Usual dose

Administration of higher-than-recommended doses or more frequent dosing of belatacept is not recommended because of an increased risk of posttransplant lymphoproliferative disorder (PTLD), progressive multifocal leukoencephalopathy (PML), and serious CNS infections.

Premedication is not required. Base the total infusion dose on actual body weight at the time of transplantation.

Regimen includes basiliximab (Simulect) induction, mycophenolate mofetil (MMF, CellCept), and corticosteroids.

Dose adjustments

Do not modify the dose during the course of therapy unless there is a change in body weight of greater than 10%. ■ Age, gender, race, renal function, hepatic function, diabetes, and concomitant dialysis do not affect the clearance of belatacept.

Dilution

Belatacept is for IV infusion only. Must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial. This syringe will be required for both reconstitution and the preparation of the final infusion. Maintain sterility. Any solution prepared with other than the provided silicone-free syringe must be discarded (contact the manufacturer to obtain an additional supply of silicone-free disposable syringes).

Each vial contains 250 mg of belatacept lyophilized powder. Calculate the number of vials needed to provide the total infusion dose. Reconstitute the contents of each vial with 10.5 mL of SWFI, NS, or D5W using the silicone-free disposable syringe and an 18- to 21-gauge needle. Direct the stream of diluent to the glass wall of the vial. To avoid foaming, rotate the vial and swirl gently until contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake. Reconstituted solution yields 25 mg/mL and should be clear to slightly opalescent and colorless to pale yellow. Calculate the total volume of reconstituted solution required to provide the prescribed dose:

Volume of 25 mg/mL belatacept solution (in mL) = Prescribed dose (in mg) ÷ 25 mg/mL

The reconstituted solution must be further diluted in infusion fluid. If reconstituted with SWFI, dilute with either NS or D5W. If reconstituted with NS, further dilute with NS. If reconstituted with D5W, further dilute with D5W. From the appropriate-size infusion bag or bottle (typically an infusion volume of 100 mL is appropriate, but volumes from 50 to 250 mL may be used), withdraw a volume of infusion fluid equal to the total volume of reconstituted belatacept required to provide the prescribed dose. Using the same silicone-free disposable syringe used for reconstitution, withdraw the required amount of belatacept and inject it into the infusion bag or bottle. Gently rotate to ensure mixing. Concentration should range from 2 mg/mL to 10 mg/mL.

Compatibility

Manufacturer states, “Must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial. Any solution prepared with other than the provided silicone-free syringe must be discarded” and “Infuse in a separate line; should not be infused concomitantly in the same IV line with other agents.”

Rate of administration

A single dose evenly distributed over 30 minutes.

Actions

A selective T-cell costimulation blocker. Produced by recombinant DNA technology. Binds to CD80 and CD86 on antigen-presenting cells, thereby blocking CD28-mediated costimulation of T-lymphocytes. Belatacept binds to CD80 and CD86 more readily than abatacept (the parent molecule from which it is derived). Belatacept-mediated co-stimulation blockade results in the inhibition of cytokine production by T-cells required for antigen-specific antibody production by B-cells and inhibits T-lymphocyte proliferation. Activated T-lymphocytes are the predominant mediators of immunologic rejection. Half-life ranges from 6.1 to 15.1 days. In clinical trials, trough concentrations were consistently maintained from 6 months up to 3 years posttransplant. Increasing body weight may result in a trend toward higher clearance.

Indications and uses

Prophylaxis of organ rejection in adult patients receiving a kidney transplant. Used in combination with basiliximab (Simulect) induction, mycophenolate mofetil (CellCept), and corticosteroids.

Contraindications

Transplant recipients who are Epstein-Barr virus (EBV) seronegative or who have unknown EBV serostatus because of risk of posttransplant lymphoproliferative disorder (PTLD) predominantly involving the CNS.

Precautions

For IV use only. ■ Usually administered by or under the direction of a physician experienced in immunosuppressive therapy and management of organ transplant patients. Adequate laboratory and supportive medical resources must be available. ■ Increased risk for developing posttransplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared with patients on a cyclosporine-based regimen. Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore use in EBV-seropositive patients only. Do not use belatacept in transplant recipients who are EBV-seronegative or who have unknown EBV serostatus. ■ Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell–depleting therapy. Use T-cell–depleting therapies to treat acute rejection with caution. CMV prophylaxis is recommended for at least 3 months after transplantation. Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD compared with patients who are EBV seropositive and CMV seropositive. ■ Minimization of the corticosteroid dose to 5 mg/day between Day 3 and Week 6 posttransplantation has been associated with an increased rate and grade of acute rejection, particularly Grade III rejection. Graft loss occurred in some patients. Corticosteroid use should be consistent with clinical trial experience; see Usual Dose. ■ Increased susceptibility to infection and possible development of malignancies may result from immunosuppression. Increased risk of developing other malignancies, including malignancies of the skin, appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight. Risk of developing bacterial, viral (e.g., CMV and herpes), fungal, and protozoal infections, including opportunistic infections such as tuberculosis (TB) or polyoma virus–associated nephropathy (PVAN), is increased and may lead to serious (including fatal) outcomes. Prophylaxis for Pneumocystis jiroveci is recommended after transplantation. ■ PML (a rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus) has been reported. ■ Infusion-related reactions have occurred within 1 hour of infusion; however, no serious reactions or anaphylaxis have been reported. ■ Use in liver transplant patients is not recommended; see Limitation of Use. ■ Anti-belatacept antibody development was not associated with an altered clearance of belatacept. The clinical impact of anti-belatacept antibodies has not been determined. ■ Do not administer live virus vaccines; see Drug/Lab Interactions.

Drug/lab interactions

A change of mycophenolic acid (MPA) exposure may occur with a crossover from cyclosporine to belatacept or from belatacept to cyclosporine in patients concomitantly receiving MMF. Cyclosporine decreases MPA exposure by preventing enterohepatic recirculation of MPA, whereas belatacept does not. A higher MMF dosage may be needed after switching from belatacept to cyclosporine because cyclosporine may result in lower MPA concentrations and increase the risk of graft rejection. A lower MMF dosage may be needed after switching from cyclosporine to belatacept because belatacept may result in higher MPA concentrations and increase the risk for adverse reactions related to MPA. ■ No dosage adjustments are needed for drugs metabolized via CYP1A2 (e.g., caffeine), CYP2C9 (e.g., losartan [Cozaar]), CYP2D6 (e.g., dextromethorphan), CYP3A (e.g., midazolam [Versed]), and CYP2C19 (e.g., omeprazole [Prilosec]). ■ Avoid the use of live vaccines during treatment with belatacept, including but not limited to intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and Ty21a typhoid vaccines.

Side effects

Anemia, constipation, cough, diarrhea, fever, graft dysfunction, headache, hyperkalemia, hypertension, hypokalemia, leukopenia, nausea, peripheral edema, urinary tract infection, and vomiting are most common. Posttransplant lymphoproliferative disorder (PTLD), predominantly CNS PTLD; other malignancies; and serious infections, including JC virus–associated progressive multifocal leukoencephalopathy (PML) and polyoma virus-associated nephropathy (PVAN), are the most serious potential side effects and may be life threatening. Abdominal pain, acne, anxiety, arthralgia, back pain, bronchitis, cytomegalovirus (CMV) and herpes infections, dyslipidemia, dysuria, hematuria, hypercholesterolemia, hyperglycemia, hyperuricemia, hypocalcemia, hypomagnesemia, hypophosphatemia, hypotension, influenza, insomnia, nasopharyngitis, proteinuria, renal tubular necrosis, tremor, tuberculosis, and upper respiratory infections may occur.

Antidote

Notify physician of all side effects. Most will be treated symptomatically. If PML is suspected, confirmation of the diagnosis by consultation with a neurologist, brain imaging, CSF testing for JC viral DNA, and/or brain biopsy is indicated. If PML is confirmed, consider reducing or discontinuing immunosuppression, taking into account the risk to the allograft. Therapy may need to be interrupted in patients who develop infections. Treat infusion reactions as indicated. Resuscitate as necessary.

Usual dose

Dilution

Available in two strengths (120 mg or 400 mg). Allow vial to reach RT before reconstitution (approximately 10 to 15 minutes). Reconstitute the 120-mg vial with 1.5 mL SWFI and the 400-mg vial with 4.8 mL SWFI. Concentration for both will equal 80 mg/mL. Direct the SWFI toward the side of the vial to minimize foaming. Gently swirl for 60 seconds. Allow to sit at RT and gently swirl for 60 seconds every 5 minutes until completely dissolved. Do not shake. Reconstitution may take up to 30 minutes. Protect from sunlight. Solution should be opalescent and colorless to pale yellow. Small air bubbles are expected and are acceptable. If reconstituted with a mechanical swirler, do not exceed 500 rpm and/or a duration of 30 minutes. Desired dose of the reconstituted solution must be further diluted to 250 mL with NS by withdrawing and discarding a volume equal to the desired dose from a 250-mL infusion bag or bottle of NS. Add the desired dose of belimumab to the infusion bag or bottle and invert to mix the solution; see Storage.

Compatibility

Manufacturer states, “Incompatible with dextrose solutions,” “No incompatibilities with polyvinylchloride or polyolefin bags observed,” and “Should not be infused concomitantly in the same IV line with other agents.”

Rate of administration

A single dose, properly diluted, as an infusion equally distributed over 1 hour. Slow or interrupt infusion rate if an infusion reaction develops.

Actions

A recombinant, DNA-derived, humanized monoclonal antibody. It is a B-lymphocyte stimulator (BLyS)–specific inhibitor that blocks the binding of soluble BLyS (a B-cell survival factor) to its receptors on B-cells. Does not bind with B-cells directly. However, by binding BLyS, it inhibits the survival of B-cells (including auto-reactive B-cells) and reduces the differentiation of B-cells into immunoglobulin-producing plasma cells. Significantly reduces circulating CD19+, CD20+, naïve, and activated B-cells, plasmacytoid cells, and the SLE B-cell subset. Reductions in IgG and anti-dsDNA and increases in complement (C3 and C4) were observed as early as Week 8 and sustained through Week 52. Terminal half-life is 19.4 days.

Indications and uses

Treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Contraindications

Patients who have experienced an anaphylactic hypersensitivity reaction with belimumab.

Precautions

For IV infusion only. ■ Administered under the direction of a physician knowledgeable in its use in a facility with adequate diagnostic and treatment facilities to monitor the patient and respond to any medical emergency. ■ Serious hypersensitivity/infusion reactions, including anaphylaxis and death, have occurred. Acute hypersensitivity reactions usually occur within hours of the infusion. Nonacute reactions, including rash, nausea, fatigue, myalgia, headache, and facial edema, may occur up to a week following the infusion. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Administration of premedications (which can mask or mitigate a reaction) and the overlap in S/S may make it difficult to distinguish between a hypersensitivity reaction and an infusion reaction. ■ Serious and sometimes fatal infections have been reported. Use with caution in patients with chronic infections. Therapy should not be started if a patient is receiving any therapy for a chronic infection. ■ Cases of JC virus–associated progressive multifocal leukoencephalopathy (PML) resulting in neurologic deficits, including fatal cases, have been reported. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. ■ Psychiatric events, including depression, insomnia, and anxiety, have been reported. Most patients had a history of depression or other serious psychiatric disorders and were receiving psychoactive medications. ■ More deaths were reported with belimumab than with placebo during the controlled period of clinical trials. Etiologies included cardiovascular disease, infection, and suicide. No single cause of death predominated. ■ The impact of treatment with belimumab on the development of malignancies is not known. ■ Anti-belimumab antibodies developed in a small percentage of patients. Clinical relevance is unknown. ■ Response rates were lower in black/African-American patients; use with caution. ■ Use in patients with impaired renal or hepatic function has not been studied.

Drug/lab interactions

Formal drug interaction studies have not been performed. ■ Has not been studied in combination with other biologics, including B-cell–targeted therapies or IV cyclophosphamide; concurrent use is not recommended. ■ Do not administer live virus vaccines for 30 days before or concurrently with belimumab. ■ Has been administered concomitantly with corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin-pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without meaningful clinical effect on belimumab pharmacokinetics.

Side effects

Bronchitis, depression, diarrhea, fever, insomnia, nasopharyngitis, migraine, nausea, pain in extremities, and pharyngitis were most commonly reported. The most common serious infections included bronchitis, cellulitis, pneumonia, and urinary tract infections. Anxiety, cystitis, depression, hypersensitivity/infusion reactions, influenza, leukopenia, sinusitis, and viral gastroenteritis also were reported.

Antidote

Notify physician of all side effects. Treatment of most side effects will be supportive. Consider interrupting therapy if a new infection develops during treatment with belimumab. If PML is confirmed, consider discontinuing immunosuppressant therapy, including belimumab. Slow or interrupt infusion rate if an infusion reaction develops. Infusion reactions may be treated with acetaminophen, antiemetics (e.g., ondansetron [Zofran]), antihistamines (e.g., diphenhydramine [Benadryl]), H₂ antagonists (e.g., ranitidine [Zantac]), or corticosteroids (e.g., hydrocortisone sodium succinate [Solu-Cortef]) as indicated. Discontinue if a serious hypersensitivity reaction occurs. Treat hypersensitivity reactions as indicated; may require epinephrine, airway management, oxygen, IV fluids, antihistamines (e.g., diphenhydramine [Benadryl]), corticosteroids (e.g., hydrocortisone sodium succinate [Solu-Cortef]), and pressor amines (e.g., dopamine).

Usual dose

1,000 mg/M² administered over 30 minutes by IV infusion once each day on Days 1 through 5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity.

Dose adjustments

Before the start of each cycle and before resuming treatment following toxicity, the absolute neutrophil count (ANC) should be greater than or equal to 1 × 10⁹/L (1,000/mm³), and the platelet count should be greater than or equal to 50 × 10⁹/L (50,000/mm³). ■ Other toxicities must be NCI-CTCAE Grade 2 or less before retreatment. ■ Reduce the starting dose of belinostat to 750 mg/M² in patients known to be homozygous for the UGTIA*28 allele. ■ See the following chart for dose modifications for hematologic and nonhematologic toxicities. Base the dose adjustments for thrombocytopenia and neutropenia on platelet and absolute neutrophil nadir (lowest value) counts in the preceding cycle of therapy.

Dilution

Specific techniques required; see Precautions. Available in single-use vials containing lyophilized powder equivalent to 500 mg belinostat. Reconstitute each vial with 9 mL of SWI (concentration is 50 mg/mL). Swirl contents until no visible particles remain. Withdraw the required dose and transfer to an infusion bag containing 250 mL of NS. Do not use if cloudiness or particulates are observed.

Compatibility

Specific information not available.

Rate of administration

A single dose as an IV infusion equally distributed over 30 minutes. Infusion time may be extended to 45 minutes for infusion site pain or other symptoms potentially attributable to the infusion.

Actions

A histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell-cycle arrest and/or apoptosis of some transformed cells. It shows preferential cytotoxicity toward tumor cells compared with normal cells. Highly bound to protein. Primarily metabolized by UGT1A1. Also undergoes some metabolism by selected cytochrome P₄₅₀ isoenzymes. Elimination half-life is 1.1 hours. Excreted in urine.

Indications and uses

Treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Approval is based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established.

Contraindications

Manufacturer states, “None.”

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Usually administered by or under the direction of a physician specialist with adequate diagnostic and treatment facilities to monitor the patient and respond to any medical emergency. ■ Can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia. See Monitor and Dose Adjustments. ■ Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred. Do not administer belinostat to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk for life-threatening infections. ■ Can cause fatal hepatotoxicity and liver function test abnormalities. Interrupt or adjust dose until recovery, or permanently discontinue belinostat based on the severity of the hepatic toxicity. ■ Tumor lysis syndrome (TLS) has occurred. May cause acute renal failure requiring dialysis and can be fatal. ■ Gastrointestinal toxicity has been reported. ■ Use caution in patients with hepatic impairment. Patients with moderate and severe hepatic impairment (total bilirubin greater than 1.5 × ULN) were excluded from clinical trials. ■ See Monitor.

Drug/lab interactions

Avoid concomitant administration of belinostat with strong inhibitors of UGT1A1 (e.g., atazanavir [Reyataz], indinavir [Crixivan], ketoconazole [Nizoral]). ■ Belinostat did not increase the AUC or C_max of warfarin (Coumadin). Dose adjustment of warfarin is not required when coadministered with belinostat. ■ Likely a glycoprotein (P-gp) substrate but not likely to inhibit P-gp.

Side effects

The most common side effects reported are anemia, fatigue, fever, nausea and vomiting. Serious side effects reported include hematologic toxicity (anemia, lymphopenia, neutropenia, thrombocytopenia), hepatotoxicity and liver function abnormalities, increased SCr, infections (pneumonia, sepsis), multiorgan failure, and tumor lysis syndrome. Anemia, fatigue, febrile neutropenia, and multiorgan failure were reported as the reason for discontinuation of treatment. Other side effects reported include abdominal pain, chills, constipation, cough, decreased appetite, diarrhea, dizziness, dyspnea, headache, hypokalemia, hypotension, increased blood lactate dehydrogenase, infusion site pain, peripheral edema, phlebitis, prolonged QT, pruritus, and rash. Treatment-related deaths have occurred.

Antidote

Notify physician of all side effects. Minor side effects may be treated symptomatically. Supportive therapy as indicated will help sustain the patient in toxicity. Interrupt or adjust dose until recovery, or permanently discontinue belinostat based on the severity of the hematologic or hepatic toxicity. Hematologic toxicity may require dose adjustment. Neutropenia may be treated with filgrastim (Neupogen, Zarxio). Severe thrombocytopenia or anemia may require transfusion. Should a hypersensitivity reaction occur, treat as indicated.

Usual dose

Dose adjustments

Dilution

Compatibility

Manufacturer states, “Use SWFI for reconstitution (for Treanda for Injection) and then (for both formulations) either NS or D2.5/¹/₂NS for dilution. No other diluents have been shown to be compatible.”

Rate of administration

Actions

A bifunctional mechlorethamine derivative. An alkylating agent. Active against both quiescent and dividing cells. Exact mode of action unknown. May lead to cell death by damaging the DNA in cancer cells as well as by disrupting normal cell division. Highly protein bound. Distributes freely in human red blood cells. Extensively metabolized via hydrolytic, oxidative, and conjugative pathways. Excreted in urine and feces.

Indications and uses

Treatment of patients with chronic lymphocytic leukemia (CLL). Study demonstrated a higher rate of overall response and a longer progression-free survival for bendamustine compared with chlorambucil (Leukeran). Effectiveness compared with first-line therapies other than chlorambucil has not been studied. ■ Treatment of patients with indolent B-cell non-Hodgkin’s lymphoma that has progressed during or within 6 months of treatment with rituximab (Rituxan) or a rituximab-containing regimen.

Contraindications

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Administered by or under the direction of the physician specialist in a facility equipped to monitor the patient and respond to any medical emergency. ■ Do not use in patients with a CrCl less than 40 mL/min. Use with caution in patients with mild or moderate renal impairment; no formal studies conducted. ■ Use with caution in patients with mild hepatic impairment. Do not use in patients with moderate hepatic impairment (AST or ALT 2.5 to 10 times the ULN and total bilirubin 1.5 to 3 times the ULN) or severe hepatic impairment (total bilirubin greater than 3 times the ULN). No formal studies conducted. ■ Myelosuppression may be severe and require dose delays and/or subsequent dose reductions. Deaths from myelosuppression-related adverse reactions have occurred; see Dose Adjustments. ■ Infections, including hepatitis, pneumonia, and sepsis, have been reported. Has been associated with septic shock and death. ■ Patients treated with bendamustine are at risk for reactivation of infections, including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster; see Monitor. ■ Infusion reactions are common. In rare instances anaphylaxis or anaphylactoid reactions have occurred. Usually occur in the second and/or subsequent cycles of therapy. ■ Tumor lysis syndrome (TLS) has been reported and may occur in the first treatment cycle. S/S are rapid reduction in tumor volume, renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia. May lead to acute renal failure and death. ■ Skin reactions, including rash, toxic skin reactions, and bullous exanthema, have been reported; see Drug/Lab Interactions and Antidote. ■ Premalignant and malignant diseases, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma have been reported. Causal relationship has not been determined.

Drug/lab interactions

No formal drug interaction studies have been conducted. ■ Active metabolites of bendamustine are formed via cytochrome P₄₅₀ CYP1A2. Inhibitors of CYP1A2 (e.g., ciprofloxacin [Cipro], fluvoxamine [Luvox]) may increase plasma concentrations of bendamustine and decrease plasma concentrations of active metabolites. Inducers of CYP1A2 (e.g., omeprazole [Prilosec], smoking) may decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites. Use caution or consider alternative treatments if concomitant treatment with CYP1A2 inhibitors or inducers is indicated. ■ Not likely to inhibit metabolism via other selected CYP isoenzymes or to induce the metabolism of substrates of cytochrome P₄₅₀ enzymes. ■ Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with concomitant administration of allopurinol and other medications known to cause these syndromes (e.g., rituximab [Rituxan]). ■ In vitro data suggest that P-glycoprotein breast cancer resistance protein (BCRP) and/or other efflux transporters may have a role in bendamustine transport.

Side effects

Anorexia, constipation, cough, diarrhea, dyspnea, fatigue, fever, headache, myelosuppression (anemia, febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombocytopenia), nausea, rash, stomatitis, vomiting, and weight loss were most common. Other side effects reported include asthenia; chills; decreased CrCl; dry mouth; elevated AST, ALT, and bilirubin levels; herpes simplex; hypersensitivity and/or infusion reactions (e.g., anaphylaxis [rare], pruritus, rash); hypertension; hyperuricemia; infections; malaise; malignancies; mucosal inflammation; nasopharyngitis; pneumonia; sepsis; somnolence; stomatitis; TLS; and weakness. Hypersensitivity reactions and fever required study withdrawal in some patients.

Antidote

Keep physician informed of all side effects and hematologic parameters. Side effects may decrease in severity with reduced dose. Bone marrow depression may require withholding bendamustine until recovery occurs. Administration of whole blood products (e.g., packed RBCs, platelets, leukocytes) may be required. Selected blood modifiers (e.g., erythropoiesis-stimulating agents [ESAs (Aranesp, Epogen, Mircera)], filgrastim [Neupogen, Zarxio], pegfilgrastim [Neulasta], sargramostim [Leukine]) may be indicated to treat bone marrow toxicity. Discontinue the infusion immediately for any life-threatening side effect (e.g., clinically significant bronchospasm, cardiac arrhythmias, severe hypotension). Consider premedication with antihistamines (e.g., diphenhydramine [Benadryl]), antipyretics (e.g., acetaminophen [Tylenol]), and corticosteroids in subsequent cycles in patients who have experienced a Grade 1 or 2 hypersensitivity and/or infusion reaction. Grade 3 or 4 reactions have not typically been rechallenged; consider discontinuing bendamustine. Withhold or discontinue bendamustine if skin reactions are severe or progressive. There is no specific antidote. Supportive therapy as indicated will help sustain the patient in toxicity. ECG monitoring may be indicated to evaluate cardiac side effects.

Usual dose

Do not begin therapy until at least 28 days after major surgery. Surgical incisions should be fully healed. May be used in combination with other antineoplastic agents or as a single agent. See Dose Adjustments, Monitor, and Precautions. Continue treatment until disease progression or unacceptable toxicity occurs.

Dose adjustments

No dose adjustments are recommended based on age, gender, or race. ■ No dose adjustments are recommended for patients with impaired hepatic or renal function; bevacizumab was not studied in these patients. ■ Permanently discontinue if GI perforation, fistula formation in the GI tract (e.g., enterocutaneous, esophageal, duodenal, rectal), intra-abdominal abscess, fistula formation involving an internal organ, wound dehiscence (parting of the sutured lips of a surgical wound) or wound healing complications requiring medical intervention, serious bleeding, severe arterial thromboembolic event, life-threatening (Grade 4) venous thromboembolic events (including pulmonary embolism), nephrotic syndrome, hypertensive crisis or hypertensive encephalopathy, or posterior reversible encephalopathy syndrome (PRES) develops; see Monitor and Precautions. ■ Temporarily discontinue if moderate to severe proteinuria (equal to or greater than 2 Gm/24 hr), severe hypertension not controlled with medical management, and/or a severe infusion reaction occurs; see Monitor and Precautions. ■ Withhold bevacizumab for at least 4 weeks before elective surgery (half-life is approximately 20 days but has a wide range). Incision must be fully healed before therapy is resumed.

Dilution

Available in single-use vials containing 100 mg in 4 mL or 400 mg in 16 mL (25 mg/mL). Calculate desired dose and choose the appropriate vial or combination of vials. Withdraw the required volume of bevacizumab and dilute in a total volume of 100 mL of NS.

Compatibility

Manufacturer states, “Should not be administered with or mixed with dextrose solutions.” Incompatibilities with polyvinylchloride or polyolefin bags have not been observed.

Rate of administration

Do not administer as an IV push or bolus. Must be given as an infusion. Administer following concurrent chemotherapy. Infusion reactions are not common but may occur; see Monitor.

Actions

A humanized IgG₁ monoclonal antibody produced by recombinant DNA technology. Has antiangiogenesis properties; it binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation. By binding VEGF, bevacizumab prevents the interaction of VEGF with its receptors on the surface of endothelial cells, thus inhibiting the development of new blood vessels around tumors (a tumor-starving mechanism) and resulting in a reduction of microvascular growth and an inhibition of metastatic disease progression. Predicted time to steady-state was 100 days. Half-life is approximately 20 days (range is 11 to 50 days). IgG antibodies may cross the placental barrier and be secreted in breast milk.

Indications and uses

First-line or second-line treatment of metastatic carcinoma of the colon or rectum. Used in combination with intravenous 5-fluorouracil–based chemotherapy (e.g., IFL, FOLFOX4). ■ Second-line treatment of metastatic colorectal cancer in patients who have progressed on a first-line bevacizumab-containing regimen. Used in combination with fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin–based chemotherapy. ■ First-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous, non–small-cell lung cancer. Given in combination with carboplatin and paclitaxel. ■ Treatment of glioblastoma in adult patients as a single agent for patients with progressive disease following prior therapy. (Effectiveness is based on an improvement in objective response rate. There are no data showing an improvement in disease-related symptoms or increased survival with bevacizumab.) ■ Treatment of metastatic renal cell cancer. Given in combination with interferon alfa. ■ Treatment of persistent, recurrent, or metastatic carcinoma of the cervix. Given in combination with paclitaxel and cisplatin or paclitaxel and topotecan. ■ Treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens. Given in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan.

Contraindications

Manufacturer states, “No known contraindications.” However, bevacizumab must be discontinued if GI perforation, wound dehiscence requiring medical intervention, serious bleeding, nephrotic syndrome, or hypertensive crisis develops; see Antidote. ■ Use with caution in patients with known hypersensitivity to murine proteins, bevacizumab, or any of its components. ■ Not recommended for use in patients with recent hemoptysis (greater than or equal to ¹/₂ teaspoon of red blood). ■ Avoid use in patients with ovarian cancer who have evidence of rectosigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction.

Precautions

Do not administer as an IV push or bolus. Must be given as an infusion. ■ Should be administered by or under the direction of a physician specialist in a facility equipped to monitor the patient and respond to any medical emergency. ■ Has been shown to impair wound healing; withhold bevacizumab for a minimum of 28 days after major surgery; surgical incision must be fully healed. Withhold at least 28 days before elective surgery (half-life is approximately 20 days but has a wide range). Appropriate intervals between surgery and the beginning of bevacizumab therapy and/or the end of bevacizumab therapy and subsequent elective surgery have not been determined. ■ GI perforation with or without fistula formation and/or intra-abdominal abscesses has occurred; deaths have been reported. The majority of cases occurred within the first 50 days of initiation of bevacizumab. Consider GI perforation in any patient with complaints of abdominal pain associated with constipation, fever, nausea, and vomiting. ■ Nongastrointestinal fistula formation has been reported, in some cases with a fatal outcome. Fistula formations involving tracheoesophageal, bronchopleural, biliary, vaginal, renal, and bladder areas have been reported. Most events occurred within the first 6 months of bevacizumab therapy. ■ Necrotizing fasciitis (including fatal cases) has been reported, usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation. ■ Severe or fatal hemorrhage, including CNS hemorrhage, epistaxis, GI bleed, hematemesis, hemoptysis, and vaginal bleeding occurred up to five times more frequently in patients receiving bevacizumab. Do not administer bevacizumab to patients with serious bleeding or hemoptysis. ■ May cause severe hypertension that may be persistent. Treatment is required; see Monitor and Antidote. ■ Posterior reversible encephalopathy syndrome (PRES) has been reported. Onset of symptoms occurred from 16 hours to 1 year after initiation of therapy. May present with blindness and other visual and neurologic disturbances, confusion, headache, lethargy, and seizures. Mild to severe hypertension may be present. MRI is required to confirm diagnosis. Symptoms usually resolve gradually with discontinuation of bevacizumab and treatment of hypertension. ■ Severe neutropenia, febrile neutropenia, and infection with neutropenia have been reported in patients treated with myelosuppressive chemotherapy plus bevacizumab. ■ Proteinuria occurred during studies and progressed to nephrotic syndrome in some patients. Findings consistent with thrombotic microangiopathy have been found on kidney biopsy in some patients. In other patients, proteinuria decreased within several months after therapy was discontinued. Increased serum creatinine levels have occurred and may not return to baseline. ■ CHF has been reported. Incidence is higher in patients receiving chemotherapy plus bevacizumab compared with patients receiving chemotherapy alone. ■ Infusion reactions are infrequent but have occurred. S/S may include chest pain, diaphoresis, Grade 3 hypersensitivity, headache, hypertension, hypertensive crisis associated with neurologic S/S, oxygen desaturation, rigors, and wheezing. ■ Serious and sometimes fatal arterial thromboembolic events (e.g., CVA [stroke], MI, TIA, angina) have been reported. Incidence is greater with bevacizumab given in combination with chemotherapy as compared to those receiving chemotherapy alone. Risk increased in patients with a history of arterial thromboembolism or diabetes and in patients greater than 65 years of age. ■ Venous thromboembolic events (e.g., deep vein thrombosis, intra-abdominal thrombosis, and pulmonary embolism) have been reported. Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab may be at increased risk for venous thromboembolic events; see Antidote. ■ Avastin may cause fetal harm; see Maternal/Child. ■ Bevacizumab increases the risk of ovarian failure (defined as amenorrhea lasting 3 or more months, FSH level equal to or greater than 30 mIU/mL, and a negative serum β-HCG pregnancy test). Recovery of ovarian function occurred in some but not all women following discontinuation of therapy. Long-term effects of bevacizumab exposure on fertility are unknown. ■ A protein substance, it has the potential for producing an immune response. Neutralizing antibodies against bevacizumab have been found using a specific immunosorbent assay; clinical significance is not known. ■ See Drug/Lab Interactions and Antidote.

Drug/lab interactions

Drug interaction studies have not been completed. ■ Has been administered concurrently with a regimen of irinotecan, 5-fluorouracil, and leucovorin. Studies indicate no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN-38. ■ Has been administered with carboplatin, paclitaxel, and interferon alfa. ■ Several cases of microangiopathic hemolytic anemia (MAHA) have been reported in patients with solid tumors who are receiving concomitant therapy with bevacizumab and sunitinib malate (Sutent). This combination therapy is not approved and not recommended. ■ ACE inhibitors, beta-blockers, calcium channel blockers, and diuretics have been coadministered to control hypertension.

Side effects

The most common side effects include back pain, dry skin, epistaxis, exfoliative dermatitis, headache, hypertension, lacrimation (excess), proteinuria, rectal hemorrhage, rhinitis, and taste alteration. Major, dose-limiting, and potentially life-threatening side effects include arterial thromboembolic events (e.g., angina, cerebral infarction, MI, TIA), bleeding episodes (e.g., CNS hemorrhage, epistaxis [severe], GI hemorrhage, hemoptysis, vaginal bleeding), GI perforations, hypertensive crises, infusion reactions, nongastric intestinal fistula formation, posterior reversible encephalopathy syndrome (PRES), proteinuria and/or nephrotic syndrome, surgery and wound healing complications, and venous thromboembolic events. Other reported side effects included abdominal pain, abnormal gait, alopecia, anorexia, anxiety, asthenia, bilirubinemia, CHF, colitis, confusion, constipation, cough, dehydration, diarrhea, dizziness, dry mouth, dysarthria, dyspepsia, dysphonia, dyspnea, edema, fatigue, flatulence, hematologic toxicity (e.g., anemia, leukopenia, neutropenia, thrombocytopenia), hyperglycemia, hypertension, hypoalbuminemia, hypokalemia, hypomagnesemia, hyponatremia, hypotension, ileus, increased serum creatinine, infection, myalgia, nail disorder, nausea, pain, palmar-plantar erythrodysesthesia syndrome, pneumonitis, renal thrombotic microangiopathy (manifested as severe proteinuria), sensory neuropathy, sepsis, skin discoloration, skin ulcer, stomatitis, syncope, urinary frequency and urgency, venous thromboembolic events (e.g., deep vein thrombosis, intra-abdominal thrombosis, pulmonary embolism), voice alteration, vomiting, weight loss.

Antidote

Keep physician informed of all side effects. May constitute a medical emergency or will be treated symptomatically as indicated. Permanently discontinue if any of the following develop: GI perforation, fistula formation in the GI tract (e.g., enterocutaneous, esophageal, duodenal, rectal), intra-abdominal abscess, fistula formation involving an internal organ, formation of a tracheoesophageal fistula or any Grade 4 fistula, wound dehiscence or wound healing complications requiring medical intervention, necrotizing fasciitis, serious bleeding requiring medical intervention, nephrotic syndrome, a severe arterial thromboembolic event, life-threatening (Grade 4) venous thromboembolic events (including pulmonary embolism), PRES, hypertensive crisis, or hypertensive encephalopathy. Treat these side effects aggressively; see Precautions and Monitor. Discontinue bevacizumab for severe infusion reactions and treat as indicated (e.g., epinephrine, diphenhydramine [Benadryl], IV fluids, oxygen). Data on rechallenge not available. Temporarily discontinue if moderate to severe proteinuria (equal to or greater than 2 Gm/24 hr) occurs. Resume therapy when proteinuria is less than 2 Gm/24hr; see Monitor and Precautions. Temporarily discontinue if severe hypertension not controlled with medical management occurs; see Monitor and Precautions. Thromboembolic events (e.g., deep vein thrombosis, intra-abdominal thrombosis, pulmonary embolism) were treated with full-dose warfarin (Coumadin) during clinical trials. Monitor INR closely. Bleeding occurred in patients with elevated INRs; relationship to bevacizumab not determined. Withhold bevacizumab for at least 28 days before elective surgery (half-life is approximately 20 days but has a wide range). Incision must be fully healed before therapy is resumed.

Usual dose

Initiate just before percutaneous coronary intervention (PCI) or percutaneous transluminal coronary angioplasty (PTCA). Given in combination with aspirin.

For patients who DO NOT HAVE heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS):

Bivalirudin:

Begin with an IV bolus dose of 0.75 mg/kg. Follow immediately with an infusion at 1.75 mg/kg/hr for the duration of the PCI/PTCA procedure. Perform an ACT 5 minutes after the bolus dose has been administered. An additional bolus dose of 0.3 mg/kg should be given if needed (e.g., ACT less than 225 seconds). Administration with a glycoprotein IIb/IIIa inhibitor (e.g., abciximab [ReoPro], eptifibatide [Integrilin], tirofiban [Aggrastat]) should be considered in any of the following circumstances:

• Decreased TIMI (0 to 2) or slow reflow (Thrombolysis in Myocardial Infarction [TIMI])

• Dissection with decreased flow

• New or suspected thrombus

• Persistent residual stenosis

• Distal embolization

• Unplanned stent placement

• Suboptimal stenting

• Side branch closure

• Abrupt closure, clinical instability

• Prolonged ischemia

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