Avastin® (bevacizumab)
BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION
Boxed WARNINGS
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Gastrointestinal (GI) perforation |
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Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls |
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The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies |
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Discontinue Avastin in patients with GI perforation |
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Surgery and wound healing complications |
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The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients |
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Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined |
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Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention |
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Hemorrhage |
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Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade >3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%
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Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (>1/2 tsp of red blood)
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Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) |
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Additional serious adverse events
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Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included |
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Non-GI fistula formation (<0.3%) |
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Arterial thromboembolic events (grade >3, 2.6%) |
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Proteinuria (nephrotic syndrome, <1%) |
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Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included |
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Hypertension (grade 3–4, 5%–18%) |
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Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) |
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Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients |
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Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin |
Most common adverse events
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Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were |
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— Epistaxis
— Headache
— Hypertension
— Rhinitis |
— Proteinuria
— Taste alteration
— Dry skin
— Rectal hemorrhage |
— Lacrimation disorder
— Back pain
— Exfoliative dermatitis |
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Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions |
Pregnancy warning
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Avastin may impair fertility |
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Based on animal data, Avastin may cause fetal harm |
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Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin |
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For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother
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In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a >2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)
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In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade >3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection
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In GBM patients receiving Avastin alone or Avastin plus irinotecan,* the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage
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In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a >2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
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In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a >2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
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In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (>2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)
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*Avastin is not approved for use in combination with irinotecan.
Please see full Prescribing Information, including BOXED WARNINGS, for additional important safety information.
Erivedge™ (vismodegib)
BOXED WARNING AND ADDITIONAL IMPORTANT SAFETY INFORMATION
Embryo-Fetal Death and Severe Birth Defects
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Erivedge capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Erivedge is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations |
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Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen |
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Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning |
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Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555 |
Female patients
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Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of Erivedge |
Male patients
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Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with Erivedge and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib |
Blood Donation
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Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge |
Nursing Mothers
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It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erivedge, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother |
Adverse Reactions
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The most common adverse reactions (>10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia |
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Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of fertility impairment is unknown. In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge |
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Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) |
Please see the full Prescribing Information for a complete discussion of the risks associated with Erivedge, including the BOXED WARNING and the Medication Guide.
Herceptin® (trastuzumab)
BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION
Cardiomyopathy
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Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant trial, one patient who developed CHF died of cardiomyopathy |
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Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death |
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Herceptin can also cause asymptomatic decline in LVEF |
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Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function |
Cardiac Monitoring
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Evaluate cardiac function prior to and during treatment. For adjuvant therapy, also evaluate cardiac function after completion of Herceptin |
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Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan |
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Monitor frequently for decreased left ventricular function during and after Herceptin treatment |
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Monitor more frequently if Herceptin is withheld for significant left ventricular cardiac dysfunction |
Infusion Reactions
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Herceptin administration can result in serious and fatal infusion reactions |
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Symptoms usually occur during or within 24 hours of Herceptin administration |
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Interrupt Herceptin infusion for dyspnea or clinically significant hypotension |
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Monitor patients until symptoms completely resolve |
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Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Strongly consider permanent discontinuation in all patients with severe infusion reactions |
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Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion include nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia |
Embryo-Fetal Toxicity
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Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death |
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Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide counseling to women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin |
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Advise nursing mothers treated with Herceptin to discontinue nursing or discontinue Herceptin, taking into account the importance of the drug to the mother |
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Encourage women who are exposed to Herceptin during pregnancy to enroll in MotHER–the Herceptin Pregnancy Registry |
Pulmonary Toxicity
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Herceptin administration can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions |
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Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity |
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Discontinue Herceptin in patients experiencing pulmonary toxicity |
Exacerbation of Chemotherapy-Induced Neutropenia
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In randomized, controlled clinical trials, the per-patient incidences of NCI CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not
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HER2 Testing
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Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized |
Most Common Adverse Reactions
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The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia |
Boxed WARNINGS and Additional Important Safety Information
Cardiomyopathy
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Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy |
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Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death |
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Herceptin can also cause asymptomatic decline in LVEF |
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Discontinue Herceptin treatment in patients receiving adjuvant breast cancer therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function |
Cardiac Monitoring
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Evaluate cardiac function prior to and during treatment |
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Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan |
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Monitor frequently for decreased left ventricular function during and after Herceptin treatment |
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Monitor more frequently if Herceptin is withheld for significant left ventricular cardiac dysfunction |
Infusion Reactions
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Herceptin administration can result in serious and fatal infusion reactions |
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Symptoms usually occur during or within 24 hours of Herceptin administration |
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Interrupt Herceptin infusion for dyspnea or clinically significant hypotension |
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Monitor patients until symptoms completely resolve |
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Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Strongly consider permanent discontinuation in all patients with severe infusion reactions |
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Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion include nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia |
Embryo-Fetal Toxicity
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Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death |
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Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide counseling to women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin |
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Advise nursing mothers treated with Herceptin to discontinue nursing or discontinue Herceptin, taking into account the importance of the drug to the mother |
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Encourage women who are exposed to Herceptin during pregnancy to enroll in MotHER–the Herceptin Pregnancy Registry |
Pulmonary Toxicity
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Herceptin administration can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions |
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Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity |
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Discontinue Herceptin in patients experiencing pulmonary toxicity |
Exacerbation of Chemotherapy-Induced Neutropenia
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In randomized, controlled clinical trials, the per-patient incidences of NCI CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not |
HER2 Testing
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Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized |
Most Common Adverse Reactions
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The most common adverse reactions associated with Herceptin were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia |
Boxed WARNINGS
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Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy |
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Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of Herceptin. Discontinue Herceptin for cardiomyopathy |
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Herceptin can result in serious and fatal infusion reactions and pulmonary toxicity. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome |
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Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death |
Important Safety Information
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Exacerbation of chemotherapy-induced neutropenia has also occurred |
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| Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy |
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The most common adverse reactions associated with Herceptin use in breast cancer were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia |
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The most common adverse reactions associated with Herceptin use in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia |
Please see full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.
Rituxan (Rituximab)
BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION
Long Safety—NHL and CLL
WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
Infusion Reactions: RITUXAN administration can result in serious, including fatal, infusion reactions. Deaths within 24 hours of RITUXAN infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue RITUXAN infusion and provide medical treatment for Grade 3 or 4 infusion reactions.
Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) with RITUXAN monotherapy.
Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving RITUXAN.
Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving RITUXAN.
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WARNINGS AND PRECAUTIONS
Infusion Reactions
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RITUXAN can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion, with time to onset of 30 to 120 minutes |
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RITUXAN-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death |
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Premedicate patients with an antihistamine and acetaminophen prior to dosing. Depending on the severity of the infusion reaction and the required interventions, slow the infusion rate, interrupt the infusion, or permanently discontinue RITUXAN |
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Closely monitor patients with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (>25,000/mm3) |
Tumor Lysis Syndrome (TLS)
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Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12 to 24 hours after the first infusion of RITUXAN. A high number of circulating malignant cells (>25,000/mm3) or high tumor burden confers a greater risk of TLS |
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Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated |
Severe Mucocutaneous Reactions
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Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with RITUXAN. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. Discontinue RITUXAN in patients who experience a severe mucocutaneous reaction |
Progressive Multifocal Leukoencephalopathy (PML)
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JC virus infection resulting in PML and death can occur in RITUXAN-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received RITUXAN in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy |
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Most cases of PML were diagnosed within 12 months of their last infusion of RITUXAN. Consider the diagnosis of PML in any patient presenting with new onset neurologic manifestations. Discontinue RITUXAN and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML |
Hepatitis B Virus (HBV) Reactivation
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HBV reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients treated with RITUXAN. The median time to the diagnosis of hepatitis among patients with hematologic malignancies was approximately 4 months after the initiation of RITUXAN and approximately 1 month after the last dose |
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Screen patients at high risk of HBV infection before initiation of RITUXAN. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following RITUXAN therapy. Discontinue RITUXAN and any concomitant chemotherapy in patients who develop viral hepatitis and institute appropriate treatment, including antiviral therapy |
Infections
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Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of RITUXAN-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after RITUXAN exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue RITUXAN for serious infections and institute appropriate anti-infective therapy |
Cardiovascular
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Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform 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 |
Renal
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Severe, including fatal, renal toxicity can occur after RITUXAN administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RITUXAN in patients with a rising serum creatinine or oliguria |
Bowel Obstruction and Perforation
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Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain |
Immunization
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The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied and vaccination with live virus vaccines is not recommended |
Laboratory Monitoring
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In patients with lymphoid malignancies, during treatment with RITUXAN monotherapy, obtain complete blood counts (CBC) and platelet 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 patients who develop cytopenias. The duration of cytopenias caused by RITUXAN can extend months beyond the treatment period |
Pregnancy and Nursing Mothers
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There are no adequate and well-controlled studies of RITUXAN in pregnant women. In the postmarketing experience, limited data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to RITUXAN in utero. RITUXAN was detected postnatally in the serum of infants exposed in utero. RITUXAN should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Caution should be exercised when RITUXAN is administered to a nursing woman |
Geriatric Use
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Clinical trials in CLL evaluating RITUXAN in combination with fludarabine and cyclophosphamide (R-FC) showed that the incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared with younger patients for neutropenia, febrile neutropenia, anemia, thrombocytopenia, pancytopenia, and infections |
Additional Important Safety Information
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The most common adverse reactions of RITUXAN (incidence >25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. These infusion reactions typically resolved with slowing or interruption of the infusion and with supportive care. The most frequent Grade 3 or 4 adverse reactions observed in NHL were cytopenias, including lymphopenia |
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The most common adverse reactions of RITUXAN (incidence >25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Infusion-related adverse reactions occurring during or within 24 hours of the start of infusion included nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The Grade 3 or 4 adverse reactions observed more frequently with R-FC compared with FC alone were neutropenia, leukopenia, febrile neutropenia, thrombocytopenia, infusion reactions, pancytopenia, hypotension, and hepatitis B |
For additional safety information, please see the full prescribing information, including BOXED WARNINGS and Medication Guide.
Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.
Tarceva® (erlotinib)
IMPORTANT SAFETY INFORMATION
Important Safety Information
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There have been reports of serious interstitial lung disease (ILD)-like events, including fatalities, in patients receiving Tarceva. In the advanced NSCLC studies, the incidence of serious ILD-like events in the Tarceva-treated patients vs placebo-treated patients was 0.7% vs 0% in the maintenance study and 0.8% for both groups in the 2nd/3rd line study. In the advanced pancreatic cancer study, the incidence was 2.5% in the Tarceva/gemcitabine group vs 0.4% in the placebo/gemcitabine arm. The overall incidence of ILD-like events in approximately 32,000 Tarceva-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately 1.1%. |
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Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, ILD, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating Tarceva therapy. |
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Tarceva should be interrupted for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, and if ILD is diagnosed, Tarceva should be discontinued and appropriate treatment instituted as needed. |
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Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment, while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions, including advanced age), Tarceva therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration. |
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Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of Tarceva, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. Tarceva dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values. |
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Treatment with Tarceva should be used with extra caution in patients with total bilirubin >3 x ULN. Patients with hepatic impairment (total bilirubin >ULN or Child-Pugh A, B, and C) should be closely monitored during therapy with Tarceva. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe, such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range. |
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Gastrointestinal perforation (including fatalities) has been reported in patients receiving Tarceva. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane-based chemotherapy or who have prior history of peptic ulceration or diverticular disease are at increased risk. Permanently discontinue Tarceva in patients who develop gastrointestinal perforation. |
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Bullous, blistering, and exfoliative skin conditions have been reported, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal. Interrupt or discontinue Tarceva treatment if the patient develops severe bullous, blistering, or exfoliating conditions. |
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In the pancreatic cancer trial, myocardial infarction/ischemia occurred in 2.3% of patients (6 patients) in the Tarceva/gemcitabine group vs 1.2% (3 patients) in the placebo/gemcitabine group. One patient in the Tarceva/gemcitabine group and one patient in the placebo/gemcitabine group died due to myocardial infarction. |
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In the pancreatic cancer trial, 2.3% of patients (6 patients) in the Tarceva/gemcitabine group developed cerebrovascular accidents vs no cerebrovascular accidents in the placebo/gemcitabine group. One of the cerebrovascular accidents was hemorrhagic and fatal. |
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In the pancreatic cancer trial, 0.8% of patients (2 patients) developed microangiopathic hemolytic anemia with thrombocytopenia in the Tarceva/gemcitabine group vs no cases in the placebo/gemcitabine group. |
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Corneal perforation and ulceration have been reported during use of Tarceva. Other ocular disorders, including abnormal eyelash growth, keratoconjunctivitis sicca, or keratitis, have been observed with Tarceva treatment and are known risk factors for corneal ulceration/perforation. Interrupt or discontinue Tarceva therapy if patients present with acute/worsening ocular disorders such as eye pain. |
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International Normalized Ratio (INR) elevations and bleeding events, including gastrointestinal and non-gastrointestinal bleeding (including fatalities), have been associated with concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR. Cases of gastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID administration. |
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Tarceva is pregnancy category D. When receiving Tarceva, women of childbearing potential should be advised to avoid pregnancy and pregnant women apprised of the potential hazard to a fetus. Adequate contraception methods should be used during therapy, and for at least 2 weeks after completing therapy. Because of the potential for serious adverse reactions in nursing infants from Tarceva, a decision should be made whether to discontinue nursing or discontinue the drug. |
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Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Caution should be used during co-treatment with Tarceva and ketoconazole or other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, and grapefruit or grapefruit juice. |
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The CYP3A4 inducer rifampicin has been shown to decrease erlotinib AUC; thus, alternate treatments lacking CYP3A4-inducing activity are strongly recommended. In the absence of an alternative treatment, Tarceva dose modification should be considered. If the Tarceva dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other CYP3A4 inducers such as, but not limited to, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St. John’s wort. |
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Patients should be advised to stop smoking while taking Tarceva, as cigarette smoking has been shown to reduce erlotinib AUC. However, if patients continue to smoke, a cautious increase in the dose of Tarceva, not to exceed 300 mg, may be considered while monitoring the patient’s safety. If the Tarceva dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking. |
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Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. The concomitant use of proton pump inhibitors such as omeprazole with Tarceva should be avoided if possible. If patients need to be treated with an H2-receptor antagonist such as ranitidine, it should be used in a staggered manner. Tarceva must be taken once a day, 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist. Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the Tarceva dose should be separated by several hours, if an antacid is necessary. |
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The combination of Tarceva and a statin may increase the potential for statin-induced myopathy, including rhabdomyolysis, which was observed rarely. The mechanism of this interaction is not clear. |
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The most common adverse reactions in patients with advanced NSCLC receiving single-agent Tarceva 150 mg were rash and diarrhea. In the 2nd/3rd line study, severe rash and diarrhea (9% and 6% NCI-CTC Grades 3/4, respectively) were reported. Rash and diarrhea each resulted in dose reductions (6% and 1%, respectively) and discontinuation in 1% of Tarceva-treated patients. In the maintenance study, severe rash and diarrhea (6.0% and 1.8% NCI-CTC Grades 3/4, respectively) were reported. Rash and diarrhea resulted in dose reductions or interruption (5.1% and 2.8%, respectively) and discontinuation (1.2% and 0.5%, respectively) of Tarceva-treated patients. |
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The most common adverse reactions in patients with advanced pancreatic cancer receiving Tarceva 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia, and diarrhea. Severe rash and diarrhea (5% and 5% NCI-CTC, Grades 3/4, respectively) were reported. Rash and diarrhea each resulted in dose reductions in 2% of patients and discontinuation in up to 1% of patients receiving Tarceva/gemcitabine. |
For additional Important Safety Information, please see accompanying full prescribing information.
XELODA® (capecitabine)
INDICATIONS, BOXED WARNING AND ADDITIONAL IMPORTANT SAFETY INFORMATION
Indications
XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent XELODA in the adjuvant treatment of Dukes’ C colon cancer.
XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
XELODA monotherapy is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents. Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.
XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
Boxed WARNING and Additional Important Safety Information
Warfarin Interaction - Coagulopathy
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Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. |
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A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial. |
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Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. |
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Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR have been observed in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy, and in a few cases within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. |
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Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy. |
Contraindications
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XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components or to 5-fluorouracil. |
Dihydropyrimidine Dehydrogenase (DPD) Deficiency
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XELODA is contraindicated in patients with known DPD deficiency. Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia, and neurotoxicity) associated with 5 fluorouracil has been attributed to a deficiency of DPD activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded. |
Renal Insufficiency
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XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]).
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Patients with moderate renal impairment at baseline require dose reduction. Patients with mild or moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in the Dosage and Administration section of the XELODA prescribing information.
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Warnings and Precautions
Diarrhea
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XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated.
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If grade 2, 3, or 4 diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased. Standard antidiarrheal treatments are recommended. |
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Necrotizing enterocolitis (typhlitis) has been reported. |
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Cardiotoxicity
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The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease. |
Pregnancy Category D
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XELODA may cause fetal harm when given to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with XELODA. Because of the potential for serious adverse reactions in nursing infants from capecitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. |
Hand-and-Foot Syndrome
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Hand-and-Foot Syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. |
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Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving XELODA monotherapy in the metastatic setting. |
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If grade 2 or 3 hand-and-foot syndrome occurs, administration of XELODA should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of XELODA should be decreased. |
Hyperbilirubinemia
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If drug-related grade 3 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia decreases to < 3.0 x ULN. |
Hematologic
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Patients with baseline neutrophil counts <1.5 x 109/L and/or thrombocyte counts <100 x 109/L should not be treated with XELODA. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with XELODA should be interrupted. |
Geriatric Patients
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Patients >80 years old may experience a greater incidence of grade 3 or 4 adverse events. |
Hepatic Insufficiency
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Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when XELODA is administered. The effect of severe hepatic dysfunction on the disposition of XELODA is not known. |
Drug Interactions
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Use of XELODA in combination with irinotecan has not been adequately studied. |
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The level of phenytoin should be carefully monitored in patients taking XELODA and the dose of phenytoin may need to be reduced. Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels. |
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The concentration of 5 fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. |
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Other than warfarin, no formal drug-drug interaction studies between XELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA is coadministered with CYP2C9 substrates. |
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Food was shown to reduce both the rate of and extent of absorption of capecitabine. |
Please see full Prescribing Information, including BOXED WARNINGS, for additional important safety information.
ZELBORAF® (vemurafenib)
INDICATIONS AND IMPORTANT SAFETY INFORMATION
Indication and Usage
ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.
ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.
Important Safety Information
Cutaneous squamous cell carcinoma (cuSCC)
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Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7-8 weeks. Potential risk factors included age >65 years, prior skin cancer, and chronic sun exposure. |
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All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. |
Hypersensitivity
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Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension.
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ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity reaction.
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Dermatologic Reactions
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Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study.
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In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. |
QT prolongation
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Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes. |
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Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval. ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. |
Liver laboratory abnormalities
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Liver laboratory abnormalities have occurred with ZELBORAF. |
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Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation.
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Photosensitivity
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Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials.
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While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF >30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. |
Ophthalmologic Reactions
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In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.
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Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis.
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Additionally, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study.
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New Primary Malignant Melanoma
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Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study.
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Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC].
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Use in Pregnancy: Pregnancy Category D
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ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. |
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If ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus. |
BRAF Testing
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Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. |
Most common adverse events
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The most common adverse reactions of any grade (>30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.
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The most common (>5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event. |
Please see full Prescribing Information, including Medication Guide, for additional Important Safety Information.
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