Treanda Side Effects

Please note - some side effects for Treanda 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 Treanda - for the Consumer

Treanda

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 Treanda:

Constipation; cough; diarrhea; drowsiness; dry mouth; headache; loss of appetite; mild fever; mild itching, pain, redness, or swelling at the injection site; mouth sores; nausea; stomach pain; tiredness; vomiting; weakness.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); dark urine; decreased urination; fast or irregular heartbeat; fever, chills, or persistent sore throat; persistent or severe cough; redness, swelling, peeling, or blistering of the skin; severe or persistent tiredness or weakness; severe pain, redness, swelling, or sores at the injection site; shortness of breath; unusual bruising or bleeding; unusual swelling; unusual weight loss.

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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Treanda Side Effects - for the Professional

Treanda

The data described below reflect exposure to Treanda in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL.  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.

The following serious adverse reactions have been associated with Treanda in clinical trials and are discussed in greater detail in other sections of the label.

• Myelosuppression [See Warnings and Precautions(5.1)]
• Infections [See Warnings and Precautions(5.2)]
• Infusion Reactions and Anaphylaxis [See Warnings and Precautions(5.3)]
• Tumor Lysis Syndrome [See Warnings and Precautions(5.4)]
• Skin Reactions [See Warnings and Precautions(5.5)]
• Other Malignancies [See Warnings and Precautions(5.6)]

 Clinical Trials Experience in CLL

The data described below reflect exposure to Treanda in 153 patients.  Treanda was studied in an active-controlled trial.  The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. 

Adverse reactions were reported according to NCI CTC v.2.0.  In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the Treanda group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).  

Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. 

Worsening hypertension was reported in 4 patients treated with Treanda in the randomized CLL clinical study and none treated with chlorambucil.  Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.

The most frequent adverse reactions leading to study withdrawal for patients receiving Treanda were hypersensitivity (2%) and pyrexia (1%).

Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients 

	Number (%) of patients
	Treanda (N=153)		Chlorambucil (N=143)
System organ class Preferred term	All Grades	Grade 3/4	All Grades	Grade 3/4
Total number of patients with at least 1 adverse reaction	121 (79)	52 (34)	96 (67)	25 (17)
Gastrointestinal disorders
Nausea	31 (20)	1 (<1)	21 (15)	1 (<1)
Vomiting	24 (16)	1 (<1)	9 (6)	0
Diarrhea	14 (9)	2 (1)	5 (3)	0
General disorders and administration site conditions
Pyrexia	36 (24)	6 (4)	8 (6)	2 (1)
Fatigue	14 (9)	2 (1)	8 (6)	0
Asthenia	13 (8)	0	6 (4)	0
Chills	9 (6)	0	1 (<1)	0
Immune system disorders
Hypersensitivity	7 (5)	2 (1)	3 (2)	0
Infections and infestations
Nasopharyngitis	10 (7)	0	12 (8)	0
Infection	9 (6)	3 (2)	1 (<1)	1 (<1)
Herpes simplex	5 (3)	0	7 (5)	0
Investigations
Weight decreased	11 (7)	0	5 (3)	0
Metabolism and nutrition disorders
Hyperuricemia	11 (7)	3 (2)	2 (1)	0
Respiratory, thoracic and mediastinal disorders
Cough	6 (4)	1 (<1)	7 (5)	1 (<1)
Skin and subcutaneous tissue disorders
Rash	12 (8)	4 (3)	7 (5)	3 (2)
Pruritus	8 (5)	0	2 (1)	0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with Treanda. Red blood cell transfusions were administered to 20% of patients receiving Treanda compared with 6% of patients receiving chlorambucil.

Table 2:  Incidence of Hematology Laboratory Abnormalities in Patients Who Received Treanda or Chlorambucil in the Randomized CLL Clinical Study

	Treanda N=150		Chlorambucil N=141
Laboratory Abnormality	All Grades n (%)	Grade 3/4 n (%)	All Grades n (%)	Grade 3/4 n (%)
Hemoglobin Decreased	134 (89)	20 (13)	115 (82)	12 (9)
Platelets Decreased	116 (77)	16 (11)	110 (78)	14 (10)
Leukocytes Decreased	92 (61)	42 (28)	26 (18)	4 (3)
Lymphocytes Decreased	102 (68)	70 (47)	27 (19)	6 (4)
Neutrophils Decreased	113 (75)	65 (43)	86 (61)	30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT.  Grade 3 or 4 increased bilirubin occurred in 3% of patients.  Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively.  Patients treated with Treanda may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur.

 Clinical Trials Experience in NHL

The data described below reflect exposure to Treanda in 176 patients with indolent B-cell NHL treated in two single-arm studies.  The population was 31-84 years of age, 60% male, and 40% female.  The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received Treanda at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%).  The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with Treanda by System Organ Class and Preferred Term (N=176) 

System organ class	Number (%) of patients*
Preferred term	All Grades	Grade 3/4
Total number of patients with at least 1 adverse reaction	176 (100)	94 (53)
Cardiac Disorders
Tachycardia	13 (7)	0
Gastrointestinal disorders
Nausea	132 (75)	7 (4)
Vomiting	71 (40)	5 (3)
Diarrhea	65 (37)	6 (3)
Constipation	51 (29)	1 (<1)
Stomatitis	27 (15)	1 (<1)
Abdominal pain	22 (13)	2 (1)
Dyspepsia	20 (11)	0
Gastroesophageal reflux disease	18 (10)	0
Dry mouth	15 (9)	1 (<1)
Abdominal pain upper	8 (5)	0
Abdominal distension	8 (5)	0
General disorders and administration site conditions
Fatigue	101 (57)	19 (11)
Pyrexia	59 (34)	3 (2)
Chills	24 (14)	0
Edema peripheral	23 (13)	1 (<1)
Asthenia	19 (11)	4 (2)
Chest pain	11 (6)	1 (<1)
Infusion site pain	11 (6)	0
Pain	10 (6)	0
Catheter site pain	8 (5)	0
Infections and infestations
Herpes zoster	18 (10)	5 (3)
Upper respiratory tract infection	18 (10)	0
Urinary tract infection	17 (10)	4 (2)
Sinusitis	15 (9)	0
Pneumonia	14 (8)	9 (5)
Febrile Neutropenia	11 (6)	11 (6)
Oral Candidiasis	11 (6)	2 (1)
Nasopharyngitis	11 (6)	0
Investigations
Weight decreased	31 (18)	3 (2)
Metabolism and nutrition disorders
Anorexia	40 (23)	3 (2)
Dehydration	24 (14)	8 (5)
Decreased appetite	22 (13)	1 (<1)
Hypokalemia	15 (9)	9 (5)
Musculoskeletal and connective tissue disorders
Back pain	25 (14)	5 (3)
Arthralgia	11 (6)	0
Pain in extremity	8 (5)	2 (1)
Bone pain	8 (5)	0
Nervous system disorders
Headache	36 (21)	0
Dizziness	25 (14)	0
Dysgeusia	13 (7)	0
Psychiatric disorders
Insomnia	23 (13)	0
Anxiety	14 (8)	1 (<1)
Depression	10 (6)	0
Respiratory, thoracic and mediastinal disorders
Cough	38 (22)	1 (<1)
Dyspnea	28 (16)	3 (2)
Pharyngolaryngeal pain	14 (8)	1 (<1)
Wheezing	8 (5)	0
Nasal congestion	8 (5)	0
Skin and subcutaneous tissue disorders
Rash	28 (16)	1 (<1)
Pruritus	11 (6)	0
Dry skin	9 (5)	0
Night sweats	9 (5)	0
Hyperhidrosis	8 (5)	0
Vascular disorders
Hypotension	10 (6)	2 (1)
*Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4.  Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4,  in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving Treanda.  The most common serious adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia.  Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome.

Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions [see Warnings and Precautions(5)]. Adverse reactions occurring less frequently but possibly related to Treanda treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Treanda.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling.

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Hematologic side effects including neutropenia (28%), thrombocytopenia (23%), anemia (19%), leukopenia (18%), lymphopenia (7%), and tumor lysis syndrome have been reported.

Laboratory abnormalities have included decreased lymphocytes (up to 99%), decreased leukocytes (up to 94%). decreased hemoglobin (up to 89%), decreased platelets (up to 86%), and decreased neutrophils (up to 86%).

Tumor lysis syndrome associated with bendamustine treatment has been reported in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of bendamustine and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine therapy. However, there may be an increased risk of severe skin toxicity when bendamustine and allopurinol are administered concomitantly.

Red blood cell transfusions were administered to 20% of patients receiving bendamustine.

Gastrointestinal

Gastrointestinal side effects including nausea (up to 75%), vomiting (up to 40%), diarrhea (up to 37%) constipation (29%), stomatitis (15%), abdominal pain (13%), dyspepsia (11%), gastroesophageal reflux disease (10%), dry mouth (9%), upper abdominal pain (5%), and abdominal distension (5%) have been reported.

General

General side effects including fatigue (up to 57%), pyrexia (up to 34%), chills (up to 14%), peripheral edema (13%), asthenia (up to 11%), and chest pain (6%) have been reported.

Metabolic

Metabolic side effects including anorexia (23%), dehydration (14%), decreased appetite (13%), hypokalemia (9%), and hyperuricemia (7%) have been reported.

Respiratory

Respiratory side effects including cough (up to 22%), dyspnea (16%), upper respiratory tract infection (10%), sinusitis (9%), pneumonia (8%), pharyngolaryngeal pain (8%), nasopharyngitis (7%), wheezing (5%), nasal congestion (5%), and cough (4%) have been reported.

Nervous system

Nervous system side effects including headache (21%), dizziness (14%), and dysgeusia (7%) have been reported.

Dermatologic

Dermatologic side effects including rash (up to 16%) pruritus (up to 6%), dry skin (5%), night sweats (5%), hyperhidrosis (5%), toxic skin reactions, and bullous exanthema have been reported. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) some fatal, have also been reported.

Some skin reactions have occurred when bendamustine was given in combination with other anticancer agents, so the precise relationship to bendamustine is uncertain.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are severe or progressive, bendamustine should be withheld or discontinued.

Musculoskeletal

Musculoskeletal side effects including back pain (14%), arthralgia (6%), pain in extremity (5%), and bone pain (5%) have been reported.

Psychiatric

Psychiatric side effects including insomnia (13%), anxiety (8%), and depression (6%) have been reported.

Other

Other side effects including herpes zoster (10%), decreased weight (7%), febrile neutropenia (6%), oral candidiasis (6%), infection (6%), and herpes simplex (3%) have been reported.

Renal

Renal side effects including urinary tract infection (10%) have been reported.

Cardiovascular

Cardiovascular side effects including tachycardia (7%) and hypotension (6%) have been reported.

Local

There have been postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasation, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis both during and after administration.

Local side effects including infusion site pain (6%), catheter site pain (5%), extravasations, phlebitis, pruritus, irritation, pain, and swelling have been reported.

Immunologic

Immunologic side effects including hypersensitivity (5%) have been reported.

Hypersensitivity

Hypersensitivity side effects including anaphylaxis have been reported.

Oncologic

Oncologic side effects have included pre-malignant and malignant diseases that have been reported in patients who have been treated with bendamustine, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma.

The association between the oncologic side effects and bendamustine therapy has not been determined.

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