobin concentration decrease by at least 2 g percent, and 55% develop a platelet count decrease by 50%. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in sometimes fatal pancytopenia have been reported. Rarely, bone marrow fibrosis or clinically significant hemolytic anemia have been associated with the use of fludarabine. A single case of pure red cell aplasia has been reported.

Myelosuppression may be severe, cumulative, and may affect multiple cell lines.

Immunologic

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported after one or more cycles of treatment 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 for their disease. Steroids may be effective in controlling these hemolytic episodes. The majority of affected patients developed a recurrence upon rechallenge.

An increased incidence of infections with pathogens not commonly associated with chronic lymphocytic leukemia have been associated with the use of fludarabine, especially when given with corticosteroids. These have included Listeria, Pneumocystis carinii pneumonia, disseminated varicella-zoster, cytomegalovirus, and unusual fungal pathogens. Fludarabine can significantly decrease the quantity of T-helper cells.

Immunologic side effects have been reported secondary to neutropenia which predisposes patients to infection. Pneumonia has been reported in 16% to 22% of treated patients from major clinical trials. Other, less common, infections include minor bacterial and/or fungal infections of the oropharynx, upper respiratory tract, urinary tract, and soft tissue, as well as herpes zoster infections. The risk of sepsis or life-threatening infection appears greatest during the first three courses of chemotherapy with fludarabine in patients with extensive disease.

Gastrointestinal

Gastrointestinal side effects including nausea, vomiting, and/or diarrhea have been reported in up to 36% of patients. Anorexia, stomatitis, esophagitis, mucositis, constipation, taste disturbances, abdominal pain, and gastrointestinal bleeding have been reported in less than 30% of patients.

Nervous system

Central and peripheral nervous system toxicities have been reported, including weakness/fatigue (asthenia) (up to 31%), headache (up to 9%), hearing disturbances (6%), paresthesias (4%), confusion (1%), visual disturbances (3%), and coma (less than 1%). In postmarketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Rare cases of disabling, severe, but reversible neurologic toxicity have been reported.

Most cases of progressive multifocal leukoencephalopathy 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.

The early trials of fludarabine given at high doses in the treatment of acute leukemia (up to 125 mg/m2 per day for up to 7 days) revealed evidence of severe CNS toxicity. Progressive optic neuritis, cortical blindness, seizures, and paralysis developed in some patients up to 2 months after therapy ended. Use of lower doses for low-grade lymphoid malignancy has not generally been associated with these severe side effects. However, progressive headaches, paresthesias, hemiparesis, and progressive and fatal neurologic dysfunction have rarely been associated with recommended doses.

Respiratory

Respiratory side effects have been reported including severe cases of pulmonary toxicity which resulted in adult respiratory distress syndrome, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, respiratory failure, and death. Cough (10% to 44%), upper respiratory tract infection or pneumonia (up to 22%), dyspnea (1% to 22%), rhinitis (up to 11%), increased cough (up to 6%), bronchitis (up to 5%), and sinusitis (up to 5%) have also been reported. Diffuse interstitial pneumonitis has been reported rarely.

Rare cases of diffuse alveolar damage have been associated with tumor lysis syndrome and the use of fludarabine.

In a clinical investigation using fludarabine injection in combination with pentostatin for the treatment of refractory chronic lymphocytic leukemia in adults, there was an unacceptably high incidence of fatal pulmonary toxicity.

Cardiovascular

Cardiovascular side effects including peripheral edema (8%) and chest pain (up to 5%) have been reported. A single case of pericardial effusion has been associated with the use of fludarabine.

Genitourinary

Genitourinary side effects including dysuria, hematuria, or proteinuria have been reported in 1% to 4% of patients. Rare cases of hemorrhagic cystitis have also been reported.

Renal

A single case of acute renal failure secondary to mesangiocapillary glomerulonephritis has been associated with the use of fludarabine in a 60-year-old man who had refractory chronic lymphocytic leukemia (CLL). This lesion has rarely been associated with CLL itself.

Renal side effects including hemolytic uremic syndrome and acute renal failure have rarely been associated with the use of fludarabine.

Hypersensitivity

Hypersensitivity reactions--usually skin rashes-- to fludarabine are relatively rare. Corticosteroid-responsive acute interstitial pulmonary infiltrates have been reported. Extremely rare cases of anaphylaxis have been reported.

Metabolic

Metabolic side effects including tumor lysis syndrome (TLS) has been reported to have occurred in approximately 1% of patients. A single case of diffuse alveolar damage has been associated with TLS and the use of fludarabine.

TLS may result in serious metabolic problems, including hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, renal failure, and even death. (Allopurinol before and during therapy is recommended.) The onset of this syndrome may be heralded by flank pain and hematuria.

Dermatologic

Most dermatologic problems are related to allergic reactions to fludarabine.

Dermatologic side effects including increased sweating (up to 14%), diaphoresis (up to 8%), skin disorder (up to 6%), and rash (up to 5%) have been reported. Alopecia has been reported only rarely.

Oncologic

Oncologic side effects have been reported in animal studies. Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberrations in the presence of metabolic activation and induce sister chromatid exchanges both with and without metabolic activation). In addition, fludarabine phosphate was clastogenic in vivo (mouse micronucleus assay).

Hepatic

Hepatic side effects including increased lactic dehydrogenase (up to 6%) have been reported.

Musculoskeletal

Musculoskeletal side effects including back pain (up to 9%) have been reported.

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