EVOMELA^TM (melphalan) for Injection

Important Safety Information

Contraindications

• History of serious allergic reaction to melphalan.

Warnings and Precautions

• Bone Marrow Suppression: For patients receiving EVOMELA as part of a conditioning regimen, myeloablation occurs in all patients. Do not begin the conditioning regimen if a stem cell product is not available for rescue. Monitor complete blood counts, provide supportive care for infections, anemia and thrombocytopenia until there is adequate hematopoietic recovery.
  For patients receiving EVOMELA as palliative treatment, if the bone marrow has been compromised by prior irradiation, prior chemotherapy or is recovering from chemotherapy, the risk of severe myelosuppression with EVOMELA is increased. Perform periodic complete blood counts during the course of treatment with EVOMELA. Provide supportive care for infections, bleeding, and symptomatic anemia.
• Gastrointestinal Toxicity: For patients receiving EVOMELA as part of a conditioning regimen, nausea, vomiting, mucositis, and diarrhea may occur in over 50% of patients. Use prophylactic antiemetic medication. Provide supportive care for nausea, vomiting, diarrhea, and mucositis. The frequency of grade 3/4 mucositis in clinical studies was 13%. Provide nutritional support and analgesics for patients with severe mucositis.
  For patients receiving EVOMELA as palliative treatment, nausea and vomiting, diarrhea, and oral ulceration may occur. Use prophylactic antiemetics. Provide supportive care for nausea, vomiting, diarrhea and mucositis.
• Hepatotoxicity: Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported after treatment with melphalan. Hepatic veno-occlusive disease has also been reported. Monitor liver chemistries.
• Hypersensitivity: Acute hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received an intravenous formulation of melphalan. Symptoms may include urticaria, pruritus, edema, and skin rashes and, in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. Discontinue treatment with EVOMELA for serious hypersensitivity reactions.
• Secondary Malignancies: Secondary malignancies such as myeloproliferative syndrome or acute leukemia have been reported in multiple myeloma patients treated with melphalan-containing chemotherapy regimens. The potential benefit of EVOMELA therapy must be considered against the possible risk of the induction of a secondary malignancy.
• Embryo-Fetal Toxicity: EVOMELA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during and after treatment with EVOMELA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, advise the patient of potential risk to the fetus.
• Infertility: Melphalan-based chemotherapy regimens have been reported to cause suppression of ovarian function in premenopausal women, resulting in persistent amenorrhea in approximately 9% of patients. Reversible or irreversible testicular suppression has also been reported.

Adverse Events

• The most common adverse reactions observed in at least 50% of patients with multiple myeloma treated with EVOMELA were neutrophil count decreased (100%), white blood cell count decreased (100%), lymphocyte count decreased (98%), platelet count decreased (98%), diarrhea (93%), nausea (90%), fatigue (77%), hypokalemia (74%), anemia (66%), and vomiting (64%).
• For myeloablative conditioning in multiple myeloma patients undergoing ASCT, twelve (20%) patients experienced a treatment emergent serious adverse reaction while on study. The most common serious adverse reactions ( >1 patient, 1.6%) were pyrexia, hematochezia, febrile neutropenia, and renal failure. Treatment-related serious adverse reactions reported in >1 patient were pyrexia (n=2, 3%), febrile neutropenia (n=2, 3%), and hematochezia (n=2, 3%).
• In a randomized clinical trial studying the palliative treatment of patients with multiple myeloma, severe myelotoxicity (WBC ≤1,000 and/or platelets ≤25,000) was more common in the IV melphalan arm (28%) than in the oral melphalan arm (11%).
• In this randomized study, the rate of severe leukopenia in the IV arm in the patients with BUN over 30 mg/dL decreased from 50% (8/16) to 11% (3/28) after 50% reduction in IV melphalan dose. In addition, the incidence of drug-related death in the IV arm decreased from 10% (8/77) to 3% (3/108) after this dose reduction. This compares to an overall 1% (1/100) incidence of drug-related death in the oral melphalan arm.

Drug Interactions

• No formal drug interaction studies have been conducted. When nalidixic acid and IV melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients.

Use in Specific Populations

• Lactation: It is not known whether melphalan is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from melphalan, breastfeeding is not recommended during treatment with EVOMELA.
• Patients with Renal Impairment: For Palliative Treatment, consider dose reduction for patients with renal impairment receiving EVOMELA. Bone marrow suppression has been observed in patients with BUN levels ≥30 mg/dL. A 50% reduction in the IV melphalan dose decreased the incidence of severe bone marrow suppression in the latter portion of this study.

Please click here to see full Prescribing Information, including BOXED WARNINGS, for EVOMELA

ISI-PP-EVO-00-0067

FOLOTYN^® (pralatrexate injection)

Important Safety Information

Warnings and Precautions

• FOLOTYN may suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Monitor blood counts and omit and/or reduce dose for hematologic toxicities.
• Mucositis may occur. Monitor at least weekly. If ≥Grade 2 mucositis is observed, omit and/or reduce dose. Patients should be instructed to take folic acid and receive vitamin B₁₂ to potentially reduce treatment-related hematological toxicity and mucositis.
• Dermatologic reactions, including fatal reactions, have occurred and may be progressive and increase in severity with further treatment. Patients with dermatologic reactions should be monitored closely, and omit, and/or reduce dose or discontinue FOLOTYN.
• Tumor lysis syndrome may occur. Monitor patients and treat promptly.
• FOLOTYN can cause hepatic toxicity and liver function test abnormalities. Monitor liver function tests and if abnormalities are =Grade 3, omit until recovery then reduce dose or discontinue FOLOTYN as required.
• Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly. Avoid FOLOTYN use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk.
• FOLOTYN can cause fetal harm. Women should avoid becoming pregnant while being treated with FOLOTYN and pregnant women should be informed of the potential harm to the fetus.

Adverse Reactions

• The most common adverse reactions were mucositis (70%), thrombocytopenia (41%), nausea (40%), and fatigue (36%). The most common serious adverse events were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia.

Drug Interactions

• Co-administration with probenecid or other drugs that may affect relevant transporter systems (eg, NSAIDs), requires close monitoring for signs of systemic toxicity.

Use in Specific Populations

• Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother.
• The FOLOTYN dose is reduced for patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m²). For patients with mild to moderate renal impairment, dose reduction is not necessary.

Please click here to see full Prescribing Information for FOLOTYN.

KHAPZORY^TM (levoleucovorin) for Injection

Important Safety Information

Contraindications

• KHAPZORY is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid, or folinic acid.

Warnings and Precautions

• Increased gastrointestinal toxicities with fluorouracil: Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly d,l-leucovorin and fluorouracil. Do not initiate or continue therapy with KHAPZORY and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until it has resolved as rapid deterioration leading to death can occur.
• Drug interaction with trimethoprim-sulfamethoxazole: Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection increased treatment failure and morbidity.

Adverse Reactions

• The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue were stomatitis (38%) and vomiting (38%).
• The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer were stomatitis (72%), diarrhea (70%), and nausea (62%).

Drug Interactions

• Leucovorin products increase the toxicity of fluorouracil.

Use in Specific Populations

• Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information.

Please click here to see full Prescribing Information for KHAPZORY

ISI-PP-KAP-00-0001

ZEVALIN^® (ibritumomab tiuxetan) injection for intravenous use

Important Safety Information

Risk of Developing Myelodysplastic Syndrome, Leukemia and Other Malignancies:

The radiation dose resulting from therapeutic exposure to Y-90 radiolabeled ZEVALIN may result in secondary malignancies.

Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients with relapsed or refractory NHL enrolled in clinical studies and 1.5% (8/535) of patients included in the expanded-access trial, with median follow-up of 6.5 and 4.4 years, respectively. Among the 19 reported cases, the median time to diagnosis of MDS or AML was 1.9 years following treatment with the ZEVALIN therapeutic regimen; however, the cumulative incidence continues to increase.

Among 204 patients receiving Y-90-ZEVALIN following first-line chemotherapy, 26 (12.7%) patients in the ZEVALIN arm developed a second primary malignancy compared to 14 (6.8%) of patients in the control arm. Seven patients (3.4%, 7/204) were diagnosed with MDS/AML after receiving ZEVALIN, compared to one patient (0.5%, 1/205) in the control arm, with a median follow-up of 7.3 years. Deaths due to second primary malignancy included 8 (3.9%) patients in the ZEVALIN arm compared to 3 (1.5%) patients in the control arm. Deaths due to MDS/AML included five (2.5%) patients in the ZEVALIN arm compared to no patients in the control arm.

Monitor patients for hematological toxicity including development of MDS or AML.

Extravasation: Monitor for extravasation and terminate infusion if it occurs. Resume infusion in another limb.

Immunization: Do not administer live viral vaccines to patients who recently received ZEVALIN.

Laboratory Monitoring: Obtain complete blood counts (CBC) and platelet counts at least weekly.

Radionuclide Precautions: During and after radiolabeling ZEVALIN with Y-90, minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures.

Embryo-fetal Toxicity: May cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception during treatment and for a minimum of 12 months after the last dose of ZEVALIN treatment.

Impairment of Fertility: There is a potential risk that the ZEVALIN therapeutic regimen could cause toxic effects on the male and female gonads. Effective contraceptive methods should be used during treatment and for up to 12 months following the ZEVALIN therapeutic regimen.

Lactation: Patients should be advised to discontinue breastfeeding during and for 6 months after the last dose of ZEVALIN treatment.

Adverse Reactions:

The most common adverse reactions of ZEVALIN are cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and pyrexia. Common adverse reactions (≥10%) in clinical trials were: cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and pyrexia. The most serious adverse reactions of ZEVALIN are prolonged and severe cytopenias (thrombocytopenia, anemia, lymphopenia, neutropenia) and secondary malignancies.

When administered following first-line chemotherapy, grade 3/4 adverse reactions of ZEVALIN include prolonged and severe cytopenias (thrombocytopenia [51%], neutropenia [41%], leukopenia [36%], lymphopenia [18%], and anemia [5%]) and secondary malignancies (12.7%). Cytopenias were more severe and more prolonged among eleven (5%) patients who received ZEVALIN after first-line fludarabine or a fludarabine-containing chemotherapy regimen as compared to patients receiving non–fludarabine-containing regimens. Grade 3/4 infections occurred in 8% of ZEVALIN-treated patients and in 2% of controls and included neutropenic sepsis (1%), bronchitis, catheter sepsis, diverticulitis, herpes zoster, influenza, lower respiratory tract infection, sinusitis, and upper respiratory tract infection.

Grade 3/4 adverse reactions of ZEVALIN in relapsed or refractory NHL patients include prolonged and severe cytopenias (thrombocytopenia [63%], neutropenia [60%], anemia [17%], and ecchymosis [<1%]) and secondary malignancies (5.2%). Serious infections occurred in 3% of patients (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection). Life-threatening infections were reported in 2% of patients (sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent-associated cholangitis).

Please click here to see the full Prescribing Information, including BOXED WARNINGS, for ZEVALIN. Because the ZEVALIN therapeutic regimen includes the use of rituximab, please also consult Prescribing Information for rituximab.

ISI-0154-079503

BELEODAQ (belinostat) for Injection

Important Safety Information

Warnings and Precautions

• BELEODAQ can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary.
• Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with BELEODAQ. Do not administer BELEODAQ to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections.
• BELEODAQ can cause fatal hepatotoxicity and liver function test abnormalities. Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue BELEODAQ based on the severity of the hepatic toxicity.
• Tumor lysis syndrome has occurred in BELEODAQ-treated patients in the clinical trial of patients with relapsed or refractory PTCL. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions.
• Nausea, vomiting and diarrhea occur with BELEODAQ and may require the use of antiemetic and antidiarrheal medications.
• BELEODAQ can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy while receiving BELEODAQ. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus.

Adverse Reactions

• The most common adverse reactions observed in the trial in patients with relapsed or refractory PTCL treated with BELEODAQ were nausea (42%), fatigue (37%), pyrexia (35%), anemia (32%), and vomiting (29%).
• Sixty-one patients (47.3%) experienced serious adverse reactions while taking BELEODAQ or within 30 days after their last dose of BELEODAQ.

Drug Interactions

• BELEODAQ is primarily metabolized by UGT1A1. Avoid concomitant administration of BELEODAQ with strong inhibitors of UGT1A1.

Use in Specific Populations

• It is not known whether belinostat is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from BELEODAQ, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother.

Please click here to see Full Prescribing Information for BELEODAQ.

ISI-0154-096200

MARQIBO^® (vinCRIStine sulfate LIPOSOME injection)

Important Safety Information

Contraindications

• MARQIBO is contraindicated in patients with demyelinating conditions, including Charcot-Marie-Tooth syndrome; in patients with hypersensitivity to vincristine sulfate or any of the other components of MARQIBO; and for intrathecal administration

Warnings and Precautions

• MARQIBO is for intravenous use only—fatal if given by other routes. Intrathecal use is fatal.
• Extravasation causes tissue injury. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures
• Sensory and motor neuropathy are common and cumulative. Monitor patients for peripheral motor and sensory, central and autonomic neuropathy and reduce, interrupt, or discontinue dosing. Patients with preexisting severe neuropathy should be treated with MARQIBO only after careful risk-benefit assessment
• Neutropenia, thrombocytopenia, or anemia may occur. Monitor blood counts prior to each dose. Consider dose modification or reduction as well as supportive care measures if Grade 3 or 4 myelosuppression develops
• Anticipate, monitor for, and manage tumor lysis syndrome
• A prophylactic bowel regimen should be instituted with MARQIBO to prevent constipation, bowel obstruction, and/or paralytic ileus
• Severe fatigue can occur requiring dose delay, reduction, or discontinuation of MARQIBO
• Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Monitor liver function and modify or interrupt dosing for hepatic toxicity
• MARQIBO can cause fetal harm. Advise women of potential risk to fetus

Adverse Events

• The most commonly reported adverse reactions (incidence >30%) in clinical studies include constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%)
• A total of 75.9% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%)
• Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia-related (7%), and tumor lysis syndrome (2%)
• Deaths occurred in 23% of patients in study 1. The nonleukemia-related causes of death were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multisystem organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1)
  Drug Interactions
• MARQIBO is expected to interact with drugs known to interact with nonliposomal vincristine sulfate, therefore the concomitant use of strong CYP3A inhibitors or the use of potent P-glycoprotein inhibitors or inducers should be avoided

Use in Specific Populations

• The safety and effectiveness of MARQIBO in pediatric patients have not been established
• It is not known whether MARQIBO is excreted in human milk

Please click here to see the full Prescribing Information, including BOXED WARNINGS, for MARQIBO.

ISI-0154-079702

FUSILEV^® (levoleucovorin) for Injection

Important Safety Information

Contraindications

• FUSILEV is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

Warnings and Precautions

• Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute
• FUSILEV enhances the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the toxicities observed in patients treated with the combination of FUSILEV and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination.
• Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study.

Adverse Reactions

• Allergic reactions were reported in patients receiving FUSILEV.
• The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving FUSILEV in combination with 5-FU were diarrhea, nausea and stomatitis.
• Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving FUSILEV as rescue after high dose methotrexate therapy.

Drug Interactions

• FUSILEV may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients.

FUSILEV adverse event profile

Adverse reactions (≥ 10% in either arm) in patients with advanced metastatic colorectal cancer

¹ Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness

Please see the FUSILEV (levoleucovorin) for injection full prescribing information for complete safety information.

ISI-0154-079600

Download the Full Prescribing Information