Oncology and Infusion Clinics

Indications and Important Risk Information 

Indications

• Malignant Diseases: Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs.
• Cyclophosphamide is indicated for the treatment of: Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. Multiple myeloma. Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia (cyclophosphamide given during remission is effective in prolonging its duration). Mycosis fungoides (advanced disease). Neuroblastoma (disseminated disease). Adenocarcinoma of the ovary. Retinoblastoma. Carcinoma of the breast.
• Minimal Change Nephrotic Syndrome in Pediatric Patients:
• Cyclophosphamide is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatrics patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.
• Limitations of Use:
• The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

IMPORTANT RISK INFORMATION

• Cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to it. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur.
• Cyclophosphamide is contraindicated in patients with urinary outflow obstruction.
• Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated. Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm³ and platelets<50,000/mm³.
• Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infection.
• Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy. Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide. The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents. Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.
• Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide. Monitor patients for signs and symptoms of pulmonary toxicity.
• Cyclophosphamide is genotoxic. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens.
• Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens.
• Cyclophosphamide can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment and for up to 1 year after completion of therapy.
• Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause irreversible sterility in some patients. Advise patients on the potential risks for infertility.
• Cyclophosphamide may interfere with normal wound healing.
• Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.
• Common Adverse Reactions include: Neutropenia, also, fever without documented infection has been reported in neutropenic patients. Nausea and vomiting, anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur.

Please see accompanying full Prescribing Information for Cyclophosphamide for Injection, USP.

100 mg/4 mL (25 mg/mL) Multiple-Dose Vial

Indications and Important Risk Information

Indications

Bendamustine Hydrochloride Injection is an alkylating drug indicated for treatment of adult patients with:

• Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established.
• Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. 

Important Risk Information

Contraindications

Bendamustine Hydrochloride Injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, alcohol, or monothioglycerol.

Warnings and Precautions

• Myelosuppression: Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. Bendamustine Hydrochloride Injection causes myelosuppression. Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109 /L and the platelet count should be ≥ 75 x 109 /L.
• Infections: Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride. Patients with myelosuppression following treatment are more susceptible to infections; advise patients to contact a physician immediately if they have symptoms or signs of infection. Patients are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate measures for infection and infection reactivation prior to administration.
• Progressive Multifocal Leukoencephalopathy (PML): PML, including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold Bendamustine Hydrochloride Injection treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
• Anaphylaxis and Infusion Reactions: Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue Bendamustine Hydrochloride Injection for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate.
• Tumor Lysis Syndrome: Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly.
• Skin Reactions: Fatal and serious skin reactions have been reported with bendamustine hydrochloride treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), bullous exanthema, and rash]. Events occurred when bendamustine hydrochloride was given as a single agent and in combination with other anticancer agents or allopurinol. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue Bendamustine Hydrochloride Injection.
• Hepatotoxicity: Fatal and serious cases of liver injury have been reported with Bendamustine Hydrochloride Injection. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during therapy.
• Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride. Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment.
• Extravasation Injury: Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration.
• Embryo-Fetal Toxicity: Based on findings from animal reproduction studies and the drug’s mechanism of action, Bendamustine Hydrochloride Injection can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose.
• Adverse Reactions:
  • Adverse reactions (frequency >5%) during infusion and within 24 hours post-infusion are nausea and fatigue.
  • Most common adverse reactions (≥15%) for CLL are anemia, thrombocytopenia, neutropenia, lymphopenia, leukopenia, hyperbilirubinemia, pyrexia, nausea, vomiting.
  • Most common adverse reactions (≥15%) for NHL are lymphopenia, leukopenia, anemia neutropenia, thrombocytopenia, nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.
• Drug Interactions:
  • CYP1A2 Inhibitors: The coadministration with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with Bendamustine hydrochloride Injection. Consider alternative therapies that are not CYP1A2 inhibitors during treatment.
  • CYP1A2 Inducers: The coadministration with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of Bendamustine Hydrochloride Injection. Consider alternative therapies that are not CYP1A2 inducers during treatment.
• Use in Specific Populations:
  • Infertility: Based on findings from clinical studies and animal studies, Bendamustine Hydrochloride Injection may impair male fertility.
  • Renal Impairment: Do not use Bendamustine Hydrochloride Injection in patients with creatinine clearance (CLcr) < 30 mL/min.
  • Hepatic Impairment: Do not use Bendamustine Hydrochloride Injection in patients with AST or ALT 2.5-10 × upper limit of normal (ULN) and total bilirubin 1.5-3 × ULN, or total bilirubin > 3 × ULN.

Please see accompanying full Prescribing Information for Bendamustine Hydrochloride Injection.

Important Risk Information 

INDICATIONS

DOXIL® liposomal infusion is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

DOXIL® liposomal infusion is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

DOXIL® liposomal infusion, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

IMPORTANT RISK INFORMATION

WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS

DOXIL liposomal infusion can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m² to 550 mg/m². Assess left ventricular cardiac function prior to initiation of DOXIL liposomal infusion and during and after treatment. See additional information on Cardiomyopathy in Warnings and Precautions below.

Serious, life-threatening, and fatal infusion-related reactions can occur with DOXIL liposomal infusion. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold DOXIL liposomal infusion for infusion-related reactions and resume at a reduced rate.Discontinue DOXIL liposomal infusion for serious or life-threatening infusion-related reactions.
See additional information on Cardiomyopathy in Warnings and Precautions below.

Dosage and Administration - Important Use Information

Do not substitute DOXIL liposomal infusion for other doxorubicin hydrochloride products. Do not administer as an undiluted suspension or as an intravenous bolus.

Contraindications

DOXIL liposomal infusion is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride.

Warnings and Precautions

Cardiomyopathy: Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin hydrochloride is generally proportional to the cumulative exposure. Administer DOXIL liposomal infusion to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

Infusion-Related Reactions: Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with DOXIL liposomal infusion: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension.

Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of DOXIL liposomal infusion.

Discontinue DOXIL liposomal infusion for serious or life-threatening infusion-related reactions.

Hand-Foot Syndrome (HFS) may occur.

• HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier.
• Delay DOXIL liposomal infusion for the first episode of Grade 2 or greater HFS
• Dose Modification or discontinue DOXIL liposomal infusion if HFS is severe and debilitating

Secondary Oral Neoplasms: Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure to DOXIL liposomal infusion. These malignancies were diagnosed both during treatment with DOXIL liposomal infusion and up to 6 years after the last dose. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

Embryo-Fetal Toxicity: Based on animal data, DOXIL liposomal infusion can cause fetal harm when administered to a pregnant woman; avoid the use of DOXIL liposomal infusion during the 1st trimester. Advise pregnant women of the potential risk to a fetus.

Females and males of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL liposomal infusion.

Use in Specific Populations

Lactation: because of the potential for serious adverse reactions in breastfed infants from DOXIL liposomal infusion, discontinue breastfeeding during treatment with DOXIL liposomal infusion.

Adverse Reactions

Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia.

Please see accompanying full Prescribing Information, including BOXED WARNINGS for DOXIL (doxorubicin HCl liposome injection)