Download adverse reactions were defined by any of the

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy,
obtain CBC and platelet counts at weekly to monthly intervals and more frequently in
WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), patients who develop cytopenias. [See Adverse Reactions].
s The duration of cytopenias
SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL caused by Rituxan can extend months beyond the treatment period. ADVERSE
LEUKOENCEPHALOPATHY (PML)
REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%)
Infusion Reactions: Rituxan administration can result in serious, including observed in clinical trials of patients with NHL were infusion reactions, fever,
fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have lymphopenia, chills, infection, and asthenia. The most common adverse reactions of
occurred. Approximately 80% of fatal infusion reactions occurred in Rituxan (incidence ≥25%) observed in clinical trials of patients with CLL were: infusion
association with the first infusion. Carefully monitor patients during reactions and neutropenia. Clinical Trials Experience in Lymphoid Malignancies
infusions. Discontinue Rituxan infusion and provide medical treatment for Because clinical trials are conducted under widely varying conditions, adverse reaction
Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse rates observed in the clinical trials of a drug cannot be directly compared to rates in the
Reactions].
s Tumor Lysis Syndrome (TLS): Acute renal failure requiring clinical trials of another drug and may not reflect the rates observed in practice. The data
dialysis with instances of fatal outcome can occur in the setting of TLS described below reflect exposure to Rituxan in 2282 patients, with exposures ranging
from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and
following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan
active-controlled trials (n = 356 and n = 1926). The population included 679 patients
[see Warnings and Precautions, Adverse Reactions].
s Severe Mucocutaneous with low-grade follicular lymphoma, 927 patients with DLBCL, and 676 patients with
Reactions: Severe, including fatal, mucocutaneous reactions can occur in CLL. Most NHL patients received Rituxan as infusion of 375 mg/m2 per infusion, given as
patients receiving Rituxan [see Warnings and Precautions, Adverse a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8
Reactions].
s Progressive Multifocal Leukoencephalopathy (PML): JC virus doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375
infection resulting in PML and death can occur in patients receiving Rituxan mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with
[see Warnings and Precautions, Adverse Reactions].
s
fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6
cycles and 90% received at least 3 cycles of Rituxan-based therapy. Infusion
INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is Reactionss In the majority of patients with NHL, infusion reactions consisting of fever,
indicated for the treatment of patients with: Relapsed or refractory, low-grade or chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm,
follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first
CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of
(including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after beginning the first infusion and resolved with slowing or interruption of the Rituxan
first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous
NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. saline). The incidence of infusion reactions was highest during the first infusion (77%)
Chronic Lymphocytic Leukemia (CLL) Rituxan® (rituximab) is indicated, in and decreased with each subsequent infusion. [See Boxed Warning, Warnings and
combination with fludarabine and cyclophosphamide (FC), for the treatment of patients Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis,
with previously untreated and previously treated CD20-positive CLL. Limitations of use occurred in less than 5% of patients with NHL in the single-arm studies. The overall
Rituxan is not recommended for use in patients with severe, active infections.
incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal
WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan
including fatal, infusion reactions. Severe reactions typically occurred during the first was administered following chemotherapy for the treatment of follicular or low-grade
infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and NHL, the rate of infection was higher among patients who received Rituxan. In diffuse
sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, large B-cell lymphoma patients, viral infections occurred more frequently in those who
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, received Rituxan. Cytopenias and hypogammaglobulinemiaa In patients with NHL
ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in
patients with an antihistamine and acetaminophen prior to dosing. Institute medical 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia
management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia
reactions as needed. Depending on the severity of the infusion reaction and the required was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days).
interventions, temporarily or permanently discontinue Rituxan. Resume infusion at a A single occurrence of transient aplastic anemia (pure red cell aplasia) and two
minimum 50% reduction in rate after symptoms have resolved. Closely monitor the occurrences of hemolytic anemia following Rituxan therapy occurred during the singlefollowing patients: those with pre-existing cardiac or pulmonary conditions, those who arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in
experienced prior cardiopulmonary adverse reactions, and those with high numbers of 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14%
circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and of these patients. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1
Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Acute renal failure, occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive,
hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. [See
some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patients Clinical Studies.] Most patients received Rituxan 375 mg/m2 weekly for 4 doses.
with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden Table 1
confers a greater risk of TLS. Administer aggressive intravenous hydration and anti- Incidence of Adverse Reactions in ≥5% of Patients with Relapsed or Refractory, Lowhyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b
monitor renal function and fluid balance, and administer supportive care, including dialysis as
All Grades (%) Grade 3 and 4 (%)
All Grades (%) Grade 3 and 4 (%)
indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous Any Adverse Events
99
57
Respiratory
p
y System
y
38
4
reactions, some with fatal outcome, can occur in patients treated with Rituxan. These Bodyy as a Whole
86
10
Increased Cough
13
1
Fever
53
1
Rhinitis
12
1
reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid
Chills
33
3
Bronchospasm
8
1
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these
Infection
31
4
Dyspnea
7
1
Asthenia
26
1
Sinusitis
6
0
reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan
Headache
19
1
Metabolic and Nutritional
in patients who experience a severe mucocutaneous reaction. The safety of
Abdominal Pain
14
1
Disorders
38
3
Pain
12
1
Angioedema
11
1
readministration of Rituxan to patients with severe mucocutaneous reactions has not
Back Pain
10
1
Hyperglycemia
9
1
been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal
Throat Irritation
9
0
Peripheral Edema
8
0
5
0
LDH Increase
7
0
Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur HemeFlushing
and Lymphatic
y p
System
y
67
48
Digestive
g
System
y
37
2
in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases.
Lymphopenia
48
40
Nausea
23
1
Leukopenia
14
4
Diarrhea
10
1
The majority of patients with hematologic malignancies diagnosed with PML received
Neutropenia
14
6
Vomiting
10
1
Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell
Thrombocytopenia
12
2
Nervous System
y
32
1
Anemia
8
3
Dizziness
10
1
transplant. The patients with autoimmune diseases had prior or concurrent Skin and Appendages
Anxiety
5
1
pp
g
44
2
immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of
Night Sweats
15
1
Musculoskeletal System
y
26
3
Rash
15
1
Myalgia
10
1
their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting
Arthralgia
Pruritus
14
1
10
1
with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited
Urticaria
8
1
Cardiovascular System
y
25
3
Hypotension
10
1
to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan
Hypertension
6
1
and consider discontinuation or reduction of any concomitant chemotherapy or
a
b
immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Adverse reactions observed up to 12 months following Rituxan. Adverse reactions graded for severity
Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation by NCI-CTC criteria.
with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to
malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was 6 months after Rituxan infusion. Previously Untreated Low-Grade NHLL In Study 4,
approximately 4 months after the initiation of Rituxan and approximately one month after patients in the R-CVP arm experienced a higher incidence of infusional toxicity and
the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. neutropenia compared to patients in the CVP arm. The following adverse reactions
Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone:
infection for several months following Rituxan therapy. Discontinue Rituxan and any rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%),
concomitant chemotherapy in patients who develop viral hepatitis, and institute pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In
appropriate treatment including antiviral therapy. Insufficient data exist regarding the Study 5, the following adverse reactions were reported more frequently (≥5%) in
safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV patients receiving Rituxan following CVP compared to patients who received no further
reactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial, therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory
fungal, and new or reactivated viral infections can occur during and up to one year
neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs.
following the completion of Rituxan-based therapy. New or reactivated viral infections
10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%),
included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus,
arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only
West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and
Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm
institute appropriate anti-infective therapy. [See Adverse Reactions.] Cardiovascular
Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform compared with those who received no further therapy (4% vs. 1%). [See Clinical
Studies.]
DLBCLL In Studies 6 and 7, [see Clinical Studies]
s the following adverse reactions,
cardiac monitoring during and after all infusions of Rituxan for patients who develop
clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years
Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder
administration in patients with NHL. Renal toxicity has occurred in patients who (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed
experience tumor lysis syndrome and in patients with NHL administered concomitant safety data collection in these studies was primarily limited to Grade 3 and 4 adverse
cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity
approved treatment regimen. Monitor closely for signs of renal failure and discontinue determined that supraventricular arrhythmias or tachycardia accounted for most of
Rituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The
Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading following Grade 3 or 4 adverse reactions occurred more frequently among patients in
to death, can occur in patients receiving Rituxan in combination with chemotherapy. In the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs.
postmarketing reports, the mean time to documented gastrointestinal perforation was 6 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring
(range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and more frequently among patients receiving R-CHOP were viral infection (Study 7),
institute appropriate treatment for complaints of abdominal pain. [See Adverse neutropenia (Studies 7 and 8), and anemia (Study 8). CLLL The data below reflect
Reactions.] Immunization The safety of immunization with live viral vaccines following exposure to Rituxan in combination with fludarabine and cyclophosphamide in 676
s The age range was
Rituxan therapy has not been studied and vaccination with live virus vaccines is not patients with CLL in Study 9 or Study 10 [see Clinical Studies].
recommended. Laboratory Monitoring In patients with lymphoid malignancies, during 30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited
treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related
adverse reactions were defined by any of the following adverse events occurring during
or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting,
and dyspnea. In Study 9, the following Grade 3 and 4 adverse reactions occurred more
frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions
(9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia
(23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 10, the following Grade 3 or 4
adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated
patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile
neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%),
and hepatitis B (2% vs. <1%). Fifty-nine percent of R-FC–treated patients experienced
an infusion reaction of any severity. Immunogenicityy As with all therapeutic proteins,
there is a potential for immunogenicity. The observed incidence of antibody (including
neutralizing antibody) positivity in an assay is highly dependent on several factors
including assay sensitivity and specificity, assay methodology, sample handling, timing
of sample collection, concomitant medications, and underlying disease. For these
reasons, comparison of the incidence of antibodies to Rituxan with the incidence of
antibodies to other products may be misleading. Using an ELISA assay, anti-human antichimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or
follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective
clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is
unclear. Postmarketing Experience The following adverse reactions have been
identified during post-approval use of Rituxan in hematologic malignancies. 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. Decisions to include these reactions in labeling are typically based on one
or more of the following factors: (1) seriousness of the reaction, (2) frequency of
reporting, or (3) strength of causal connection to Rituxan. Hematologic:: prolonged
pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome
in Waldenstrom’s macroglobulinemia. Cardiac:: fatal cardiac failure. Immune/
Autoimmune Events:: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like
syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection:: viral
infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal
infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3
and 4 infections in patients with previously treated lymphoma without known HIV
infection. Neoplasia:: disease progression of Kaposi’s sarcoma. Skin:: severe mucocutaneous
reactions. Gastrointestinal:: bowel obstruction and perforation. Pulmonary:: fatal
bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG
INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. In
patients with CLL, Rituxan did not alter systemic exposure to fludarabine or
cyclophosphamide. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There
are no adequate and well-controlled studies of rituximab in pregnant women.
Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six
months can occur in infants exposed to rituximab in-utero. Rituximab was detected
postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a
serious condition that requires treatment. Rituximab should be used during pregnancy
only if the potential benefit to the mother justifies the potential risk to the fetus.
Reproduction studies in cynomolgus monkeys at maternal exposures similar to human
therapeutic exposures showed no evidence of teratogenic effects. However, B-cell
lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned
to normal levels, and immunologic function was restored within 6 months of birth.
Nursing Mothers It is not known whether Rituxan is secreted into human milk.
However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is
excreted in human milk. Published data suggest that antibodies in breast milk do not
enter the neonatal and infant circulations in substantial amounts. The unknown risks to
the infant from oral ingestion of Rituxan should be weighed against the known benefits of
breast-feeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric
patients have not been established. Geriatric Use Diffuse Large B-Cell NHLL Among
patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients
received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65
or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness
were observed between these patients and younger patients. Cardiac adverse reactions,
mostly supraventricular arrhythmias, occurred more frequently among elderly patients.
Serious pulmonary adverse reactions were also more common among the elderly,
including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s
Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell
NHL did not include sufficient numbers of patients aged 65 and over to determine
whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia
Among patients with CLL evaluated in two randomized active-controlled trials, 243 of
676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100
Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses
defined by age, there was no observed benefit from the addition of Rituxan to fludarabine
and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study
10; there was also no observed benefit from the addition of Rituxan to fludarabine and
cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical
Studies].
s Patients 70 years or older received lower dose intensity of fludarabine and
cyclophosphamide compared to younger patients, regardless of the addition of Rituxan.
In Study 9, the dose intensity of Rituxan was similar in older and younger patients,
however in Study 10 older patients received a lower dose intensity of Rituxan. The
incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC
who were 70 years or older compared to younger patients for neutropenia [44% vs. 31%
(Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia
[5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study
10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs.
14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in
human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical
trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of
Fertilityy No long-term animal studies have been performed to establish the carcinogenic
or mutagenic potential of Rituxan or to determine potential effects on fertility in males or
females. PATIENT COUNSELING INFORMATION Patients should be provided the
Rituxan Medication Guide and provided an opportunity to read prior to each treatment
session. It is important that the patient’s overall health be assessed at each visit and the
risks of Rituxan therapy and any questions resulting from the patient’s reading of the
Medication Guide be discussed. Rituxan is detectable in serum for up to six months
following completion of therapy. Individuals of childbearing potential should use effective
contraception during treatment and for 12 months after Rituxan therapy.
Revised 02/2010 (4851501)
Jointly Marketed by:
Biogen Idec Inc. 5200 Research Place San Diego, CA 92122
Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990
©2010 Biogen Idec Inc. and Genentech, Inc. 7140919 February 2010
Brief Summary
See package insert for full Prescribing Information. For further product information
and current package insert, please visit XYNTHA.com or call Wyeth Pharmaceuticals
toll-free at 1-800-934-5556.
INDICATIONS AND USAGE
Control and Prevention of Bleeding Episodes in Hemophilia A
XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated
for the control and prevention of bleeding episodes in patients with hemophilia A
(congenital factor VIII deficiency or classic hemophilia). XYNTHA does not contain
von Willebrand factor, and therefore is not indicated in patients with von Willebrand’s
disease.
Surgical Prophylaxis in Patients with Hemophilia A
XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for
surgical prophylaxis in patients with hemophilia A.
Study 2 (surgery) is an open-label, single-arm study of at least 25 evaluable PTPs with
severe or moderately severe hemophilia A (factor VIII activity in plasma [FVIII:C] ≤ 2%)
who required elective major surgery and were planned to receive XYNTHA
replacement therapy for at least 6 days post-surgery. Twenty-two subjects received at
least one dose of XYNTHA, resulting in 766 infusions [see Clinical Studies in full
Prescribing Information]. In Study 2, the most frequently reported treatmentemergent adverse reaction was pyrexia (41% of subjects). Other adverse reactions
reported in ≥ 5% of subjects were: headache (9%), nausea (9%), diarrhea (5%),
vomiting (5%) and asthenia (5%). The adverse reactions reported in either study were
considered mild or moderate in severity.
Immunogenicity
In Study 1, the incidence of FVIII inhibitors to XYNTHA was the primary safety
endpoint. Two subjects with inhibitors were observed in 89 subjects (2.2%) who
completed ≥ 50 exposure days. These results were consistent with the pre-specified
endpoint that no more than 2 inhibitors may be observed in at least 81 subjects.
CONTRAINDICATIONS—None.
In a Bayesian statistical analysis, results from this study were used to update PTP
results from a prior supporting study using XYNTHA manufactured at the initial
facility, where one de novo and two recurrent inhibitors were observed in 110
subjects, and the experience with predecessor product (1 inhibitor in 113 subjects).
This Bayesian analysis indicates that the population (true) inhibitor rate for XYNTHA,
the estimate of the 95% upper limit of the true inhibitor rate, was 4.17%.
WARNINGS AND PRECAUTIONS
DRUG INTERACTIONS—None known.
DOSAGE FORMS AND STRENGTHS
XYNTHA is supplied as a white to off-white freeze-dried powder in the following
dosages: 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU.
Anaphylaxis and Severe Hypersensitivity Reactions—Allergic type
hypersensitivity reactions are possible. Patients should be informed of the early
signs or symptoms of hypersensitivity reactions [including hives (rash with itching),
generalized urticaria, tightness of the chest, wheezing, and hypotension] and
anaphylaxis. Patients should be advised to discontinue use of the product and
contact their physicians if these symptoms occur.
Neutralizing Antibodies—The occurrence of neutralizing antibodies (inhibitors) is
well known in the treatment of patients with hemophilia A. Inhibitors have been
detected in patients receiving factor VIII-containing products. Inhibitors are common
in previously untreated patients and have been observed in previously treated
patients on factor VIII products. Patients using coagulation factor VIII products,
including XYNTHA, should be monitored for the development of factor VIII inhibitors.
If expected factor VIII activity plasma levels are not attained, or if bleeding is not
controlled with an appropriate dose, an assay should be performed to determine if
a factor VIII inhibitor is present. If detected, inhibitors should be titered in Bethesda
Units (BU).
Formation of Antibodies to Hamster Protein—XYNTHA contains trace amounts of
hamster proteins. Patients treated with this product could develop hypersensitivity to
these non-human mammalian proteins.
Monitoring: Laboratory Tests—Monitor plasma factor VIII activity levels by the
one-stage clotting assay to confirm that adequate factor VIII levels have been
achieved and are maintained, when clinically indicated [see Dosage and
Administration in full Prescribing Information].
It is recommended that individual factor VIII values for recovery and, if clinically
indicated, other pharmacokinetic characteristics be used to guide dosing and
administration.
Monitor for development of factor VIII inhibitors. Perform assay to determine if factor
VIII inhibitor is present when expected factor VIII activity plasma levels are not
attained, or when bleeding is not controlled with the expected dose of XYNTHA.
Use Bethesda Units (BU) to titer inhibitors.
ADVERSE REACTIONS
Clinical Trials Experience—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 clinical practice.
Study 1 is a pivotal phase 3 (safety and efficacy) study in which previously treated
patients (PTPs) with hemophilia A received XYNTHA for routine prophylaxis and
on-demand treatment, 94 subjects received at least one dose of XYNTHA, resulting
in a total of 6,775 infusions [see Clinical Studies in full Prescribing Information]. In
Study 1, the most frequently reported treatment-emergent adverse reaction was
headache (24% of subjects). Other adverse reactions reported in ≥ 5% of subjects
were: nausea (6%), diarrhea (5%), asthenia (5%) and pyrexia (5%). No subject
developed anti-CHO or anti-TN8.2 antibodies.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C - Animal reproduction studies have not been conducted with
XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free. It is also not
known whether XYNTHA can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. XYNTHA should be given to a pregnant
woman only if clinically indicated.
Labor and Delivery—There is no information available on the effect of factor VIII
replacement therapy on labor and delivery. XYNTHA should be used only if clinically
indicated.
Nursing Mothers—It is not known whether this drug is excreted into human milk.
Because many drugs are excreted into human milk, caution should be exercised if
XYNTHA is administered to nursing mothers. XYNTHA should be given to nursing
mothers only if clinically indicated.
Pediatric Use—Pharmacokinetics of XYNTHA was studied in 7 previously treated
patients 12-16 years of age. Pharmacokinetic parameters in these patients were
similar to those obtained for adults after a dose of 50 IU/kg. For these 7 patients, the
mean (± SD) Cmax and AUC∞ were 1.09 ± 0.21 IU/mL and 11.5 ± 5.2 IU·h/mL,
respectively. The mean clearance and plasma half-life values were 5.23 ± 2.36 mL/h/
kg and 8.03 ± 2.44 hours (range 3.52 – 10.6 hours), respectively. The mean K-value
and in vivo recoveries were 2.18 ± 0.41 IU/dL per IU/kg and 112 ± 23%, respectively.
Geriatric Use—Clinical studies of XYNTHA did not include subjects aged 65 and
over. In general, dose selection for an elderly patient should be individualized.
STORAGE AND HANDLING
Product as Packaged for Sale - Store XYNTHA under refrigeration at a temperature of
2° to 8°C (36° to 46°F) for up to 36 months from the date of manufacture until the
expiration date stated on the label. XYNTHA may also be stored at room temperature
not to exceed 25°C (77°F) for up to 3 months. The starting date at room temperature
storage should be clearly recorded in the space provided on the outer carton. At the
end of the 3-month period, the product must not be put back into the refrigerator, but
must be used immediately or discarded. Do not use XYNTHA after the expiration
date stated on the label or after 3 months when stored at room temperature,
whichever is earlier. Do not freeze, to prevent damage to the XYNTHA prefilled
syringe. During storage, avoid prolonged exposure of XYNTHA to light.
Product After Reconstitution - Administer XYNTHA within 3 hours after reconstitution
or after removal of the grey rubber tip cap from the XYNTHA prefilled syringe. The
reconstituted solution may be stored at room temperature prior to administration.
This brief summary is based on the Xyntha® [Antihemophilic Factor (Recombinant),
Plasma/Albumin-Free] Prescribing Information W10528C004, revised 04/08, and
W10547C002, revised 08/10.
Manufactured by Wyeth Pharmaceuticals Inc.
270327-01 Copyright © 2010 Pfizer Inc.
Marketed by Pfizer Inc.
All rights reserved.
September 2010
Available soon in 3000 IU.
Additional dosing options in 2011.
Visit PfizerHemophilia.com to learn more.
COMING SOON—for your hemophilia A patients
The only one
that’s all-in-one
Next-generation purification now in an innovative
reconstitution-ready device.
Zero transfer step. More convenience. For the first time ever, factor VIII
and diluent come preloaded in a single device for your patients.
Manufactured by Wyeth Pharmaceuticals Inc.
272199-01 © 2010 Pfizer Inc. All rights reserved.
Marketed by Pfizer Inc.
Printed in USA/September 2010
DILUENT
XYNTHA
For illustration of size only. See prescribing
information for reconstitution instructions.
Indication for XYNTHA
XYNTHA Antihemophilic Factor (Recombinant),
Plasma/Albumin-Free is indicated for the control and
prevention of bleeding episodes in patients with
hemophilia A (congenital factor VIII deficiency or classic
hemophilia) and for surgical prophylaxis in patients
with hemophilia A.
XYNTHA does not contain von Willebrand factor and,
therefore, is not indicated in von Willebrand’s disease.
Important Safety Information for XYNTHA
• Anaphylaxis and severe hypersensitivity reactions are
possible. Should such reactions occur, treatment with
the product should be discontinued, and appropriate
treatment should be administered.
• Patients using coagulation factor VIII products
should be monitored for inhibitors, which have been
detected in patients receiving factor VIII-containing
products, including XYNTHA.
• The most common adverse reaction in study 1 (safety
and efficacy study) is headache (24% of subjects)
and in study 2 (surgery study) is fever (41% of
subjects). The most common adverse reactions
(≥5% of subjects) in clinical studies were headache,
fever, nausea, diarrhea, vomiting, and weakness.
• Patients may develop hypersensitivity to hamster
protein, which is present in trace amounts in XYNTHA.
• XYNTHA is an injectable medicine administered by
intravenous (IV) infusion.
Please see brief summary of Prescribing Information.
Multiple abnormalities can lead to dysregulated
JAK signaling
Janus kinase (JAK) pathway signaling is essential for normal hematopoiesis and immune function.1 JAK pathway
dysregulation, however, leads to the development of 3 Philadelphia chromosome–negative myeloproliferative
neoplasms (MPNs): myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET).2
Excessive JAK1 and JAK2 signaling overstimulates signal transducers and activators of transcription (STATs),
which activate cell proliferation, survival of malignant cells and increased cytokine production. Manifestations
of overactive signaling in MPNs include splenomegaly and constitutional symptoms.3-8
Multiple abnormalities may cause JAK pathway dysregulation, including4:
tJAK2 mutations — leading to constitutive activation of JAK2 and increased cell proliferation
and survival of malignant cells4
–JAK2 V617F is the most common mutation and results in a constitutively active form of the JAK2 protein4
tI ncreased JAK1 signaling — associated with increased cell proliferation and constitutional symptoms9
tExcess cytokines — leading to overactivation of the JAK signaling pathway and constitutional symptoms4-6
tMPL mutations — leading to constitutive JAK2 signaling and increased megakaryocyte production10
JAK dysregulation is thought to occur in most MPN patients, independent of JAK2V617F mutational status.11
In fact, many MF and ET patients do not have a known mutation.9,11 MF patients also have elevated levels of
activated JAK1, which suggests that dysregulated JAK1 and JAK2 signaling is central to the pathogenesis of
MF.2,9,12 Regardless of the mechanism of JAK dysregulation, further research on JAK1 and JAK2 mechanisms is
providing new insight into their role in MPNs.
Visit www.MPNConnect.org/JAKs
To learn more about the dysregulated JAK pathway, visit MPNConnect.org/JAKs today and download the
JAK Signaling in MPNs video. Other benefits include free educational resources such as an MPN presentation
and brochure.
Excess myeloid and
erythroid cell proliferation
as a result of dysregulated
JAK-STAT signaling
Nucleus
DNA
Excess STAT activation leads
to transcription of genes
related to proliferation, cell
survival and differentiation
Dysregulated JAK signaling—
a common link among MF, PV and ET
MPL may be
mutated and
constitutively
active
JAK2 may be
mutated and
constitutively
active
JAK2
STATs
Excess cytokines
may continuously
activate receptors
JAK1
Excess JAK
activity leads
to overactivation
of STATs
Increased JAK1
signaling
References: 1. Pesu M et al. Immunol Rev. 2008;223:132-142. 2. Levine RL et al. Nat Rev Cancer. 2007;7:673-683. 3. Verstovsek S et al. N Engl J Med. 2010;363:1117-1127. 4. Verstovsek S. Hematology Am
Soc Hematol Educ Program. 2009:636-642. 5. Holle N et al. Neth J Med. 2010;68:293-298. 6. Panteli KE et al. Br J Haematol. 2005;130:709-715. 7. Cervantes F et al. Haematologica. 2009;94:1484-1488.
8. Hsieh P-P et al. Mod Pathol. 2007;20:929-935. 9. Quintás-Cardama A et al. Blood. 2010;115:3109-3117. 10. Pikman Y et al. PLoS Med. 2006;3:1140-1151. 11. Plo I et al. Clin Lymphoma Myeloma. 2009;9(Suppl
3):S329-S339. 12. Delhommeau F et al. Int J Hematol. 2010;91:165-173.
©2010 Incyte Corporation.
All rights reserved.
10/10.
INCY-00435A.
AVASTIN® (bevacizumab)
Table 1
NCI-CTC Grade 3−4 Adverse Events in Study 1
(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)
NCI-CTC Grade 3-4 Events
#PEZBTB8IPMF
Asthenia
Abdominal Pain
Pain
Cardiovascular
Hypertension
Deep Vein Thrombosis
Intra-Abdominal Thrombosis
Syncope
Digestive
Diarrhea
Constipation
Hemic/Lymphatic
Leukopenia
Neutropeniaa
a
Arm 1
*'-1MBDFCP
(n = 396)
74%
Arm 2
*'-"WBTUJO
(n = 392)
87%
7%
5%
5%
10%
8%
8%
2%
5%
1%
1%
12%
9%
3%
3%
25%
2%
34%
4%
31%
14%
37%
21%
Central laboratories were collected on Days 1 and 21 of each cycle.
AVASTIN® (bevacizumab)
AVASTIN® (bevacizumab)
patients. All patients in Study 6 received prior anthracycline and taxane therapy in the
adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher
incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the
capecitabine alone arm are presented in Table 3.
Table 3
NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher
Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)
may be influenced by several factors, including sample handling, timing of
TBNQMFDPMMFDUJPODPODPNJUBOUNFEJDBUJPOTBOEVOEFSMZJOHEJTFBTF'PSUIFTF
reasons, comparison of the incidence of antibodies to Avastin with the
incidence of antibodies to other products may be misleading.
6.3 Postmarketing Experience
The following adverse reactions have been identified during post-approval
use of Avastin. 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.
Body as a Whole: Polyserositis
Cardiovascular: Pulmonary hypertension, RPLS
Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration
Hemic and lymphatic: Pancytopenia
Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)
Respiratory: Nasal septum perforation, dysphonia
#PEZBTB8IPMF
Asthenia
Headache
Pain
Cardiovascular
Hypertension
Digestive
Stomatitis
Metabolic/Nutrition
8FJHIUMPTT
Musculoskeletal
Myalgia
Respiratory
Dyspnea
Epistaxis
Skin/Appendages
Exfoliative dermatitis
Urogenital
Albuminuria
Capecitabine
(n = 215)
Capecitabine
+ Avastin
(n = 229)
47%
13%
25%
57%
33%
31%
2%
24%
19%
25%
8%
14%
18%
27%
Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.
1%
16%
Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in
QBUJFOUT SFDFJWJOH CPMVT*'- QMVT "WBTUJO BT DPNQBSFE UP UIF CPMVT*'- QMVT
75%
84%
placebo arm are presented in Table 2. Grade 1–4 adverse events were collected
for the first approximately 100 patients in each of the three treatment arms who
7%
22%
XFSFFOSPMMFEVOUJMFOSPMMNFOUJO"SN'6-7"WBTUJO
XBTEJTDPOUJOVFE
Table 2
Glioblastoma
NCI-CTC Grade 1-4 Adverse Events in Study 1
All adverse events were collected in 163 patients enrolled in Study 7 who either
0DDVSSJOHBU)JHIFS*ODJEFODF<ö>JO*'-"WBTUJOWT*'-
received Avastin alone or Avastin plus irinotecan. All patients received prior
radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every
Arm 1
Arm 2
Arm 3
*'-1MBDFCP *'-"WBTUJO '6-7"WBTUJO 2 weeks alone or in combination with irinotecan. Avastin was discontinued due
to adverse events in 4.8% of patients treated with Avastin alone.
(n = 98)
(n = 102)
(n = 109)
In patients receiving Avastin alone (N=84), the most frequently reported adverse
#PEZBTB8IPMF
events of any grade were infection (55%), fatigue (45%), headache (37%),
Pain
55%
61%
62%
hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence
Abdominal Pain
55%
61%
50%
of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%),
Headache
19%
26%
26%
hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related
Cardiovascular
to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.
Hypertension
14%
23%
34%
Hypotension
7%
15%
7%
In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the
Deep Vein Thrombosis
3%
9%
6%
incidence of Avastin-related adverse events (Grade 1–4) were bleeding/
Digestive
hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension
Vomiting
47%
52%
47%
(32%), venous thromboembolic event (8%), arterial thromboembolic event
Anorexia
30%
43%
35%
(6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal
Constipation
29%
40%
29%
perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these
Stomatitis
18%
32%
30%
163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%),
Dyspepsia
15%
24%
17%
hypertension (5%), venous thromboembolic event (7%), arterial
GI Hemorrhage
6%
24%
19%
thromboembolic event (3%), wound-healing complications (3%), proteinuria
8FJHIU-PTT
(1%), and gastrointestinal perforation (2%).
Dry Mouth
2%
7%
4%
Metastatic Renal Cell Carcinoma (mRCC)
Colitis
1%
6%
1%
All grade adverse events were collected in Study 9. Grade 3–5 adverse
Hemic/Lymphatic
events occurring at a higher incidence (≥ 2%) in 337 patients receiving
Thrombocytopenia
0%
5%
5%
JOUFSGFSPO BMGB *'/α) plus Avastin compared to 304 patients receiving
Nervous
*'/α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%),
Dizziness
20%
26%
19%
proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension
Respiratory
and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis,
Upper Respiratory Infection 39%
47%
40%
small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage,
Epistaxis
10%
35%
32%
gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal
Dyspnea
15%
26%
25%
hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).
Voice Alteration
2%
9%
6%
Skin/Appendages
Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving
Alopecia
26%
32%
6%
*'/αQMVT"WBTUJODPNQBSFEUPUIF*'/α plus placebo arm are presented in Table 4.
Skin Ulcer
1%
6%
6%
Table 4
Special Senses
NCI-CTC Grades 1−5 Adverse Events in Study 9
Taste Disorder
9%
14%
21%
0DDVSJOHBU)JHIFS*ODJEFODF<ö>JO*'/α"WBTUJOWT*'/α + Placebo)
Urogenital
Proteinuria
24%
36%
36%
4ZTUFN0SHBO$MBTT
*'/α 1MBDFCP *'/α + Avastin
Preferred term*
(n = 304)
(n = 337)
Avastin in Combination with FOLFOX4 in Second-line mCRC
Gastrointestinal disorders
Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to
Diarrhea
16%
21%
treatment were collected in Study 2. The most frequent adverse events (selected
General disorders and administration
Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at
site
conditions
BIJHIFSJODJEFODFö
JOQBUJFOUTSFDFJWJOH'0-'09QMVT"WBTUJODPNQBSFEUP
'BUJHVF
QBUJFOUTSFDFJWJOH'0-'09BMPOFXFSFGBUJHVFWT
EJBSSIFBWT
Investigations
13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%),
8FJHIUEFDSFBTFE
dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%),
Metabolism and nutrition disorders
hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and
Anorexia
31%
36%
headache (3% vs. 0%). These data are likely to under-estimate the true adverse event
Musculoskeletal and connective
rates due to the reporting mechanisms used in Study 2.
tissue disorders
Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Myalgia
14%
19%
Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were
Back pain
6%
12%
collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse
Nervous system disorders
events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin
Headache
16%
24%
compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue
Renal and urinary disorders
(16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%),
Proteinuria
3%
20%
venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/
Respiratory, thoracic and
pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%),
mediastinal disorders
hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).
Epistaxis
4%
27%
Dysphonia
0%
5%
Metastatic Breast Cancer (MBC)
Vascular disorders
Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were
Hypertension
9%
28%
collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%)
in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving *Adverse events were encoded using MedDRA, Version 10.1.
paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), The following adverse events were reported at a 5-fold greater incidence in the
fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. *'/αQMVT"WBTUJOBSNDPNQBSFEUP*'/α alone and not represented in Table 4:
3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0);
(4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1);
(3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0);
0.3%) and proteinuria (3% vs. 0%).
gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).
Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute 6.2 Immunogenicity
incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.
As with all therapeutic proteins, there is a potential for immunogenicity. The incidence
'BUBMBEWFSTFSFBDUJPOTPDDVSSFEJO
PGQBUJFOUTXIPSFDFJWFEQBDMJUBYFM of antibody development in patients receiving Avastin has not been adequately
plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial determined because the assay sensitivity was inadequate to reliably detect lower
infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).
titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from
Avastin is not approved for use in combination with capecitabine or for use in second approximately 500 patients treated with Avastin, primarily in combination with
or third line treatment of MBC. The data below are presented to provide information on chemotherapy. High titer human anti-Avastin antibodies were not detected.
the overall safety profile of Avastin in women with breast cancer since Study 6 is the Immunogenicity data are highly dependent on the sensitivity and specificity of
only randomized, controlled study in which all adverse events were collected for all the assay. Additionally, the observed incidence of antibody positivity in an assay
7 DRUG INTERACTIONS
A drug interaction study was performed in which irinotecan was
BENJOJTUFSFEBTQBSUPGUIF'0-'*3*SFHJNFOXJUIPSXJUIPVU"WBTUJO5IF
results demonstrated no significant effect of bevacizumab on the
pharmacokinetics of irinotecan or its active metabolite SN38.
In a randomized study in 99 patients with NSCLC, based on limited data, there did
not appear to be a difference in the mean exposure of either carboplatin or
paclitaxel when each was administered alone or in combination with Avastin.
However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had
substantially lower paclitaxel exposure after four cycles of treatment (at Day 63)
than those at Day 0, while patients receiving paclitaxel/carboplatin without
Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.
In Study 9, there was no difference in the mean exposure of interferon alfa
administered in combination with Avastin when compared to interferon alfa alone.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no studies of bevacizumab in pregnant women. Reproduction
studies in rabbits treated with approximately 1 to 12 times the recommended
human dose of bevacizumab resulted in teratogenicity, including an
increased incidence of specific gross and skeletal fetal alterations. Adverse
fetal outcomes were observed at all doses tested. Other observed effects
included decreases in maternal and fetal body weights and an increased
number of fetal resorptions. [See Nonclinical Toxicology (13.3).]
Human IgG is known to cross the placental barrier; therefore, bevacizumab may be
transmitted from the mother to the developing fetus, and has the potential to cause
fetal harm when administered to pregnant women. Because of the observed
teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab
should be used during pregnancy only if the potential benefit to the pregnant woman
justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether Avastin is secreted in human milk, but human IgG is
excreted in human milk. Published data suggest that breast milk antibodies do not
enter the neonatal and infant circulation in substantial amounts. Because many
drugs are secreted in human milk and because of the potential for serious adverse
reactions in nursing infants from bevacizumab, a decision should be made whether
to discontinue nursing or discontinue drug, taking into account the half-life of the
bevacizumab (approximately 20 days [range 11–50 days]) and the importance of
the drug to the mother. [See Clinical Pharmacology (12.3).]
8.4 Pediatric Use
The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric
patients have not been established.
Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia
following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose
(based on mg/kg and exposure). The incidence and severity of physeal dysplasia
were dose-related and were partially reversible upon cessation of treatment.
8.5 Geriatric Use
In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients
aged ≥65 years as compared to younger patients were asthenia, sepsis, deep
thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart
failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia,
and hyponatremia. The effect of Avastin on overall survival was similar in elderly
patients as compared to younger patients.
*O 4UVEZ QBUJFOUT BHFE ö ZFBST SFDFJWJOH"WBTUJO QMVT '0-'09 IBE B
greater relative risk as compared to younger patients for the following adverse
events: nausea, emesis, ileus, and fatigue.
In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin
had a greater relative risk for proteinuria as compared to younger patients. [See
Warnings and Precautions (5.8).]
In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine
whether the overall adverse events profile was different in the elderly as compared
with younger patients.
Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all
adverse events were captured, 212 (29%) were age 65 or older and 43 (6%)
were age 75 or older. Adverse events of any severity that occurred at a higher
incidence in the elderly as compared to younger patients, in addition to those
described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis,
increased cough, and voice alteration.
In an exploratory, pooled analysis of 1745 patients treated in five randomized,
controlled studies, there were 618 (35%) patients aged ≥65 years and 1127
patients <65 years of age. The overall incidence of arterial thromboembolic events was
increased in all patients receiving Avastin with chemotherapy as compared to those
receiving chemotherapy alone, regardless of age. However, the increase in arterial
thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs.
2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and
Precautions (5.5).]
10 OVERDOSAGE
The highest dose tested in humans (20 mg/kg IV) was associated with headache
in nine of 16 patients and with severe headache in three of 16 patients.
Manufactured by:
Genentech, Inc.
%/"8BZ
4PVUI4BO'SBODJTDP$"
94080-4990
7453214
4835706
*OJUJBM64"QQSPWBM'FCSVBSZ
$PEF3FWJTJPO%BUF+VMZ
© 2009 Genentech, Inc
www.IDanemia.com
A treatment strategy for anemia
Check and address iron deficiency first.
• In chronic renal insufficiency patients, iron deficiency is a common
yet undertreated cause of anemia.1
• Identifying—and treating—iron deficiency anemia before initiating
any other treatment is the optimal strategy in these patients.
Reference: 1. Agarwal AK. Practical approach to the diagnosis and treatment of anemia associated
with CKD in elderly. J Am Med Dir Assoc. 2006;7:S7-S12.
AMAG Pharmaceuticals and the AMAG logo are trademarks of AMAG Pharmaceuticals, Inc.
©2010 AMAG Pharmaceuticals, Inc. DS-0088-0710
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New York, NY
February 4-5
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February 4-5
www.hematology.org/highlights
* Simultaneous translation into Spanish available in Dallas, TX.
** Simultaneous translation into Chinese available in Beijing, China.
+ Simultaneous translation into Spanish and Portuguese available in Punta del Este, Uruguay.
NOW ENROLLING PATIENTS
WITH POLYCYTHEMIA VERA
Randomized Study of Efficacy and Safety
in Polycythemia Vera with JAK Inhibitor
INCB018424 Versus Best Available Care
A PHASE III STUDY INVESTIGATING INCB018424 —
AN ORAL JAK1 AND JAK2 INHIBITOR
The RESPONSE trial is a global, randomized, open-label, multicenter, phase III
study of the oral JAK1 and JAK2 inhibitor INCB018424 in patients with
polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea.
RESPONSE is sponsored by both Incyte and Novartis.
Primary endpoint
Composite endpoint of phlebotomy independence and spleen volume
reduction at Week 32
Secondary endpoints
s Proportion of patients who maintain the primary endpoint response
for ≥48 weeks
s Proportion of patients achieving complete hematologic remission
at 32 weeks
Patients
with PV
(N≈300)
INCB018424 (oral) 10 mg bid
Randomized
1:1
Best available therapy as selected by physician*†
The treatment duration for the study will be 80 weeks.
Physician’s choice: hydroxyurea, interferon, anagrelide, pipobroman, IMIDs, or observation.
Patients randomized to best available therapy may be eligible to cross over to
INCB018424.
*
†
If you have a PV patient who is at least 18 years of age and
who meets the following criteria, he/she may be eligible for
enrollment in RESPONSE:
s Resistant to or intolerant of hydroxyurea
s Phlebotomy requirement due to inadequate hematocrit control
at least once every 3 months
s Palpable splenomegaly ≥5 cm below the costal margin
s Elevated white blood cell and/or platelet counts
To enroll a US patient in RESPONSE or to find out more about this trial,
please call 1-877-4-PV- TRIAL or visit www.responsetrial.com.
© 2010 Incyte Corporation.
09/10.
INCY-00450.
INCB018424 is an investigational compound. Its efficacy
and safety have not been established.There is no guarantee
that this compound will become commercially available.
blood
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BIOMED, and BIOSIS.
NOW IN THE TREATMENT OF
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
DRIVING BETTER
OUTCOMES
RITUXAN+FC improved median PFS in
first-line and previously treated CLL1,2
In relapsed/refractory* CLL
2.1-year follow-up
In first-line CLL
1.7-year follow-up
39.8 months
R-FC
vs
26.7 months
31.5 months
R-FC
FC
8.3
vs
21.7 months
FC
5.0
month
month
improvement
in median
improvement
in median
PFS
PFS
CLL8 TRIAL (N=817)
REACH TRIAL (N=552)
RITUXAN-NAIVE PATIENTS
In the CLL8 trial2
RITUXAN+FC more than doubled CR in
first-line CLL compared with FC alone
(36% vs 17%; p<0.0001)
In the REACH trial 2
Patients who responded to RITUXAN+FC
(n=167) maintained their responses for
nearly 2 years longer (48 months vs
27 months; p=0.0294) than those
treated with FC alone (n=134)
Treatment considerations
These trials were not designed or powered to detect a significant difference in PFS by age category. However, exploratory
analyses defined by age suggest no observed benefit with the addition of RITUXAN to FC chemotherapy in previously
untreated CLL patients 70 years of age or older and in previously treated CLL patients 65 years of age or older.1
*In the REACH trial, patients had received 1 prior therapy. Patients who had previously received RITUXAN or both fludarabine and cyclophosphamide, either sequentially
or in combination, were excluded from the trial, as were fludarabine-refractory patients; alkylator-refractory patients were permitted.2
R=RITUXAN; FC=fludarabine and cyclophosphamide; PFS=progression-free survival; CR=complete response.
Indication
RITUXAN® (Rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of
patients with previously untreated and previously treated CD20-positive CLL.
RITUXAN is not recommended for use in patients with severe, active infections.
BOXED WARNINGS
RITUXAN administration can result in serious, including fatal, adverse reactions. These include infusion reactions,
tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML)
Warnings and Precautions
RITUXAN can also result in serious, including fatal, adverse reactions. These include hepatitis B reactivation with
fulminant hepatitis and hepatic failure resulting in death; other infections, including bacterial, fungal, new or reactivated
viral infections; cardiovascular events; severe, including fatal, renal toxicity; and abdominal pain, bowel obstruction
and perforation, in some cases leading to death
Additional Important Safety Information
The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were
infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse
reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia
In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions
compared with younger CLL patients who received the same treatment
For additional safety information, please see following page for brief summary of full prescribing
information, including BOXED WARNINGS.
Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.
References: 1. RITUXAN® (Rituximab) full prescribing information,
Genentech, Inc., 2010. 2. Data on file, Genentech, Inc.
©2010 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved.
10021501
May 2010