Bethesda Handbook of Clinical Oncology, 2nd Edition

Common Procedures and Chemotherapy Drugs

47

Anticancer Agents

Thomas E. Hughes

Department of Pharmacy, National Institutes of Health Clinical Center, Bethesda, Maryland

All information has been obtained from the current product labeling as of June 1, 2004.

NOTES AND ABBREVIATIONS

Single-agent Dose

The doses listed for each agent are from the package inserts and apply when the agent is given alone, unless otherwise noted.

The doses are expressed in accordance with the nomenclature guidelines from Kohler et al. (1).

Abbreviations Listed under Adverse Reactions

  • CNS: central nervous system
  • CV: cardiovascular system
  • DERM: skin and integument system
  • ELECTRO: electrolyte abnormalities
  • ENDO: endocrine system
  • GI: gastrointestinal system
  • GU: genitourinary system
  • HEMAT: hematopoietic system
  • INFUS: infusion-related reactions
  • OCULAR: ocular system
  • PULM: pulmonary system
  • LFTs: liver function tests
  • Cr: serum creatinine
  • CrCl: creatinine clearance
  • N/V Lx: Nausea and vomiting graded into 5 levels (x = 1 or 2 or 3, etc., up to 5) according to Hesketh et al. (2). (Note: The emetogenic potential based on the expected frequency of acute emesis is as follows: Level 1: <10%, Level 2: 10% to 30%, Level 3: 30% to 60%, Level 4: 60% to 90%, Level 5: >90%.)

ALDESLEUKIN (PROLEUKIN)

Mechanism of Action

Aldesleukin activates cellular immunity.

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U.S. Food and Drug Administration–Approved Indications

Metastatic renal cell carcinoma and metastatic melanoma

U.S. Food and Drug Administration–Approved Dosage

  • Doses of 600,000 IU per kg of Aldesleukin i.v. over 15 minutes every 8 hours for a maximum of 14 doses
  • The dosage may be repeated after 9 days of rest for a maximum of 28 doses per course

Dose Modification Criteria

In the event of toxicity a dose may be withheld or interrupted.

Adverse Reactions

CNS: confusion, somnolence, anxiety, and dizziness; CV: hypotension, tachycardia, and arrhythmia; DERM: rash and pruritus; GI: diarrhea, N/V L3, mucositis, and anorexia; GU: oliguria and acute renal failure; HEMAT: myelosuppression; PULM: dyspnea and pulmonary edema; OTHER: pain, fever, chills, and malaise.

Comments

  • Use may be restricted to patients with normal cardiac and pulmonary function
  • Patients to be monitored for capillary-leak syndrome
  • Agent is associated with impaired neutrophil function; consider antibiotic prophylaxis for patients with indwelling central lines

ALEMTUZUMAB (CAMPATH)

Mechanism of Action

Alemtuzumab is a humanized monoclonal antibody directed against the cell surface protein, CD52. The CD52 antigen is expressed on the surface of normal and malignant B and T lymphocytes, natural killer (NK) cells, monocytes, macrophages, and a subpopulation of granulocytes. The proposed mechanism of action of alemtuzumab is the antibody-dependent lysis of leukemic cells following binding to the cell surface.

U.S. Food and Drug Administration–Approved Indications

B-cell chronic lymphocytic leukemia (CLL): It is used for second-line therapy in patients who have been treated with alkylating agents and in those who have failed fludarabine therapy.

U.S. Food and Drug Administration–Approved Dosage

  • Alemtuzumab is dose-escalated in a stepwise manner to a maintenance dose of 30 mg. The initial recommended dosage is 3 mg i.v. over 2 hours daily. When this dosage is tolerated (infusion-related toxicities are grade 2 or less), it should be escalated to 10 mg i.v. over 2 hours daily and continued until tolerated. When the 10-mg dose is tolerated, the maintenance dose of 30 mg may be initiated. The maintenance dosage is 30 mg i.v. over 2 hours administered 3 times per week (i.e., Monday, Wednesday, and Friday) for up to 12 weeks. In most patients, the escalation to 30-mg dose can be accomplished in 3 to 7 days. If therapy is interrupted for 7 or more days, alemtuzumab should be reinitiated with gradual dose escalation.

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  • Patients should be premedicated with an antihistamine (e.g., diphenhydramine 50 mg PO or i.v.) and acetaminophen (650 mg PO) 30 minutes prior to alemtuzumab to ameliorate or avoid infusion-related toxicity. Antiemetics, meperidine, and corticosteroids have also been used to prevent or treat infusion-related toxicities.

Dose Modification Criteria

Dose to be modified in cases of myelosuppression.

Adverse Reactions

CNS: headache, dysthesia, and dizziness; CV: hypotension and edema or peripheral edema; DERM: rash, urticaria, and pruritus; GI: N/V L2–3, diarrhea, anorexia, and mucositis or stomatitis; HEMAT: myelosuppression and lymphopenia; INFUS: rigors, fever, chills, N/VL2–3, hypotension, dyspnea, bronchospasm, headache, rash, and urticaria; PULM: dyspnea, cough, bronchitis, pneumonia, and bronchospasm; OTHER: opportunistic infections, sepsis, fatigue, asthenia, and pain.

Comments

  • Patients treated with alemtuzumab are at risk of opportunistic infections caused by profound lymphopenia. Anti-infective prophylaxis is recommended upon initiation of therapy and for a minimum of 2 months following the last dose of alemtuzumab or until the CD4 count is equal to 200 cells per µL or more. Prophylaxis directed against Pneumocystis cariniipneumonia (PCP) (e.g., trimethoprim–sulfamethoxazole) and herpesvirus infections (e.g., famciclovir or equivalent) should be utilized.
  • Alemtuzumab should not be administered as an intravenous push or bolus.
  • Careful monitoring of blood pressure and hypotension is recommended, especially in patients with ischemic heart disease and in patients treated with antihypertensive medications.
  • Patients who have recently been treated with alemtuzumab should not be immunized with live viral vaccines.

ALTRETAMINE (HEXALEN)

Mechanism of Action

Altretamine has an unknown mechanism of action, but structure is similar to an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

Ovarian cancer: second-line therapy; palliative therapy for persistent or recurrent ovarian cancer

U.S. Food and Drug Administration–Approved Dosage

65 mg per m2 PO q.i.d. (4 times daily; total daily dose: 260 mg per m2) for 14 or 21 consecutive days, every 28 days

Dose Modification Criteria

Dose modified in case of myelosuppression and nonhematologic toxicity (i.e., GI intolerance and progressive neurotoxicity).

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Adverse Reactions

CNS: peripheral sensory neuropathy, mood disorders, ataxia, and dizziness; GI: N/V L3; HEMAT: myelosuppression [white blood cells (WBCs), red blood cells (RBCs), platelets].

Comments

Patients to be monitored for neurologic toxicity

ANASTROZOLE (ARIMIDEX)

Mechanism of Action

Anastrozole is a selective, nonsteroidal aromatase inhibitor.

U.S. Food and Drug Administration–Approved Indications

Breast Cancer:

  • Adjuvant treatment: Postmenopausal women with hormone-receptor–positive early breast cancer
  • First-line therapy: Postmenopausal women with hormone-receptor–positive or hormone-receptor–unknown locally advanced or metastatic breast cancer
  • Second-line therapy (after tamoxifen): Postmenopausal women with advanced breast cancer

U.S. Food and Drug Administration–Approved Dosage

1 mg PO daily (no requirement for glucocorticoid or mineralocorticoid replacement therapy)

Dose Modification Criteria

Renal impairment: no dose modification; hepatic impairment (mild to moderate): no dose modification; hepatic impairment (severe): no data available

Adverse Reactions

CNS: headache; CV: hot flashes/flushing; GI: nausea, diarrhea, and elevated LFT values (in patients with liver metastases); PULM: dyspnea; OTHER: asthenia, pain, back pain, and vaginal bleeding.

Comments

Patients with estrogen-receptor (ER)–negative disease and patients who do not respond to tamoxifen rarely respond to anastrozole.

ARSENIC TRIOXIDE (TRISENOX)

Mechanism of Action

The mechanism of action of arsenic trioxide is not completely defined. It induces apoptosis in NB4 human promyelocytic leukemia cells in vitro and damages or degrades the fusion protein PML/RAR α.

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U.S. Food and Drug Administration–Approved Indications

Acute promyelocytic leukemia (APL): second-line therapy for the induction of remission and for consolidation of APL patients who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy.

U.S. Food and Drug Administration–Approved Dosage

  • For APL induction: 0.15 mg per kg i.v. over 1 to 2 hours daily until bone marrow remission. Total induction dose should not exceed 60 doses.
  • For APL consolidation: 0.15 mg per kg i.v. over 1 to 2 hours daily × 25 doses over a period of up to 5 weeks. Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy.

Dose Modification Criteria

Renal impairment: no data available (use with caution); hepatic impairment: no data available.

Adverse Reactions

CNS: headache, dizziness, and paresthesias; CV: QT interval prolongation, complete atrioventricular block, torsade de pointes–type ventricular arrhythmia, atrial dysrhythmias, tachycardia, hypotension, and edema; DERM: rash, dermatitis, dry skin, and pruritus; ENDO: hyperglycemia, hypokalemia, and hypomagnesemia; GI: N/V L3, diarrhea, abdominal pain, anorexia, constipation, and elevated LFT values; HEMAT: leukocytosis and myelosuppression; PULM: dyspnea and cough; OTHER: fatigue, arthralgia, myalgia, pain, and APL differentiation syndrome or retinoic acid acute promyelocytic leukemia (RA-APL) syndrome (RA-APL syndrome: fever, dyspnea, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusion).

Comments

  • The APL differentiation syndrome (RA-APL syndrome) occurs in some patients treated with arsenic trioxide. Early recognition and high-dose corticosteroids (dexamethasone 10 mg i.v. every 12 hours × 3 days or until the resolution of symptoms) have been used for the management of this syndrome.
  • Before starting treatment with arsenic trioxide, a 12-lead electrocardiogram (ECG) should be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine levels should be assessed; preexisting electrolyte abnormalities should be corrected. Concomitant drugs that may prolong the QT interval should be avoided. During therapy with arsenic trioxide, normal potassium and magnesium concentrations should be monitored and maintained as outlined in the package insert.
  • The risk factors for QT prolongation and subsequent arrhythmias include other QT-prolonging drugs, a history of torsades de pointes, preexisting QT prolongation, congestive heart failure (CHF), administration of potassium-wasting diuretics, or other drugs or conditions that result in hypokalemia or hypomagnesemia.

ASPARAGINASE (ELSPAR)

Mechanism of Action

Asparaginase depletes asparagine, an amino acid required by some leukemic cells.

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U.S. Food and Drug Administration–Approved Indications

For acute lymphoblastic leukemia (ALL): induction therapy with asparaginase (primarily in combination with other agents)

U.S. Food and Drug Administration–Approved Dosage

  • Current literature to be consulted for doses
  • ALL: Induction therapy in combination with prednisone and vincristine—1,000 IU per kg of asparaginase i.v. daily × 10 days, starting day 22 or6,000 IU per m2 i.m. every 3 days for nine doses, starting day 4 of induction (day 1 is the first day of chemotherapy).

Dose Modification Criteria

No data available

Adverse Reactions

DERM: skin rash; ENDO: hyperglycemia; GI: N/V L2, pancreatitis, increased LFT values, increased bilirubin levels, and decreased serum albumin; GU: prerenal azotemia; HEMAT: coagulopathy; CNS: a variety of changes in mental status; OTHER: hypersensitivity, anaphylactic reactions, and hyperthermia.

Comments

  • [increased bilirubin levels] Asparaginase is contraindicated in patients with active pancreatitis or with a history of pancreatitis.
  • Hypersensitivity and anaphylactic reactions can occur during therapy.
  • Package insert may be consulted for test doses and desensitization schedules.
  • i.m. administration is preferred over i.v. administration (lower incidence of anaphylaxis).
  • i.v. infusions should be over a period of at least 30 minutes.

AZACITIDINE (VIDAZA)

Mechanism of Action

Azacitidine is an antimetabolite; a pyrimidine nucleoside analog of cytidine. It causes hypomethylation of deoxyribonucleic acid (DNA) and produces direct cytotoxicity on abnormal hematopoietic cells in the bone marrow.

U.S. Food and Drug Administration–Approved Indications

Myelodysplastic syndrome (MDS): The specific subtypes of MDS for which azacitidine is indicated include refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or when tranfusions are required), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

U.S. Food and Drug Administration–Approved Dosage

  • MDS: The recommended starting dosage is 75 mg per m2by s.c. injection, daily for 7 consecutive days, every 4 weeks. The dose may be increased to 100 mg per m2 if no beneficial effect is seen after two treatment cycles and if no toxicity other than nausea and vomiting occurs. Duration: recommended minimum duration of four treatment cycles; complete or partial response may take more than four treatment cycles; it may be continued as long as the patient continues to benefit.

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Dose Modification Criteria

Renal impairment: no data available (to be used with caution); Hepatic: no data available (to be used with caution); Myelosuppression: dose to be modified; nonhematologic toxicity (i.e., renal tubular acidosis and renal toxicity): dose to be modified.

Adverse Reactions

CNS: headache and dizziness; DERM: injection-site erythema or pain, ecchymosis, rash, and pruritus; ELECTRO: renal tubular acidosis (i.e., alkaline urine, fall in serum bicarbonate concentration, and hypokalemia); GI: N/V L1, diarrhea, constipation, anorexia, abdominal pain, and hepatotoxicity; GU: increased Cr and blood urea nitrogen (BUN) concentration, and renal failure; HEMAT: anemia, neutropenia, and thrombocytopenia; PULM: cough and dyspnea; OTHER: fever, rigors, fatigue, weakness, and peripheral edema.

Comments

  • Teratogenic (pregnancy category D): Women of childbearing potential should be advised to avoid becoming pregnant while receiving azacitidine. Men should be advised to not father a child while receiving azacitidine.
  • Azacitidine should be used with caution in patients with liver disease. It is potentially hepatotoxic in patients with preexisting hepatic impairment.
  • Azacitidine and its metabolites are primarily eliminated renally. Patients with renal impairment should be closely monitored for toxicity. Renal toxicity has been reported rarely with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS conditions.

BACILLE CALMETTE-GUÉRIN LIVE (INTRAVESICAL) (THERACYS, TICE BCG)

Mechanism of Action

Bacille Calmette-Guérin has local inflammatory and immune response effect.

U.S. Food and Drug Administration–Approved Indications

Treatment and prophylaxis of carcinoma in situ of the urinary bladder and for the prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethal resection (TUR).

U.S. Food and Drug Administration–Approved Dosage

  • TheraCys [each vial contains 81 mg (dry weight) or 10.5 ± 8.7 × 108colony-forming units and comes with a 3-mL diluent vial]:

One reconstituted vial (81 mg per 3 mL), diluted in 50 mL of sterile, preservative-free normal saline (0.9% sodium chloride injection), is instilled into bladder for as long as possible (for up to 2 hours) once weekly for 6 weeks (induction therapy), followed by one treatment at 3, 6, 12, 18, and 24 months each after the initial treatment (maintenance therapy).

  • Tice BCG [each vial contains 50 mg (wet weight) or 1–8 × 108colony-forming units]:

One reconstituted vial (50 mg per mL), diluted in a total volume of 50-mL preservative-free normal saline (0.9% sodium chloride injection), is instilled into bladder for as long as possible (for up to 2 hours) once weekly for 6 weeks, followed by once monthly for 6 to 12 months.

Dose Modification Criteria

Withhold Bacille Calmette-Guérin (BCG) live in case of any suspicion of systemic infection.

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Adverse Reactions

CNS: malaise, fever, and chills; GU: irritative bladder symptoms; OTHER: infectious complications (uncommon).

Comments

  • BCG live may complicate tuberculin skin test interpretation.
  • BCG live products contain live, attenuated mycobacteria. Because of the potential risk of transmission, it should be prepared, handled, and disposed of as a biohazard material.

BEVACIZUMAB (AVASTIN)

Mechanism of Action

Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig)G1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF).

U.S. Food and Drug Administration–Approved Indications

Metastatic carcinoma of the colon or rectum: first-line therapy in combination with intravenous 5-fluorouracil–based chemotherapeutic agents.

U.S. Food and Drug Administration–Approved Dosage

  • Metastatic colorectal cancer: 5 mg per kg i.v. infusion every 14 days until disease progression is detected
  • Do not administer as an i.v. push or bolus. The initial bevacizumab dose should be delivered over 90 minutes as an i.v. infusion following chemotherapy. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.

Dose Modification Criteria

Renal impairment: no dose modification; hepatic impairment: no dose modification; myelosuppression: no dose modification; nonhematologic toxicity: dose to be modified.

Adverse Reactions

CNS: headache; CV: hypertension, hypertensive crisis, and CHF; GI: N/VL1, diarrhea, abdominal pain, gastrointestinal perforation, and wound dehiscence; GU: proteinuria and nephrotic syndrome; INFUS: fever, chills, wheezing, and stridor; PULM: dyspnea and wheezing stridor; OTHER: epistaxis and other mild to moderate hemorrhagic events, serious hemorrhagic events, wound healing complications, deep vein thrombosis or other thromboembolic events, and asthenia.

Comments

  • Bevacizumab can result in the development of gastrointestinal perforation and wound dehiscence and other wound healing complications. The appropriate interval between termination of bevacizumab and subsequent elective surgery that is required to avoid the risks of wound healing or wound dehiscence has not been determined. Product labeling suggests that bevacizumab should not be initiated for at least 28 days following major surgery, and the surgical incision should be fully healed before starting therapy.

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  • Bleeding complications secondary to bevacizumab occur in two distinct patterns: minor hemorrhage (most commonly, grade 1 epistaxis) and serious, and in some cases fatal, hemorrhagic events. Patients with squamous cell non–small cell lung cancer (NSCLC) appear to be at higher risk for serious hemorrhagic events. The risk of CNS bleeding in patients with CNS metastases who are receiving bevacizumab has not been evaluated.
  • Blood pressure should be monitored every 2 to 3 weeks during therapy and more frequently in patients who develop hypertension.
  • Urinalysis should be done serially for proteinuria; patients with a 2+ or greater urine dipstick reading should undergo further assessment (e.g., a 24-hour urine collection).
  • Teratogenic (pregnancy category C): Angiogenesis is critical to fetal development and bevacizumab has been shown to be teratogenic in rabbits.

BEXAROTENE (TARGRETIN)

Mechanism of Action

Bexarotene is a retinoid that selectively binds and activates retinoid X receptor (RXR) subtypes. Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation.

U.S. Food and Drug Administration–Approved Indications

Cutaneous T-cell lymphoma (CTCL): second-line therapy for the cutaneous manifestations of CTCL in patients who are refractory to at least one prior systemic therapy

U.S. Food and Drug Administration–Approved Dosage

300 mg per m2 PO daily with a meal

Dose Modification Criteria

Renal impairment: no dose modification (caution as a result of possible protein binding alterations); hepatic impairment: use with caution; toxicity: dose to be modified.

Adverse Reactions

CNS: headache; CV: peripheral edema; DERM: dry skin, photosensitivity, rash, and pruritus; ENDO: hypothyroidism and hypoglycemia (diabetic patients); GI: nausea, pancreatitis, elevated LFT values, and abdominal pain; HEMAT: leukopenia and anemia; OCULAR: cataracts; OTHER: lipid abnormalities (i.e., elevated triglycerides, elevated total and LDL cholesterol, and decreased HDL cholesterol), asthenia, and infection.

Comments

  • Fasting blood lipid levels should be monitored before initiation of bexarotene and weekly after initiation of therapy until the lipid response is established (usually occurs within 2 to 4 weeks) and then at 8-week intervals thereafter.
  • LFT results should be monitored before initiation of bexarotene and then after 1, 2, and 4 weeks of treatment and, if stable, at least every 8 weeks thereafter for the treatment period.
  • Complete blood count and thyroid function tests to be monitored at baseline, and periodically thereafter.
  • Bexarotene is a teratogen (pregnancy category X) and may cause harm to fetus when administered to a pregnant woman. Bexarotene must not be given to a pregnant woman or to a woman who intends to become pregnant. Women of childbearing potential should obtain a negative

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pregnancy test within 1 week before starting bexarotene therapy, and the test should be repeated at monthly intervals while the patient remains on therapy. Effective contraception (two reliable forms used simultaneously) must be used for 1 month before initiation of therapy, during therapy, and for at least 1 month following discontinuation of therapy. Bexarotene may induce the metabolism of hormonal contraceptives and reduce their effectiveness; therefore, one form of contraception should be nonhormonal.

BICALUTAMIDE (CASODEX)

Mechanism of Action

Bicalutamide has antiandrogenic activity.

U.S. Food and Drug Administration–Approved Indications

Palliation of advanced prostate cancer (stage D2) in combination with a luteinizing hormone–releasing hormone (LH-RH) agonist.

U.S. Food and Drug Administration–Approved Dosage

50 mg PO daily

Dose Modification Criteria

Renal impairment: no dose modification; hepatic impairment (mild to moderate): no dose modification; hepatic impairment (severe): use with caution.

Adverse Reactions

ENDO: loss of libido, hot flashes, and gynecomastia; GI: nausea, diarrhea, and constipation; GU: impotence.

Comments

Monitor LFT results before treatment, at regular intervals for the first 4 months, and periodically thereafter.

BLEOMYCIN (BLENOXANE)

Mechanism of Action

The mechanism of action of bleomycin is unknown, but it may inhibit DNA and ribonucleic acid (RNA) synthesis.

U.S. Food and Drug Administration–Approved Indications

Squamous cell cancers, non-Hodgkin lymphoma, testicular cancer, Hodgkin disease, and malignant pleural effusions

U.S. Food and Drug Administration–Approved Dosage

  • A test dose (2 U or less) for the first two doses is recommended in patients with lymphoma.
  • The dosage is 0.25 to 0.50 U per kg (10 to 20 U per m2) i.v. or i.m. or s.c. weekly or twice weekly.
  • Malignant pleural effusions: 60 U as a single intrapleural bolus dose.

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Dose Modification Criteria

Renal impairment: use with caution (dose modification guidelines are not provided within package insert but are available from other references).

Adverse Reactions

DERM: erythema, rash, striae, vesiculation, hyperpigmentation, skin tenderness, alopecia, nail changes, pruritus, and stomatitis; PULM: pulmonary fibrosis (increases at cumulative doses >400 U, but can occur at lower total doses) and pneumonitis; Other: fever; chills; idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in 1% of lymphoma patients; and local pain with intrapleural administration.

Comments

  • Patient should be monitored for fine rales as an early indication of pulmonary toxicity.
  • Pulmonary toxicity is increased when oxygen is used during surgery.

BORTEZOMIB (VELCADE)

Mechanism of Action

Bortezomib is a reversible inhibitor of the 26S proteosome, a large protein complex that degrades ubiquitinated proteins. Inhibition of the 26S proteosome prevents targeted proteolysis, which can effect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death.

U.S. Food and Drug Administration–Approved Indications

Multiple myeloma: second-line therapy in patients with multiple myeloma who have received at least two earlier therapies and have demonstrated disease progression during the last therapy.

U.S. Food and Drug Administration–Approved Dosage

The dosage is 1.3 mg per m2 i.v. as a bolus injection administered twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21). Three weeks (21 days) is considered to be a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.

Dose Modification Criteria

Renal impairment: no data are available (use with caution); Hepatic impairment: no data are available (use with caution); Myelosuppression: dose to be modified; nonhematologic toxicity (e.g., neuropathy and neuropathic pain): dose to be modified

Adverse Reactions

CNS: peripheral neuropathy, neuropathic pain, dizziness, and headache; CV: hypotension (including orthostatic hypotension and syncope) and edema; DERM: rash; GI: N/V L2–3, diarrhea, anorexia, and constipation; HEMAT: myelosuppression (thrombocytopenia more severe than anemia, which is more severe than neutropenia); OCULAR: diplopia and blurred vision; PULM: dyspnea; OTHER: asthenia, fatigue, fever, insomnia, and arthralgia.

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BUSULFAN (MYLERAN); BUSULFAN INJECTION (BUSULFEX)

Mechanism of Action

Busulfan is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

  • Oral busulfan: Palliative treatment of chronic myelogenous leukemia (CML).
  • Parenteral (i.v.) busulfan: Conditioning regimen (in combination with cyclophosphamide) before allogeneic hematopoietic progenitor cell transplantation for CML.

U.S. Food and Drug Administration–Approved Dosage

  • Oral busulfan: induction: 4 to 8 mg PO daily; maintenance: 1 to 3 mg PO daily.
  • Parenteral (i.v.) busulfan:
  • Premedicate patients with phenytoin before busulfan administration.
  • For nonobese patients, use ideal body weight (IBW) or actual body weight, whichever is lower.
  • For obese or severely obese patients, use adjusted IBW (AIBW). AIBW should be calculated as follows: AIBW = IBW + 0.25 × (actual weight – IBW).
  • Dosage is 0.8 mg per kg over 2 hours every 6 hours × 16 doses (total dose: 12.8 mg per kg) with cyclophosphamide.

Dose Modification Criteria

Myelosuppression: dose to be modified

Adverse Reactions

CNS: seizures; DERM: hyperpigmentation; GI: N/V oral L1, i.v. L4; HEMAT: severe myelosuppression; HEPATIC: venoocclusive disease (VOD); PULM: pulmonary fibrosis and VOD.

Comments

  • Phenytoin reduces plasma area under the curve (AUC) of busulfan by 15%. Use of other anticonvulsants may result in higher plasma AUCs of busulfan and an increased risk of VOD or seizures. Monitor plasma busulfan exposure if other anticonvulsants are used.
  • High-dose oral busulfan regimens have also been utilized for conditioning regimens in the allogeneic stem cell transplantation setting. Consult current literature for dosing regimens.

CAPECITABINE (XELODA)

Mechanism of Action

Capecitabine is an antimetabolite that is enzymatically converted to fluorouracil in tumors.

U.S. Food and Drug Administration–Approved Indications

  • Colorectal cancer: first-line therapy for patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
  • Combination therapy for breast cancer: capecitabine combined with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure with earlier anthracycline-containing chemotherapy.

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  • Monotherapy for breast cancer: Third-line therapy for metastatic breast cancer (after paclitaxel and an anthracycline-containing chemotherapeutic regimen), or second-line (after paclitaxel) therapy if anthracycline is not indicated.

U.S. Food and Drug Administration–Approved Dosage

The dosage is 1,250 mg per m2 PO twice daily (total daily dose: 2,500 mg per m2) at the end of a meal for 2 weeks, followed by a 1-week rest period, given as 3-week cycles. Product labeling may be consulted for a dosing chart.

Dose Modification Criteria

Renal (mild impairment; CrCl 51 to 80 mL per minute): no modification to dosage; renal (moderate impairment; CrCl 30 to 50 mL per minute): dosage to be modified; hepatic (mild-to-moderate impairment because of liver metastases): no modification of dosage; toxicity (grade 2 toxicity or higher): dosage to be modified. Product labeling may be consulted for dose modification guidelines.

Adverse Reactions

CNS: fatigue or weakness, paresthesia, and peripheral sensory neuropathy; DERM: hand and foot syndrome (palmar–plantar erythrodysesthesia) and dermatitis; GI: N/V L2, diarrhea, mucositis, abdominal pain, anorexia, and hyperbilirubinemia; HEMAT: myelosuppression.

CARBOPLATIN (PARAPLATIN)

Mechanism of Action

Carboplatin is an alkylating-like agent producing interstrand DNA cross-links.

U.S. Food and Drug Administration–Approved Indications

Advanced ovarian cancer:

  • First-line therapy (in combination with other agents).
  • Second-line therapy (including patients who have previously received cisplatin).

U.S. Food and Drug Administration–Approved Dosage

  • With cyclophosphamide: 300 mg per m2i.v. × one dose on day 1 of the cycle; cycles to be repeated every 4 weeks × six cycles.
  • Single agent: 360 mg per m2i.v. × one dose every 4 weeks.
  • Formula dosing may be used as an alternative to dosing based on body surface area (BSA).
  • Calvert Formula for Carboplatin Dosing:

Total dose in milligrams = (target AUC) × [glomerular filtration rate (GFR) + 25].

  • The target AUC of 4 to 6 mg/mL/minute using single-agent carboplatin appears to provide the most appropriate dose range in previously treated patients.
  • The Calvert formula was based on studies where GFR was measured by 51Cr–EDTA clearance. Alternatively, many clinicians commonly use estimated CrCl equations to determine GFR.

Dose Modification Criteria

Renal impairment: dosage is to be modified; Myelosuppression: dosage is to be modified.

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Adverse Reactions

CNS: neuropathy; GI: N/V L4, increased LFT values; ELECTRO: Mg, Na, Ca, and K alterations; GU: Increased Cr and BUN; HEMAT: myelosuppression (thrombocytopenia greater than leukopenia and anemia); OTHER: anaphylactic reactions; pain and asthenia.

Comments

Not to be confused with cisplatin for dosing or during preparation.

CARMUSTINE (BICNU)

Mechanism of Action

Carmustine is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

Indicated as palliative therapy either as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following: brain tumors, multiple myeloma, Hodgkin disease, and non-Hodgkin lymphomas.

U.S. Food and Drug Administration–Approved Dosage

Single agent in previously untreated patients: 150 to 200 mg per m2 i.v. × one dose every 6 weeks, or 75 to 100 mg per m2 i.v. daily × two doses every 6 weeks.

Dose Modification Criteria

Myelosuppression: dosage to be modified.

Adverse Reactions

GI: N/V L5 for dosage >250 mg per m2, and L4 for dosage ≤250 mg per m2; increased LFT values; GU: nephrotoxicity with large cumulative doses; HEMAT: myelosuppression (can be delayed); OCULAR: retinal hemorrhages; PULM: pulmonary fibrosis (acute and delayed).

Comments

Risk of pulmonary toxicity increases with cumulative total doses >1,400 mg per m2 and in patients with a history of lung disease, radiation therapy, or concomitant bleomycin.

CETUXIMAB (ERBITUX)

Mechanism of Action

Cetuximab is a recombinant chimeric monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor (EGFR) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, thereby blocking the phosphorylation and activation of receptor-associated kinases.

U.S. Food and Drug Administration–Approved Indications

Metastatic colorectal carcinoma (second-line therapy): cetuximab is indicated for use in combination with irinotecan in EGFR-expressing metastatic colorectal carcinoma in patients

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who are refractory to irinotecan-based chemotherapy, and as monotherapy in patients who are intolerant to irinotecan-based chemotherapy.

U.S. Food and Drug Administration–Approved Dosage

In the treatment of metastatic colorectal carcinoma (combined with irinotecan or as monotherapy): 400 mg per m2 i.v. infusion over 120 minutes as an initial loading dose (first infusion) followed by a weekly maintenance dose of 250 mg per m2 i.v. infusion over 60 minutes. Premedication with an H1 antagonist (e.g., 50 mg of diphenhydramine i.v.) is recommended.

Dose Modification Criteria

Renal impairment: no dosage modification; hepatic impairment: no dosage modification; symptoms of non-hematologic toxicity (dermatologic toxicity): dosage to be modified.

Adverse Reactions

DERM: acneform rash, skin drying and fissuring, and nail toxicity; GI: nausea, constipation, and diarrhea; INFUS: chills, fever, dyspnea, airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension; PULM: interstitial lung disease; OTHER: asthenia, malaise, and fever.

Comments

  • Patients enrolled in the clinical studies of cetuximab for metastatic colorectal carcinoma were required to have immunohistochemical evidence of positive EGFR expression. Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.
  • Grade 1 and 2 infusion reactions (chills, fever, and dyspnea) are common (16% to 23%) usually on the first day of initial dosing. Severe infusion reactions have been observed in approximately 3% of patients and are characterized by a rapid onset of airway obstruction, urticaria, and/or hypotension. Severe infusion reactions require immediate interruption of the cetuximab infusion and permanent discontinuation from further treatment.
  • An acneform rash is common (approximately 90% overall, 10% grade 3) with cetuximab therapy and is most commonly observed on the face, upper chest, and back. Drying and fissuring of the skin are common and can be associated with sequelae of inflammatory responses or infections. Interruption of therapy and dose modification is recommended for severe dermatologic toxicity (product labeling may be consulted).
  • Interstitial lung disease has rarely been reported with cetuximab therapy. In the event of acute onset or worsening pulmonary symptoms, cetuximab therapy should be interrupted and symptoms should be promptly investigated.
  • Pregnancy Category C: No animal reproduction studies have been conducted and effects in pregnant women are unknown. However, EGFR has been implicated in the control of prenatal development and human immunoglobulin (Ig)G1 is known to cross the placental barrier.

CHLORAMBUCIL (LEUKERAN)

Mechanism of Action

Alkylating agent

U.S. Food and Drug Administration–Approved Indications

Palliation of CLL, Hodgkin disease, and non-Hodgkin lymphomas

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U.S. Food and Drug Administration–Approved Dosage

  • Initial and short courses of therapy: 0.1 to 0.2 mg per kg PO daily for 3 to 6 weeks as required. Usually the 0.1 mg/kg/day dosage is used except for Hodgkin disease, in which 0.2 mg/kg/day is used.
  • Alternate regimen in treatment of CLL (intermittent, biweekly, or once monthly pulses): Initial single dose of 0.4 mg per kg PO × one dose. Dose may be increase by 0.1 mg per kg until control of lymphocytosis is achieved.
  • Maintenance: Not to exceed 0.1 mg/kg/day.

Dose Modification Criteria

Myelosuppression: dose to be modified

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Adverse Reactions

CNS: seizures, confusion, twitching, and hallucinations; DERM: rash and rare reports of progressive skin hypersensitivity reactions; GI: N/V L1 and increased LFT values; HEMAT: myelosuppression and lymphopenia; PULM: pulmonary fibrosis; OTHER: allergic reactions, secondary acute myelomonocytic leukemia (AML) (long-term therapy), and sterility.

Comments

Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage; chlorambucil should be used with caution within 4 weeks of a full course of radiation therapy or chemotherapy.

CISPLATIN (PLATINOL)

Mechanism of Action

Cisplatin is an alkylating-like agent that produces interstrand DNA cross-links.

U.S. Food and Drug Administration–Approved Indications

  • Metastatic testicular tumors (in combination with other agents)
  • Metastatic ovarian tumors (in combination with other agents)
  • Advanced transitional cell bladder cancer that is no longer amenable to local treatments such as surgery and/or radiotherapy

U.S. Food and Drug Administration–Approved Dosage

  • In the treatment of metastatic testicular tumors: 20 mg per m2i.v. daily × 5 days every 4 weeks (in combination with other agents)
  • In treatment of metastatic ovarian tumors: 75 to 100 mg per m2i.v. × one dose (in combination with cyclophosphamide) every 4 weeks, or as single-agent therapy: 100 mg per m2 i.v. × one dose every 4 weeks
  • Advanced bladder cancer: 50 to 70 mg per m2i.v. × one dose every 3 to 4 weeks (single-agent therapy)

Dose Modification Criteria

Renal impairment: dose to be modified; myelosuppression: dose to be modified

Adverse Reactions

CNS: neuropathy, paresthesia, and ototoxicity; ELECTRO: Mg, Na, Ca, and K alterations; GI: N/V (for dose ≥50 mg per m2: L5, for dose <50 mg per m2: L4) increased LFT values [especially serum glutamic-oxaloacetic transaminase (ALT), bilirubin]; GU: increased Cr and BUN (cumulative); HEMAT: myelosuppression, and anemia; OCULAR: optic neuritis, papilledema, and cerebral blindness infrequently reported; OTHER: anaphylactic reactions and rare vascular toxicities.

Comments

  • Checking auditory acuity is recommended.
  • Vigorous hydration is recommended before and after cisplatin administration.
  • Use of other nephrotoxic agents (e.g., aminoglycosides) concomitantly with cisplatin should be undertaken with caution.
  • Every precaution should be taken to avoid inadvertent cisplatin overdose and confusion with carboplatin.

CLADRIBINE (LEUSTATIN)

Mechanism of Action

Antimetabolite

U.S. Food and Drug Administration–Approved Indications

Hairy cell leukemia

U.S. Food and Drug Administration–Approved Dosage

  • 0.09 mg per kg i.v. continuous infusion over 24 hours daily × 7 days (a single course of therapy)
  • Inadequate data available on dosing of patients with renal or hepatic insufficiency.

Dose Modification Criteria

Renal impairment: no data available on dosage modification; hepatic impairment: no data available on dosage modification.

Adverse Reactions

CNS: fatigue, headache, and peripheral neuropathy; GI: N/V L1; HEMAT: myelosuppression and lymphopenia; DERM: rash; OTHER: fever.

Comments

Immunosuppression (lymphopenia) persists for up to 1 year after cladribine therapy.

CYCLOPHOSPHAMIDE (CYTOXAN)

Mechanism of Action

Cyclophosphamide is an alkylating agent that is activated by the liver.

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U.S. Food and Drug Administration–Approved Indications

Lymphomas, leukemias, multiple myeloma, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, breast cancer.

U.S. Food and Drug Administration–Approved Dosage

  • Parenteral (i.v.): Many dosing regimens reported. Current literature may be consulted.
  • Oral: 1 to 5 mg/kg/day (many other regimens reported; Current literature may be consulted)

Dose Modification Criteria

Myelosuppression: dose to be modified.

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Adverse Reactions

CNS: syndrome of inappropriate antidiuretic hormone (SIADH); DERM: rash, skin and nail pigmentation, and alopecia; GI: N/V (>1,500 mg per m2: L5, between 750 mg per m2 and 1,500 mg per m2: L4, <750 mg per m2: L3), anorexia, and diarrhea; GU: hemorrhagic cystitis, renal tubular necrosis; HEMAT: myelosuppression (leukopenia greater than thrombocytopenia and anemia); PULM: pulmonary fibrosis; OTHER: secondary malignancies; sterility, amenorrhea; anaphylactic reactions; cardiac toxicity with high-dose regimens.

Comments

Encourage forced fluid intake and frequent voiding to reduce the risk of hemorrhagic cystitis. Use of vigorous intravenous hydration and Mesna therapy with high-dose cyclophosphamide may be considered.

CYTARABINE (CYTOSAR AND OTHERS)

Mechanism of Action

Cytarabine is an antimetabolite.

U.S. Food and Drug Administration–Approved Indications

Induction therapy of acute nonlymphocytic leukemia, (ANLL), in combination with other agents, ALL, blast-phase chronic myelocytic leukemia (CML), intrathecal prophylaxis and treatment of meningeal leukemia.

U.S. Food and Drug Administration–Approved Dosage

  • ALL: Current literature may be consulted for doses.
  • ANLL induction (in combination with other agents): 100 mg per m2i.v. continuous infusion over 24 hours × 7 days or 100 mg per m2i.v. every 12 hours × 7 days. Current literature may be consulted for alternative dosing regimens (e.g., high-dose regimens such as ≥1 g/m2/dose).
  • Intrathecally: (use preservative-free diluents) 30 mg per m2intrathecally every 4 days until cerebrospinal fluid (CSF) is clear, followed by one additional dose. Other doses and frequency of administration have also been utilized.

Dose Modification Criteria

Hepatic/Renal impairment: To be used with caution and at possibly reduced dose in patients with poor hepatic or renal function (no specific criteria). Neurotoxicity: dose to be modified.

Adverse Reactions

CNS: cerebellar dysfunction, somnolence, coma (generally seen with high-dose regimens), and chemical arachnoiditis (intrathecal administration); DERM: rash and alopecia; GI: N/V L2 (>1 g per m2 L4), anorexia, diarrhea, mucositis, increased LFT values and pancreatitis (in patients who have previously received asparaginase); HEMAT: myelosuppression; OCULAR: conjunctivitis (generally seen with high-dose regimens); OTHER: cytarabine (Ara-C) syndrome (includes fever, myalgia, bone pain, rash, conjunctivitis, and malaise); acute respiratory distress syndrome reported with high-dose regimens.

Comments

  • Appropriate prophylaxis may be considered for tumor lysis syndrome when treating acute leukemias.
  • Local corticosteroid eye drops may be considered to provide prophylaxis for conjunctivitis when employing high-dose regimens of cytarabine.
  • Therapy to be withheld if acute CNS toxicity occurs with high-dose regimens.

CYTARABINE LIPOSOME INJECTION (DEPOCYT)

Mechanism of Action

Cytarabine liposome is an antimetabolite.

U.S. Food and Drug Administration–Approved Indications

Intrathecal treatment of lymphomatous meningitis.

U.S. Food and Drug Administration–Approved Dosage

  • Given only by intrathecal route either by an intraventricular reservoir or directly into the lumbar sac over a period of 1 to 5 minutes.
  • Patients should be started on dexamethasone, 4 mg PO or i.v. twice daily × 5 days beginning on the day of the cytarabine liposome injection.
  • Induction: 50 mg intrathecally every 14 days × two doses (weeks 1 and 3).
  • Consolidation: 50 mg intrathecally every 14 days × three doses (weeks 5, 7, and 9) followed by an additional dose at week 13.
  • Maintenance: 50 mg intrathecally every 28 days × four doses (weeks 17, 21, 25, 29).

Dose Modification Criteria

Neurotoxicity: dose to be modified.

Adverse Reactions

CNS: Chemical arachnoiditis, headache, asthenia, confusion, and somnolence.

DACARBAZINE (DTIC-DOME)

Mechanism of Action

Mechanism of dacarbazine is unknown.

U.S. Food and Drug Administration–Approved Indications

Metastatic malignant melanoma, Hodgkin disease (second-line therapy).

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U.S. Food and Drug Administration–Approved Dosage

  • Malignant melanoma: 2 to 4.5 mg per kg i.v. daily × 10 days; repeat every 4 weeks, or 250 mg per m2i.v. daily × 5 days; repeat every 3 weeks.
  • Hodgkin disease: 150 mg per m2i.v. daily × 5 days, repeat every 4 weeks (in combination with other agents), or 375 mg per m2 i.v. on day 1, repeat every 15 days (in combination with other agents).

Adverse Reactions

DERM: alopecia, rash, facial flushing, and facial paresthesia; GI: N/V L5, anorexia, diarrhea, increased LFT values, and hepatic necrosis; OTHER: pain and burning at infusion, anaphylaxis, fever, myalgias, and malaise.

DACTINOMYCIN (COSMEGEN)

Mechanism of Action

Dactinomycin is an intercalating agent.

U.S. Food and Drug Administration–Approved Indications

Indicated as part of a combination chemotherapy or multi-modality treatment regimen for the following malignancies: Wilms tumor; childhood rhabdomyosarcoma; Ewing sarcoma; and metastatic, nonseminomatous testicular cancer. Indicated as a single agent or as part of a combination regimen for gestational trophoblastic neoplasia. Indicated as a component of regional perfusion in the treatment of locally recurrent or locoregional solid malignancies.

U.S. Food and Drug Administration–Approved Dosage

  • For obese or edematous patients, the dosage should be based on BSA.
  • Dose intensity should not exceed 15 µg per kg i.v. daily × 5 days or 400 to 600 µg per m2i.v. daily × 5 days, repeated every 3 to 6 weeks.
  • Current literature to be consulted for dosage regimens and guidelines.

Dose Modification Criteria

Myelosuppression: dose to be modified.

Adverse Reactions

DERM: alopecia, erythema, skin eruptions, radiation recall, and tissue damage or necrosis, with extravasation; ELECTRO: hypocalcemia; GI: N/V (>1.5 mg per m2: L4, ≤1.5 mg per m2: L3), mucositis, anorexia, dysphagia, increased LFT values, and hepatotoxicity; HEMAT: myelosuppression; OTHER: fever, fatigue, myalgia, and secondary malignancies.

Comments

Vesicant

DAUNORUBICIN (CERUBIDINE)

Mechanism of Action

Daunorubicin is an intercalating agent that inhibits topoisomerase-II.

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U.S. Food and Drug Administration–Approved Indications

In adult ANLL or ALL (children and adults) in combination with other agents for remission induction.

U.S. Food and Drug Administration–Approved Dosage

  • ANLL: in combination with cytarabine
  • Age <60 years: first course: 45 mg per m2i.v. daily × 3 days (days 1, 2, and 3); subsequent course: 45 mg per m2 i.v. daily × 2 days (days 1 and 2).
  • Age ≥60 years: first course: 30 mg per m2i.v. daily × 3 days (days 1, 2, and 3); subsequent course: 30 mg per m2 i.v. daily × 2 days (days 1 and 2).
  • Adult ALL: (combined with vincristine, prednisone, and L-asparaginase) 45 mg per m2i.v. daily × 3 days (days 1, 2, and 3).
  • Pediatric ALL: (combined with vincristine and prednisone) 25 mg per m2i.v. × one dose weekly × 4 weeks initially. In children younger than 2 years or <0.5 m2 BSA, the dosage should be based on weight (1 mg per kg) instead of BSA.

Dose Modification Criteria

Renal impairment: dose to be modified; hepatic: dose is to be modified.

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Adverse Reactions

CV: CHF, (risk of cardiotoxicity increases rapidly with total lifetime cumulative doses >400 to 550 mg per m2 in adults or >300 mg per m2 in children), arrhythmias; DERM: nail hyperpigmentation, rash, alopecia, tissue damage or necrosis, with extravasation; GI: N/V L3, mucositis; HEMAT: myelosuppression; Other: red-tinged urine, fever, chills, and secondary malignancies.

Comments

  • Vesicant
  • Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.

DAUNORUBICIN CITRATE LIPOSOME INJECTION (DAUNOXOME)

Mechanism of Action

Daunorubicin is an intercalating agent that inhibits topoisomerase-II.

U.S. Food and Drug Administration–Approved Indications

Advanced human immunodeficiency virus (HIV)-associated Kaposi sarcoma (first-line therapy).

U.S. Food and Drug Administration–Approved Dosage

40 mg per m2 i.v. over 60 minutes × one dose every 2 weeks.

Dose Modification Criteria

Hepatic: dose is to be modified; renal impairment: dose is to be modified; myelosuppression: dose is to be modified.

Adverse Reactions

CV: CHF, arrhythmias; DERM: nail, alopecia, hyperpigmentation, and rash; GI: N/V L2, mucositis, and diarrhea; HEMAT: myelosuppression; INFUS: back pain, flushing, and chest tightness (infusion-related reactions usually subside with interruption of the infusion, and generally do not recur if the infusion is then resumed at a slower rate); OTHER: red-tinged urine, fever, chills, and fatigue.

Comments

  • Not to be confused with nonliposomal forms of daunorubicin.
  • Liposomal formulations of the same drug may not be equivalent.
  • In anthracycline-naïve patients, cardiac function is to be evaluated by history and physical examination in each cycle and left ventricular ejection fraction (LVEF) function is to be determined at total cumulative doses of daunorubicin citrate liposome injection of 320 mg per m2and at every 160 mg per m2 thereafter. Patients with preexisting cardiac disease, with a history of radiotherapy encompassing the heart, or with previously received anthracyclines (doxorubicin >300 mg per m2 or equivalent) should have cardiac function (LVEF) monitored before daunorubicin citrate liposome injection therapy and before every 160 mg per m2 thereafter.

DENILEUKIN DIFTITOX (ONTAK)

Mechanism of Action

Denileukin diftitox is a fusion protein composed of diphtheria toxin fragments linked to interleukin 2 (IL-2) sequences; interacts with IL-2 cell surface receptors and inhibits cellular protein synthesis.

U.S. Food and Drug Administration–Approved Indications

Treatment of persistent or recurrent CTCL in patients whose malignant cells express the CD25 component of the IL-2 receptor.

U.S. Food and Drug Administration–Approved Dosage

  • Cells should be tested for CD25 before administration.
  • 9 or 18 µg per kg i.v. over at least 15 minutes daily × 5 days; cycles should be repeated every 21 days. Infusion should be stopped or infusion rate should be reduced for severe infusion-related reactions.

Adverse Reactions

CNS: dizziness; CV: vascular leak syndrome (hypotension and edema hypoalbuminemia), hypotension, and thrombotic events; DERM: rash, pruritus; GI: N/V L3, anorexia, diarrhea, and increased LFT values; HEMAT: anemia; INFUS: acute hypersensitivity-type reactions consisting of one or more of the following: hypotension, back pain, dyspnea, vasodilation, rash, chest pain or tightness, tachycardia, dysphagia, syncope, allergic reactions, or anaphylaxis; PULM: dyspnea and cough; OTHER: flu-like syndrome consisting of one or more of the following: fever and/or chills, asthenia, digestive symptoms, myalgias, and arthralgias (appears several hours to days after dose infusion).

Comments

  • Premedication with antipyretics and antihistamines to be considered; emergency medications and resuscitative equipment to be readily available during administration.

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  • Weight, blood pressure, and serum albumin level should be monitored for vascular leak syndrome. Patients with preexisting low serum albumin levels may be predisposed to the syndrome.
  • Patients should be monitored carefully for infection.

DOCETAXEL (TAXOTERE)

Mechanism of Action

Docetaxel has the effect of microtubule assembly stabilization.

U.S. Food and Drug Administration–Approved Indications

  • Unresectable, locally advanced, or metastatic NSCLC: first-line therapy in combination with cisplatin and second-line therapy as single agent after failure of prior platinum-based chemotherapy.
  • Locally advanced or metastatic breast cancer (after failure of earlier chemotherapy).
  • Androgen-independent (hormone-refractory) metastatic prostate cancer (in combination with prednisone).

U.S. Food and Drug Administration–Approved Dosage

  • Premedication for hypersensitivity reactions and fluid retention: dexamethasone, 8 mg PO twice daily for 3 days starting 1 day before docetaxel administration.
  • NSCLC:
  • First-line therapy (combined with cisplatin): 75 mg per m2i.v. over 1 hour × one dose every 3 weeks (administered immediately prior to cisplatin)
  • Second-line therapy (single agent): 75 mg per m2i.v. over 1 hour × one dose every 3 weeks.
  • Breast cancer: 60 to 100 mg per m2i.v. over 1 hour × one dose every 3 weeks.
  • Prostate cancer: 75 mg per m2i.v. over 1 hour × one dose every 3 weeks. Prednisone 5 mg orally twice daily is administered continuously.

Dose Modification Criteria

Hepatic: dose to be modified; myelosuppression: dose to be modified; nonhematologic toxicity: dose to be modified (package labeling to be consulted for dose modification guidelines)

Adverse Reactions

CNS: peripheral neurosensory toxicity (paresthesia, dysesthesia, and pain), fever, and asthenia; DERM: rash with localized skin eruptions, erythema and pruritus, nail changes (pigmentation, onycholysis, and pain), and alopecia; GI: N/V L2, diarrhea, mucositis, and increased LFT values; HEMAT: myelosuppression; INFUS: acute hypersensitivity-type reactions consisting of hypotension and/or bronchospasm or generalized rash/erythema; OTHER: severe fluid retention and myalgia.

Comments

  • Patients with preexisting hepatic dysfunction are at increased risk of severe toxicity.
  • Patients with preexisting effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.
  • Lower dose, weekly dosage regimens are commonly utilized. Current literature to be consulted for dose guidelines.
  • Non–diethylhexyl phthalate (DEHP) plasticized solution containers and administration sets to be used.

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DOXORUBICIN (ADRIAMYCIN AND OTHERS)

Mechanism of Action

Doxorubicin is an intercalating agent and inhibits topoisomerase-II.

U.S. Food and Drug Administration–Approved Indications

ALL, acute nonlymphocytic leukemia; Wilms tumor; neuroblastoma; soft tissue and bone sarcoma; breast, ovarian, thyroid, bronchiogenic, gastric cancer and transitional cell bladder cancer; Hodgkin disease; malignant lymphoma.

U.S. Food and Drug Administration–Approved Dosage

  • Many dosing regimens reported. Current literature may be consulted. Common dose regimens listed below.
  • Single agent: 60 to 75 mg per m2i.v. × one dose repeated every 3 weeks.
  • In combination with other agents: 40 to 60 mg per m2i.v. × one dose, repeated every 3 to 4 weeks.

Dose Modification Criteria

Hepatic: dose to be modified; myelosuppression: dose to be modified.

Adverse Reactions

CV: CHF, (risk of cardiotoxicity increases rapidly with total lifetime cumulative doses >450 mg per m2) and arrhythmias; DERM: nail hyperpigmentation, onycholysis, alopecia, radiation recall, tissue damage or necrosis with extravasation; GI: N/V (>60 mg per m2: L4, 20 to 60 mg per m2: L3, <20 mg per m2: L2) and mucositis; HEMAT: myelosuppression; OTHER: red-tinged urine, fever, chills, and secondary malignancies.

Comments

Vesicant

DOXORUBICIN HYDROCHLORIDE LIPOSOME INJECTION (DOXIL)

Mechanism of Action

Doxorubicin is an intercalating agent and inhibits topoisomerase-II.

U.S. Food and Drug Administration–Approved Indications

  • Acquired immunodeficiency syndrome (AIDS)–related Kaposi sarcoma (progressive disease after earlier combination chemotherapy or in patients intolerant to such therapy)
  • Metastatic ovarian cancer (second-line therapy after both paclitaxel- and platinum-based chemotherapy regimens)

U.S. Food and Drug Administration–Approved Dosage

  • AIDS-related Kaposi sarcoma: 20 mg per m2i.v. over 30 minutes × one dose, repeated every 3 weeks.
  • Ovarian cancer: 50 mg per m2i.v. over 60 minutes × one dose, repeated every 4 weeks.

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  • Note: Infusion should start at an initial rate of 1 mg per minute to minimize the risk of infusion reactions. If no infusion-related adverse events are observed, the rate of infusion can be increased to complete administration of the drug over 1 hour.

Dose Modification Criteria

Hepatic: dose to be modified; Palmar–plantar erythrodysesthesia: dose to be modified; Myelosuppression: dose to be modified; Stomatitis: dose to be modified.

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Adverse Reactions

CV: CHF and arrhythmias; DERM: palmar–plantar erythrodysesthesia, alopecia, and rash; GI: N/V L2, mucositis or stomatitis; HEMAT: myelosuppression; INFUS: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in chest or throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and/or hypotension; OTHER: asthenia and red-tinged urine.

Comments

  • Not to be confused with nonliposomal forms of doxorubicin.
  • Liposomal formulations of the same drug may not be equivalent.
  • Irritant
  • Mixed only with 5% dextrose water; not to be used in line filters
  • Most infusion-related events occur during the first infusion.
  • Experience with large cumulative doses of doxorubicin hydrochloride liposome injection is limited and cumulative dose limits based on cardiotoxicity risk have not been established. It is recommended by the manufacturer that cumulative dose limits established for conventional doxorubicin be followed for the liposomal product (e.g., cumulative doses ≥400 to 550 mg per m2depending on risk factors).

EPIRUBICIN (ELLENCE)

Mechanism of Action

Epirubicin is an intercalating agent and inhibits topoisomerase-II.

U.S. Food and Drug Administration–Approved Indications

Adjuvant therapy of axillary node–positive breast cancer.

U.S. Food and Drug Administration–Approved Dosage

The following dosage regimens were used in the trials supporting use of epirubicin as a component of adjuvant therapy in patients with axillary-node–positive breast cancer.

  • CEF 120: 60 mg per m2i.v. × one dose on days 1 and 8, (120 mg per m2 total dose each cycle), repeated every 28 days for six cycles. (Combined with cyclophosphamide and fluorouracil.)
  • FEC 100: 100 mg per m2i.v. × one dose on day 1 only, repeated every 21 days for six cycles. (Combined with cyclophosphamide and fluorouracil.)

Dose Modification Criteria

Renal impairment: dose to be modified; hepatic impairment: dose to be modified; myelosuppression: dose to be modified.

Adverse Reactions

CV: CHF (risk of cardiotoxicity increases rapidly with total lifetime cumulative doses >900 mg per m2), arrhythmias; DERM: alopecia, radiation recall, tissue damage or necrosis with extravasation; GI: N/V (>90 mg per m2: L4, ≤90 mg per m2: L3), and mucositis; HEMAT: myelosuppression; OTHER: facial flushing, and secondary malignancies.

Comments

Vesicant

ESTRAMUSTINE (EMCYT)

Mechanism of Action

Estramustine is an alkylating agent, an estrogen, and induces microtubule instability.

U.S. Food and Drug Administration–Approved Indications

Palliative treatment of metastatic and/or progressive carcinoma of the prostate.

U.S. Food and Drug Administration–Approved Dosage

  • 4.67 mg per kg PO three times daily (t.i.d.) or 3.5 mg per kg PO four times daily (q.i.d.); total daily dose: 14 mg per kg.
  • Administer with water, 1 hour before or 2 hours after meals. Avoid the simultaneous administration of milk, milk products, and calcium-rich foods and drugs.

Dose Modification Criteria

Hepatic impairment: to be administered with caution, no specific dose modifications

Adverse Reactions

CV: Edema, fluid retention, and venous thromboembolism; ENDO: hyperglycemia, gynecomastia, and impotence; GI: diarrhea, nausea, and elevated LFT values [especially glutamic-oxaloacetic transaminase (SGOT) or lactate dehydrogenase (LDH)]; PULM: dyspnea.

ETOPOSIDE (VEPESID)

Mechanism of Action

Etoposide leads to topoisomerase-II interaction.

U.S. Food and Drug Administration–Approved Indications

Refractory testicular cancer; small cell lung cancer (SCLC, first-line therapy in combination with other agents).

U.S. Food and Drug Administration–Approved Dosage

  • Testicular cancer: 50 to 100 mg per m2i.v. over 30 to 60 minutes daily × 5 days (days 1 to 5), repeated every 3 to 4 weeks or 100 mg per m2 i.v. over 30 to 60 minutes on days 1, 3, and 5,

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repeated every 3 to 4 weeks (in combination with other approved agents). Current literature may be consulted for dose recommendations.

  • SCLC: 35 to 50 mg per m2i.v. over 30 to 60 minutes daily × 4 to 5 days, repeated every 3 to 4 weeks (in combination with other agents). Current literature to be consulted for dose recommendations.
  • Oral capsules: In SCLC, the recommended dose of etoposide capsules is two times the i.v. dose rounded to the nearest 50 mg.

Dose Modification Criteria

Renal impairment: dose to be modified.

Adverse Reactions

DERM: alopecia, rash, urticaria, and pruritus; GI: N/V L2, mucositis, and anorexia; HEMAT: myelosuppression; INFUS: hypotension (infusion-rate related), anaphylactic-like reactions (characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension); OTHER: secondary malignancies.

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ETOPOSIDE PHOSPHATE (ETOPHOS)

Mechanism of Action

Etoposide phosphate is rapidly and completely converted to etoposide in plasma, leading to topoisomerase-II interaction.

U.S. Food and Drug Administration–Approved Indications

Refractory testicular cancer; SCLC, first-line therapy in combination with other agents.

U.S. Food and Drug Administration–Approved Dosage

  • Testicular cancer: 50 to 100 mg per m2i.v. daily × 5 days (days 1 to 5), repeated every 3 to 4 weeks or 100 mg per m2 i.v. on days 1, 3, and 5, repeated every 3 to 4 weeks (in combination with other approved agents). Current literature may be consulted for dose recommendations.
  • SCLC: 35 to 50 mg per m2i.v. daily × 4 to 5 days, repeated every 3 to 4 weeks (in combination with other agents). Current literature may be consulted for dose recommendations.
  • Higher rates of intravenous administration have been utilized and tolerated by patients with etoposide phosphate compared to etoposide. Etoposide phosphate can be administered at infusion rates from 5 to 210 minutes (generally infusion durations of 5 to 30 minutes have been utilized).

Dose Modification Criteria

Renal impairment: dose to be modified.

Adverse Reactions

DERM: alopecia, rash, urticaria, and pruritus; GI: N/V L2, mucositis, and anorexia; HEMAT: myelosuppression; INFUS: hypotension (infusion-rate related) and anaphylactic-like reactions (characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension); OTHER: secondary malignancies.

Comments

Etoposide phosphate is a water-soluble ester of etoposide. The water solubility of etoposide phosphate lessens the potential for precipitation following dilution and during intravenous administration. Enhanced water solubility also allows for lower dilution volumes and more rapid intravenous administration compared to conventional etoposide.

EXEMESTANE (AROMISAN)

Mechanism of Action

Exemestane is an irreversible steroidal aromatase inactivator.

U.S. Food and Drug Administration–Approved Indications

Advanced breast cancer after tamoxifen failure in postmenopausal women.

U.S. Food and Drug Administration–Approved Dosage

25 mg PO daily after a meal.

Dose Modification Criteria

Renal impairment: no dose modification; hepatic impairment: no dose modification.

Note: Drug exposure is increased with hepatic and/or renal insufficiency. The safety of chronic dosing in these settings has not been studied. On the basis of experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non–life-threatening adverse effects, dosage adjustment does not appear to be necessary.

Adverse Reactions

CNS: depression, insomnia, and anxiety; CV: hot flashes and edema; GI: nausea or increased appetite; HEMAT: lymphocytopenia; OTHER: tumor site pain, asthenia, fatigue, increased sweating, and fever.

FLOXURIDINE

Mechanism of Action

Floxuridine is an antimetabolite catabolized to fluorouracil.

U.S. Food and Drug Administration–Approved Indications

Palliative management of gastrointestinal adenocarcinoma metastasis to the liver when given by continuous regional intraarterial infusion in carefully selected patients who are considered incurable by surgery or other means.

U.S. Food and Drug Administration–Approved Dosage

0.1 to 0.6 mg/kg/day by continuous arterial infusion. The higher dose ranges (0.4 to 0.6 mg/kg/day) are usually employed for hepatic artery infusion because the liver metabolizes the drug, thereby reducing the potential for systemic toxicity. Therapy may be given until adverse reactions appear; when toxicities have subsided, therapy may be resumed. Patients may be maintained on therapy as long as response to floxuridine continues.

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Dose Modification Criteria

Renal impairment: no dose modification; hepatic impairment: no dose modification; myelosuppression: dose to be modified; nonhematologic toxicity: dose to be modified

Adverse Reactions

CV: myocardial ischemia; DERM: alopecia, dermatitis, and rash; GI: N/VL1–2, stomatitis, diarrhea, enteritis, gastrointestinal ulceration and bleeding, and elevated LFT values; HEMAT: myelosuppression; INFUS: procedural complications of regional arterial infusion: arterial aneurysm, arterial ischemia, arterial thrombosis, embolism, fibromyositis, thrombophlebitis, hepatic necrosis, abscesses, infection at catheter site, bleeding at catheter site, catheter blocked, displaced or leaking; OTHER: fever, lethargy, malaise, and weakness.

FLUDARABINE (FLUDARA)

Mechanism of Action

Fludarabine is an antimetabolite.

U.S. Food and Drug Administration–Approved Indications

B-cell CLL (second-line after alkylating agent therapy)

U.S. Food and Drug Administration–Approved Dosage

25 mg per m2 i.v. over 30 minutes daily × 5 days, repeated every 28 days.

Dose Modification Criteria

Renal impairment: dose to be modified

Adverse Reactions

CNS: weakness, agitation, confusion, visual disturbances, coma (severe neurotoxicity generally seen with high-dose regimens but have been reported rarely at recommended doses), and peripheral neuropathy; CV: edema; DERM: rash; GI: N/V L1, diarrhea, and anorexia; HEMAT: myelosuppression, autoimmune hemolytic anemia, and lymphopenia; PULM: pneumonitis and cases of severe pulmonary toxicity have been reported; OTHER: myalgia, tumor lysis syndrome, and fatigue.

Comments

  • Monitor for hemolytic anemia.
  • A high incidence of fatal pulmonary toxicity was seen in a trial investigating the combination of fludarabine with pentostatin. The combined use of fludarabine and pentostatin is not recommended.
  • Transfusion-associated graft versus host disease has been observed rarely after transfusion of nonirradiated blood in fludarabine-treated patients. Using only irradiated blood products should be considered if transfusions are necessary in patients undergoing treatment with fludarabine.
  • Monitor for tumor lysis syndrome and consider prophylaxis for patients with CLL with a large tumor burden who are initiated on fludarabine.

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FLUOROURACIL (ADRUCIL AND OTHERS)

Mechanism of Action

Fluorouracil is an antimetabolite.

U.S. Food and Drug Administration–Approved Indications

Palliative management of cancer of colon, rectum, breast, stomach, and pancreas.

U.S. Food and Drug Administration–Approved Dosage

Current literature may be consulted.

Adverse Reactions

CNS: Acute cerebellar syndrome, nystagmus, headache, visual changes, and photophobia; CV: angina and ischemia; DERM: dry skin, photosensitivity, hand-foot syndrome (palmar–plantar erythrodysesthesia), alopecia, dermatitis, and thrombophlebitis; GI: N/V L2, mucositis, diarrhea, anorexia, and gastrointestinal ulceration and bleeding; HEMAT: myelosuppression; OTHER: anaphylaxis and generalized allergic reactions.

Comments

Fluorouracil may be given by continuous intravenous infusion or by rapid i.v. administration (i.v. bolus or push). The method of administration will change the toxicity profile of fluorouracil (e.g., greater potential for GI toxicities such as mucositis and diarrhea with continuous i.v. infusions and more hematologic toxicity with bolus administration).

FLUTAMIDE (EULEXIN)

Mechanism of Action

Flutamide is an antiandrogen.

U.S. Food and Drug Administration–Approved Indications

Stage D2 metastatic prostate carcinoma [in combination with luteinizing hormone releasing hormone (LHRH) agonists] or locally confined stage B2–C prostate carcinoma (in combination with LHRH agonists and radiation therapy).

U.S. Food and Drug Administration–Approved Dosage

  • Stage D2 metastatic prostate carcinoma: 250 mg PO t.i.d. (every 8 hours).
  • Stage B2–C prostate cancer: 250 mg PO t.i.d. (every 8 hours) beginning 8 weeks before and continuing through radiation.

Adverse Reactions

DERM: Rash; GI: nausea, diarrhea, constipation, increased LFT values (LFT results to be monitored periodically because of rare associations with cholestatic jaundice, hepatic necrosis, and encephalopathy); GU: impotence; ENDO: loss of libido, hot flashes, and gynecomastia.

Comments

Interacts with warfarin; international normalized ratio (INR) to be monitored closely.

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FULVESTRANT (FASLODEX)

Mechanism of Action

Fulvestrant is an ER antagonist.

U.S. Food and Drug Administration–Approved Indications

Breast cancer: second-line therapy for hormone-receptor–positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

U.S. Food and Drug Administration–Approved Dosage

250 mg i.m. injection × one dose and repeated at 1-month intervals.

Dose Modification Criteria

Renal impairment: no dosage modification; hepatic (mild impairment): no dosage modification; hepatic (moderate-to-severe impairment): no data available, to be used with caution.

Adverse Reactions

CNS: headache; CV: peripheral edema; ENDO: hot flashes; GI: nausea, constipation, diarrhea, abdominal pain, and anorexia; OTHER: pain, pharyngitis, injection-site reactions, and asthenia.

GEFITINIB (IRESSA)

Mechanism of Action

Gefitinib is an inhibitor of multiple tyrosine kinases, including those associated with the EGFR.

U.S. Food and Drug Administration–Approved Indications

NSCLC: second-line monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.

U.S. Food and Drug Administration–Approved Dosage

250 mg PO daily

Dose Modification Criteria

Renal impairment: no dose modification; hepatic impairment: no dose modification.

Adverse Reactions

DERM: rash, acne, dry skin, and pruritus; GI: nausea, diarrhea, anorexia, and elevated LFT values; OCULAR: eye pain, corneal erosion or ulcer (sometimes in association with aberrant eyelash growth); PULM: interstitial lung disease (interstitial pneumonia, pneumonitis, and alveolitis); OTHER: asthenia, and weight loss.

Comments

  • For patients who present with acute onset or worsening of pulmonary symptoms (dyspnea, cough, and fever), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. Fatalities related to interstitial lung disease have been reported.

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  • Gefitinib is extensively hepatically metabolized, predominantly by cytochrome P450 (CYP) 3A4. Patients should be monitored for potential drug interactions with either potent inhibitors or inducers of CYP 3A4. A dose increase of gefitinib to 500 mg per day may be considered when given concomitantly with a potent CYP 3A4 enzyme inducer such as phenytoin or rifampin.
  • Gefitinib may potentially interact with warfarin, leading to an elevated prothrombin time (PT) and INR and bleeding events; PT/INR to be monitored regularly with concomitant use.

GEMCITABINE (GEMZAR)

Mechanism of Action

Gemcitabine is an antimetabolite.

U.S. Food and Drug Administration–Approved Indications

  • Pancreatic Cancer: first-line therapy for patients with locally advanced (nonresectable stage II or stage III) or metastatic (stage IV) adenocarcinoma of the pancreas and in patients with pancreatic cancer who were previously treated with fluorouracil.
  • NSCLC: first-line therapy (in combination with cisplatin) for patients with inoperable, locally advanced (stage IIIa or IIIb) or metastatic (stage IV) NSCLC.
  • Metastatic breast cancer: first-line therapy (in combination with paclitaxel) for patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

U.S. Food and Drug Administration–Approved Dosage

  • Pancreatic cancer (single agent use): 1,000 mg per m2i.v. over 30 minutes once weekly for up to 7 weeks, followed by 1 week of rest from treatment. Subsequent cycles should consist of 1,000 mg per m2 i.v. over 30 minutes once weekly for 3 consecutive weeks out of every 4 weeks.
  • NSCLC (combination therapy with cisplatin):
  • 4-week schedule: 1,000 mg per m2i.v. over 30 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin (100 mg per m2 i.v. × one dose) should be administered after gemcitabine only on day 1.
  • or 3-week schedule: 1,250 mg per m2i.v. over 30 minutes on days 1 and 8 of each 21-day cycle. Cisplatin (100 mg per m2 i.v. × one dose) should be administered after gemcitabine only on day 1.
  • Metastatic breast cancer (combination therapy with paclitaxel): 1,250 mg per m2i.v. over 30 minutes on days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg per m2 i.v. over 3 hours × one dose (day 1 only) before gemcitabine administration.

Dose Modification Criteria

Renal impairment: dose to be used with caution; hepatic impairment: dose to be used with caution; myelosuppression: dose to be modified; nonhematologic toxicity: dose to be modified.

Adverse Reactions

DERM: rash and alopecia; GI: N/V L2, constipation, diarrhea, mucositis, increased LFT values and bilirubin, and rare reports of severe hepatotoxicity; GU: proteinuria, hematuria, and hemolytic-uremic syndrome; HEMAT: myelosuppression; PULM: dyspnea, rare reports of severe pulmonary toxicity (pneumonitis, pulmonary fibrosis, pulmonary edema, and acute respiratory distress syndrome); OTHER: fever, pain, and rare reports of vascular toxicity (vasculitis).

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Comments

  • Clearance in women and elderly is reduced.
  • Intravenous administration rate has been shown to influence both efficacy and toxicity. Published literature should be referred to for the appropriate rate of administration for a specific regimen.

GEMTUZUMAB OZOGAMICIN (MYLOTARG)

Mechanism of Action

Gemtuzumab is a humanized monoclonal antibody directed at the CD33 cell surface antigen conjugated with a cytotoxic antitumor antibiotic, calicheamicin. Binding of the anti-CD33 antibody portion of gemtuzumab ozogamicin results in the internalization and release of the calicheamicin, which subsequently causes DNA double strand breakage and cell death.

U.S. Food and Drug Administration–Approved Indications

AML: second-line therapy for patients with CD33-positive AML who are in first relapse, who are 60 years of age or older, and who are not considered candidates for other cytotoxic chemotherapy.

U.S. Food and Drug Administration–Approved Dosage

  • 9 mg per m2i.v. over 2 hours × one dose. The recommended treatment course is a total of two doses with 14 days between the doses.
  • Consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white blood cell count to <30,000 per µL before administration of gemtuzumab ozogamicin.
  • Patients to be premedicated with diphenhydramine 50 mg PO and acetaminophen 650 to 1,000 mg PO 1 hour before the administration of gemtuzumab ozogamicin; thereafter, two additional doses of acetaminophen to be given every 4 hours as needed.
  • Consider prophylaxis for tumor lysis syndrome with hydration and allopurinol.

Dose Modification Criteria

Renal impairment: no data available for determining dosage; hepatic impairment: no data available for determining dosage (use with caution)

Adverse Reactions

CNS: headache; CV: hypotension, hypertension; DERM: rash; GI: N/V L3, mucositis, anorexia, constipation, diarrhea, elevated LFT values and/or bilirubin level, hepatic VOD; HEMAT: myelosuppression; INFUS: fever, chills, nausea, vomiting, headache, hypotension, hypertension, hyperglycemia, hypoxia, dyspnea, and anaphylaxis; PULM: dyspnea, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, and acute respiratory distress syndrome; OTHER: tumor lysis syndrome, infection, bleeding episodes, and asthenia.

Comments

  • Hepatotoxicity, including severe VOD, has been reported with gemtuzumab ozogamicin as a single agent and as part of a combination regimen. Patients who receive gemtuzumab ozogamicin either before or after hematopoietic stem cell transplantation, patients with underlying hepatic disease or abnormal liver function, and patients receiving combination regimens containing

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gemtuzumab ozogamicin may be at increased risk. Monitor for rapid weight gain, right upper quadrant pain, hepatomegaly, ascites, and elevations in bilirubin and/or liver enzymes.

  • Severe hypersensitivity reactions and other infusion-related reactions can occur (including severe pulmonary events) and can be fatal. Interrupt infusion for patients experiencing dyspnea or clinically significant hypotension. Discontinue treatment for patients who develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome.

GOSERELIN ACETATE IMPLANT (ZOLADEX)

Mechanism of Action

Goserelin is an LHRH agonist; chronic administration leads to sustained suppression of pituitary gonadotropins and subsequent suppression of serum testosterone in men and serum estradiol in women.

U.S. Food and Drug Administration–Approved Indications

  • Stage D2 metastatic prostate carcinoma or locally confined stage B2-C (in combination with flutamide and radiation therapy).
  • Palliative treatment of advanced breast cancer in pre- and perimenopausal women.
  • Other indications: endometriosis, endometrial thinning

U.S. Food and Drug Administration–Approved Dosage

  • Stage D2 metastatic prostate carcinoma: 3.6 mg s.c. depot monthly, or 10.8 mg s.c. depot every 12 weeks.
  • Stage B2-C prostate cancer: Start 8 weeks prior to initiating radiotherapy and continue through radiation. A treatment regimen of 3.6 mg s.c. depot, followed in 28 days by 10.8 mg s.c. depot. Alternatively, four injections of 3.6-mg s.c. depot can be administered at 28-day intervals, two depots preceding and two during radiotherapy.
  • Breast cancer: 3.6-mg s.c. depot every 4 weeks.

Dose Modification Criteria

Renal impairment: no dosage modification; hepatic impairment: no dosage modification.

Adverse Reactions

CV: transient changes in blood pressure (hypo- or hypertension); CNS: pain; ENDO: (men) hot flashes, gynecomastia, sexual dysfunction, and decreased erections; (women) hot flashes, headache, vaginal dryness, vaginitis, emotional lability, change in libido, depression, increased sweating, and change in breast size; GU: erectile dysfunction and lower urinary tract symptoms; OTHER: tumor flare in the first few weeks of therapy, loss of bone mineral density, osteoporosis, bone fracture, and asthenia.

Comments

Use with caution in patients at risk for developing ureteral obstruction or spinal cord compression.

HYDROXYUREA (HYDREA, DROXIA)

Mechanism of Action

Hydroxyurea inhibits DNA synthesis; it is a radiation sensitizer.

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U.S. Food and Drug Administration–Approved Indications

Use in combination with radiation therapy for melanoma; recurrent, metastatic, or inoperable ovarian cancer; resistant CML; and primary squamous cell carcinomas of the head and neck (excluding the lip). Hydroxyurea is also indicated in adult patients with sickle cell anemia with recurrent moderate-to-severe painful crises.

U.S. Food and Drug Administration–Approved Dosage

  • Dose based on actual or IBW, whichever is less.
  • Solid tumors:
  • Intermittent therapy: 80 mg per kg PO as a single dose every third day.
  • Continuous therapy: 20 to 30 mg per kg PO daily.
  • In combination with irradiation for head and neck cancer: 80 mg per kg PO as a single dose every third day, beginning 7 days before initiation of irradiation and continued indefinitely thereafter, based on adverse effects and response.
  • Resistant CML: 20 to 30 mg per kg PO daily

Dose Modification Criteria

Renal impairment: dose to be used with caution; hepatic impairment: dose to be used with caution; myelosuppression: dose to be modified.

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Adverse Reactions

CNS: drowsiness (large doses); DERM: rash, peripheral and facial erythema, skin ulceration, dermatomyositis-like skin changes, hyperpigmentation; GI: N/V L1, diarrhea, anorexia, mucositis, and constipation; HEMAT: myelosuppression (leukopenia and anemia more severe than thrombocytopenia).

Comments

  • Capsule contents may be emptied into glass of water and taken immediately (some inert particles may float on surface).
  • Patients should be counseled about proper handling precautions if they open the capsules.

IDARUBICIN (IDAMYCIN)

Mechanism of Action

Idarubicin is an intercalating agent and a topoisomerase-II inhibitor.

U.S. Food and Drug Administration–Approved Indications

In combination with other agents for adult AML (FAB classification M1 to M7).

U.S. Food and Drug Administration–Approved Dosage

AML induction in combination with cytarabine: 12 mg per m2 slow i.v. injection (over 10 to 15 minutes) daily for 3 days.

Dose Modification Criteria

Renal impairment: dose to be modified; hepatic impairment: dose to be modified; mucositis: dose to be modified.

Adverse Reactions

CV: CHF, arrhythmia; DERM: alopecia, radiation recall, and rash; GI: N/V L3, mucositis, abdominal cramps, and diarrhea; HEMAT: myelosuppression.

Comments

  • Vesicant.
  • Myocardial toxicity is increased in patients with prior anthracycline therapy or heart disease. Cumulative dose limit not established within package literature.
  • Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.

IFOSFAMIDE (IFEX)

Mechanism of Action

Ifosfamide is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

Germ cell testicular cancer (third-line therapy in combination with other agents).

U.S. Food and Drug Administration–Approved Dosage

1.2 g per m2 i.v. daily for 5 days, repeated every 3 weeks. Give Mesna 20% (wt/wt; 240 mg per m2 per dose for a 1.2 g per m2 ifosfamide dose) at time of ifosfamide, and then 4 and 8 hours after ifosfamide.

Dose Modification Criteria

Renal impairment: no known experience with dosage; hepatic impairment: no known experience with dosage; myelosuppression: dose to be modified; neurotoxicity: dose to be modified.

Adverse Reactions

CNS: encephalopathy, somnolence, confusion, depressive psychosis, hallucinations, and dizziness; DERM: alopecia; GI: N/V L3, increased LFT values; GU: hemorrhagic cystitis, Fanconi syndrome (proximal tubular impairment), glomerular or tubular toxicity; HEMAT: myelosuppression.

Comments

  • Ensure adequate hydration. Administer Mesna concurrently. Monitor for microscopic hematuria.
  • Discontinue therapy with the occurrence of neurologic toxicity. The incidence of CNS toxicity may be higher in patients with impaired renal function and/or low serum albumin.

IMATINIB (GLEEVEC)

Mechanism of Action

Imatinib is an inhibitor of multiple tyrosine kinases, including the Bcr-Abl tyrosine kinase, which is created by the Philadelphia chromosome abnormality in CML. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events.

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U.S. Food and Drug Administration–Approved Indications

  • CML:
  • First-line therapy for newly diagnosed adult patients with Philadelphia chromosome positive (Ph+) CML in chronic phase.
  • Second-line therapy for patients in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
  • Second-line therapy for pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplantation or who are resistant to interferon-α therapy.
  • Gastrointestinal stromal tumors (GIST): treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant GIST.

U.S. Food and Drug Administration–Approved Dosage

  • CLS:
  • Adult patients, chronic phase: 400 mg PO daily. Doses may be escalated to 600 mg per day as clinically indicated (package insert may be consulted for criteria).
  • Adult patients, accelerated phase: 600 mg PO daily. Doses may be escalated to 800 mg per day (400 mg PO b.i.d.) as clinically indicated (package insert may be consulted for criteria).
  • Children: 260 mg per m2PO daily. Doses may be escalated to 340 mg per day as clinically indicated (package insert may be consulted for criteria).
  • GIST: 400 mg or 600 mg PO daily.
  • The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. In children, imatinib can be given either as a once-a-day dose or divided into two doses (b.i.d.).

Dose Modification Criteria

Renal impairment: no data available; hepatic impairment: no data available; myelosuppression: dose to be modified; nonhematologic toxicity: dose to be modified

Adverse Reactions

CNS: headache and dizziness; CV: superficial edema (periorbital, lower limb), severe fluid retention (pleural effusion, ascites, pulmonary edema, and rapid weight gain); DERM: rash GI: nausea, diarrhea, GI irritation, dyspepsia, elevated LFT values, and severe hepatotoxicity; HEMAT: myelosuppression, and hemorrhage; PULM: cough; OTHER: muscle cramps, pain (musculoskeletal, joint, and abdominal), myalgia, arthralgia, nasopharyngitis, fatigue, and fever.

Comments

  • The CYP 3A4 enzyme is the major enzyme responsible for the metabolism of imatinib. Potential drug interactions with either potent inhibitors or inducers of CYP 3A4. Dosage of imatinib should be increased at least 50% and clinical response should be carefully monitored in patients receiving imatinib with a potent CYP3A4 inducer such as rifampin or phenytoin.
  • Monitor patient regularly for weight gain and signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema is increased with higher doses of imatinib and in patients older than 65 years.
  • LFT results are to be monitored before initiation of imatinib therapy and monthly thereafter or as clinically indicated.

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  • Complete blood counts (CBC) to be monitored before initiation of imatinib therapy, and then weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (e.g., every 2 to 3 months).

INTERFERON α-2A (ROFERON-A)

Mechanism of Action

Interferon α-2A suppresses cell proliferation and enhances macrophage phagocytic activity and lymphocyte cytotoxicity.

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U.S. Food and Drug Administration–Approved Indications

Oncology indications (adults, as old as 18 years or older): Hairy cell leukemia, AIDS-related Kaposi sarcoma, and CML (Philadelphia chromosome positive).

Other indications: chronic hepatitis C

U.S. Food and Drug Administration–Approved Dosage

  • Hairy cell leukemia: Induction, 3 million IU i.m. or s.c. daily for 16 to 24 weeks; maintenance, 3 million IU s.c. or i.m. 3 times a week.
  • AIDS-related Kaposi sarcoma: Induction, 36 million IU i.m. or s.c. daily for 10 to 12 weeks; maintenance, 36 million IU i.m. or s.c. 3 times a week.
  • CML: 9 million IU i.m. or s.c. daily. Initial tolerance may be improved over first week by giving 3 million IU daily × 3 days, then 6 million IU daily × 3 days, then increased to target dose of 9 million IU daily.
  • Continue treatment until disease progression or severe toxicity.

Dose Modification Criteria

In cases of serious adverse events: dose is to be modified.

Adverse Reactions

CNS: dizziness, depression, suicidal ideation, and paresthesias; DERM: skin rash, alopecia; ENDO: thyroid abnormalities; GI: diarrhea, nausea, anorexia, taste alteration, abdominal pain, and increased LFT values; HEMAT: myelosuppression; PULM: dyspnea, pulmonary infiltrates, pneumonitis, and pneumonia; OTHER: flu-like symptoms (i.e., fever, chills, headache, fatigue, malaise, and myalgia), hypersensitivity reactions, ophthalmologic disorders, and autoimmune disorders.

Comments

  • Patients with a preexisting psychiatric condition, especially depression, should not be treated.
  • Use with caution in patients with pulmonary disease, diabetes mellitus, coagulopathies, cardiac disorders, autoimmune diseases, or ophthalmologic disorders.
  • Recommended laboratory monitoring includes CBC, blood chemistries, LFTs, and thyroid-stimulating hormone (TSH) levels prior to beginning treatment and then periodically thereafter.
  • Other recommended baseline studies include a chest x-ray and an ophthalmologic examination.

INTERFERON α-2B (INTRON A)

Mechanism of Action

Interferon α-2B suppresses cell-proliferation and enhances macrophage phagocytic activity and lymphocyte cytotoxicity.

U.S. Food and Drug Administration–Approved Indications

Oncology indications (adults, as old as 18 years or older): hairy cell leukemia, malignant melanoma (adjuvant therapy to surgical treatment), AIDS-related Kaposi sarcoma, and follicular lymphoma (clinically aggressive disease in conjunction with anthracycline-containing combination chemotherapy).

Other indications: condyloma acuminata, chronic hepatitis C, and chronic hepatitis B

U.S. Food and Drug Administration–Approved Dosage

  • Hairy cell leukemia: 2 million IU per m2i.m. or s.c. 3 times a week for up to 6 months.
  • Malignant melanoma: Induction, 20 million IU per m2i.v. for 5 consecutive days per week for 4 weeks; maintenance, 10 million IU per m2 s.c. 3 times per week for 48 weeks.
  • Kaposi sarcoma: 30 million IU per m2s.c. or i.m. 3 times a week.
  • Follicular lymphoma (in combination with an anthracycline-containing chemotherapy regimen): 5 million IU s.c. 3 times a week for up to 18 months.

Dose Modification Criteria

In case of serious adverse events: dose is to be modified.

Adverse Reactions

CNS: dizziness, depression, suicidal ideation, and paresthesias; DERM: skin rash, alopecia; ENDO: thyroid abnormalities; GI: diarrhea, nausea, anorexia, taste alteration, abdominal pain, and increased LFT values; HEMAT: myelosuppression; PULM: dyspnea, pulmonary infiltrates, pneumonitis, and pneumonia; OTHER: “flu-like symptoms” (fever, chills, headache, fatigue, malaise, and myalgia), hypersensitivity reactions, ophthalmologic disorders, and autoimmune disorders.

Comments

  • Patients with a preexisting psychiatric condition, especially depression, should not be treated.
  • Use with caution in patients with pulmonary disease, diabetes mellitus, coagulopathies, cardiac disorders, autoimmune diseases, or ophthalmologic disorders.
  • Recommended laboratory monitoring includes CBC, blood chemistries, LFTs, and TSH levels before beginning treatment and then periodically thereafter.
  • Other recommended baseline studies include a chest x-ray and an ophthalmologic examination.

IRINOTECAN (CAMPTOSAR)

Mechanism of Action

Irinotecan is a topoisomerase-I inhibitor.

U.S. Food and Drug Administration–Approved Indications

  • Metastatic colon or rectal cancer
  • First-line therapy in combination with fluorouracil and leucovorin
  • Second-line therapy (single agent) after fluorouracil-based therapy.

U.S. Food and Drug Administration–Approved Dosage

  • First-line combination-agent dosing (product labeling may be consulted for fluorouracil/leucovorin dosing):
  • Regimen 1: 125 mg per m2i.v. over 90 minutes weekly × four doses (days 1, 8, 15, and 22) followed by 2 weeks of rest. Repeat every 6 weeks

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  • Regimen 2: 180 mg per m2i.v. over 90 minutes every 2 weeks (days 1, 15, and 29) for each cycle. Each cycle is 6 weeks in duration
  • Second-line single-agent dosing:
  • Weekly regimen: 125 mg per m2i.v. over 90 minutes weekly for four doses (days 1, 8, 15, and 22) followed by 2 weeks rest. Repeat every 6 weeks
  • Once-every-three-week regimen: 350 mg per m2i.v. over 90 minutes every 3 weeks.

Dose Modification Criteria

Hepatic impairment: dose to be modified; pelvic or abdominal irradiation: dose to be modified; myelosuppression: dose to be modified; nonhematologic toxicity: dose to be modified (package labeling to be consulted for dose modifications).

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Adverse Reactions

CNS: insomnia and dizziness; CV: vasodilation; DERM: alopecia, sweating, and rash; GI: N/V L3, diarrhea (early and late), abdominal pain, mucositis, anorexia, flatulence, and increased bilirubin, LFT values; HEMAT: myelosuppression; PULM: dyspnea, coughing, and rhinitis; OTHER: asthenia and fevers.

Comments

Can induce both early (within 24 hours of administration) and late forms of diarrhea. The early onset diarrhea is cholinergic in nature and may be accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and abdominal cramping. These early cholinergic symptoms can be treated by administration of atropine. Late onset of diarrhea (generally after 24 hours) should be treated aggressively with high-dose loperamide. Each patient should be instructed to have loperamide readily available so that treatment can be initiated at the earliest onset of diarrhea. Package labeling may be consulted for dosage recommendations for atropine and loperamide.

LETROZOLE (FEMARA)

Mechanism of Action

Letrozole is a selective, nonsteroidal aromatase inhibitor.

U.S. Food and Drug Administration–Approved Indications

Breast cancer:

  • First-line treatment of postmenopausal women with hormone-receptor–positive or hormone-receptor–unknown, locally advanced or metastatic breast cancer.
  • Second-line treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

U.S. Food and Drug Administration–Approved Dosage

2.5 mg PO daily.

Dose Modification Criteria

Renal impairment (CrCl ≥10 mL per minute): no dose modification; hepatic (mild-to-moderate impairment): no dose modification; hepatic (severe impairment): dose to be modified.

Adverse Reactions

CNS: headache; GI: nausea, constipation, or diarrhea; OTHER: hot flashes, fatigue, musculoskeletal pain, arthralgia, and peripheral edema.

LEUPROLIDE ACETATE (LUPRON, LUPRON DEPOT, LUPRON DEPOT-3 MONTH, LUPRON DEPOT-4 MONTH, VIADUR)

Mechanism of Action

Leuprolide acetate is an LHRH agonist; chronic administration leads to sustained suppression of pituitary gonadotropins and subsequent suppression of serum testosterone in men and serum estradiol in women.

U.S. Food and Drug Administration–Approved Indications

  • Palliative treatment of advanced prostate cancer.
  • Other indications: endometriosis, uterine leiomyomata (fibroids), central precocious puberty.

U.S. Food and Drug Administration–Approved Dosage

Prostate cancer: Lupron: 1 mg s.c. daily; Lupron Depot: 7.5 mg i.m. monthly; Lupron Depot-3 month: 22.5 mg i.m. every 3 months; Lupron Depot-4 month: 30 mg i.m. every 4 months; Viadur implant: one implant (contains 72 mg of leuprolide acetate) every 12 months.

Adverse Reactions

CV: transient changes in blood pressure (hypo- or hypertension); ENDO: hot flashes, gynecomastia, sexual dysfunction, and decreased erections; GU: erectile dysfunction, lower urinary tract symptoms, and testicular atrophy; OTHER: tumor flare in the first few weeks of therapy, bone pain, injection-site reactions, loss of bone mineral density, osteoporosis, bone fracture, and asthenia.

Comments

  • Use with caution in patients at risk for developing ureteral obstruction or spinal cord compression.
  • Because of different release characteristics, a fractional dose of the 3-month or 4-month Lupron Depot formulation is not equivalent to the same dose of the monthly formulation and should not be given.

LEVAMISOLE (ERGAMISOL)

Mechanism of Action

Mechanism of levamisole is unknown; levamisole may be an immunomodulator.

U.S. Food and Drug Administration–Approved Indications

Adjuvant treatment in combination with fluorouracil after surgical resection in patients with Dukes stage C colon cancer

U.S. Food and Drug Administration–Approved Dosage

  • Initial therapy:
  • Levamisole 50 mg PO every 8 hours for 3 days (starting 7 to 30 days after surgery) and
  • Fluorouracil 450 mg per m2i.v. daily × 5 days (starting 21 to 34 days postsurgery) and concomitant with a 3-day course of levamisole.

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  • Maintenance therapy:
  • Levamisole 50 mg PO every 8 hours for 3 days every 2 weeks for 1 year
  • Fluorouracil 450 mg per m2i.v. once a week, beginning 28 days after the initiation of the 5-day initial course and continued for a total treatment time of 1 year.

Dose Modification Criteria

Hepatic (severe impairment): use with caution; myelosuppression: dose to be modified.

Adverse Reactions

CNS: cases of an encephalopathy syndrome associated with demyelination reported; DERM: rash, dermatitis, and alopecia; GI: nausea, diarrhea, mucositis, anorexia, and abdominal pain; HEMAT: myelosuppression and agranulocytosis; OTHER: dysgeusia and fatigue.

Comments

Monitor for myelosuppression and agranulocytosis. Concomitant use with alcohol may result in a disulfiram (Antabuse) reaction. Levamisole may interact with phenytoin, leading to elevated phenytoin plasma levels; monitor phenytoin plasma levels with concomitant use. Levamisole may also interact with warfarin, leading to an increased PT and INR.

LOMUSTINE (CCNU, CEE NU)

Mechanism of Action

Lomustine is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

Primary and metastatic brain tumors; Hodgkin disease (second-line therapy in combination with other agents).

U.S. Food and Drug Administration–Approved Dosage

Single-agent therapy: 100 to 130 mg per m2 as a single oral dose every 6 weeks.

Dose Modification Criteria

Myelosuppression: dose to be modified.

Adverse Reactions

GI: N/V (≥60 mg per m2: L5, ≤60 mg per m2: L3) increased LFT values, and mucositis; GU: increased BUN and Cr; HEMAT: severe delayed myelosuppression and cumulative myelosuppression; PULM: (cumulative and usually occurs after 6 months of therapy or a cumulative lifetime dose of 1,100 mg per m2, although it has been reported with total lifetime doses as low as 600 mg), fibrosis, and infiltrate; OTHER: secondary malignancies.

Comments

  • A single dose is given every 6 weeks.
  • Blood counts to be monitored at least weekly for 6 weeks after a dose.

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MECHLORETHAMINE (MUSTARGEN)

Mechanism of Action

Mechlorethamine is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

  • Systemic (intravenous) palliative treatment of bronchogenic carcinoma, CLL, CML, Hodgkin disease (stages III and IV), lymphosarcoma, malignant effusions, mycosis fungoides, and polycythemia vera.
  • Palliative treatment of malignant effusions from metastatic carcinoma; administered intrapleurally, intraperitoneally, or intrapericardially.

U.S. Food and Drug Administration–Approved Dosage

  • Intravenous administration: 0.4 mg per kg i.v. × one dose per course or 0.2 mg per kg i.v. daily × 2 days repeated every 3 to 6 weeks. Dosage should be based on ideal dry body weight. Other dosing regimens are utilized; current literature may be consulted.
  • MOPP regimen (Hodgkin disease): mechlorethamine 6 mg per m2i.v. × one dose administered on days 1 and 8 of a 28-day cycle (combined with vincristine, prednisone, and procarbazine).
  • Intracavitary administration: 0.2 to 0.4 mg per kg for intracavitary injection. Current literature may be consulted for dose and administration technique. The technique and the dose vary for the various intracavitary routes (intrapleural, intraperitoneal, and intrapericardial).

Dose Modification Criteria

Myelosuppression: dose to be modified.

Adverse Reactions

CNS: vertigo, tinnitus, and diminished hearing; DERM: alopecia, phlebitis, tissue damage or necrosis with extravasation, rash; GI: N/V L5, metallic taste in mouth, and diarrhea; HEMAT: myelosuppression; OTHER: hyperuricemia, secondary malignancies, infertility, and azoospermia.

Comments

Vesicant.

MEDROXYPROGESTERONE ACETATE (DEPO-PROVERA)

Mechanism of Action

Medroxyprogesterone acetate is a derivative of progesterone.

U.S. Food and Drug Administration–Approved Indications

Adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal cancer.

U.S. Food and Drug Administration–Approved Dosage

400 to 1,000 mg i.m. injection × one dose. Doses may be repeated weekly initially; if improvement is noted, the dose may be reduced to maintenance doses as low as 400 mg i.m. monthly.

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Adverse Reactions

CNS: headache, nervousness, dizziness, and depression; CV: edema, weight gain, and thromboembolic events; DERM: urticaria, pruritus, rash, acne, alopecia, and hirsutism; ENDO: breast tenderness and galactorrhea; GI: nausea, cholestatic jaundice; GU: breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, and changes in cervical erosion and secretions; OCULAR: neuroocular lesions (retinal thrombosis and optic neuritis); OTHER: hypersensitivity reactions, fever, fatigue, insomnia, somnolence, and injection-site reactions.

MEGESTROL (MEGACE AND OTHERS)

Mechanism of Action

Megestrol is a progestational agent.

U.S. Food and Drug Administration–Approved Indications

Palliative therapy of advanced breast cancer and endometrial cancer.

U.S. Food and Drug Administration–Approved Dosage

  • Breast cancer: 40 mg PO q.i.d. (four times daily; total daily dose: 160 mg per day).
  • Endometrial cancer: 10 mg PO q.i.d. to 80 mg PO q.i.d. (four times daily; total daily dose: 40 to 320 mg per day).

Adverse Reactions

CNS: mood changes; CV: deep vein thrombosis; DERM: alopecia; ENDO: Cushing-like syndrome, hyperglycemia, glucose intolerance, weight gain, and hot flashes; GU: vaginal bleeding; OTHER: carpal tunnel syndrome and tumor flare.

Comments

Other indications include cancer and AIDS-related anorexia and cachexia as an appetite stimulant and to promote weight gain. Usual dose range: 160 to 800 mg per day (consult current literature).

MELPHALAN (ALKERAN); MELPHALAN INJECTION

Mechanism of Action

Melphalan is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

Palliative therapy for multiple myeloma and nonresectable ovarian cancer.

U.S. Food and Drug Administration–Approved Dosage

  • Multiple myeloma:
  • Oral administration: 6 mg PO daily × 2 to 3 weeks. Wait up to 4 weeks for count recovery, and then 2 mg PO daily to achieve mild myelosuppression. Package insert and current literature may be consulted for other dosing regimens.
  • Intravenous administration. (if oral therapy not appropriate): 16 mg per m2i.v. over 15 to 20 minutes every 2 weeks × four doses, and then after adequate recovery from toxicity,

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repeat administration at 4-week intervals. Current literature to be referred to for other dosing regimens.

  • Ovarian cancer: 0.2 mg per kg PO daily × 5 days, repeated every 4 to 5 weeks depending on hematologic tolerance. Current literature to be referred for other dosing regimens.

Dose Modification Criteria

Renal impairment: dose to be modified; myelosuppression: dose to be modified.

Adverse Reactions

DERM: vasculitis, alopecia, and skin ulceration or necrosis at injection site (rare); HEMAT: myelosuppression and hemolytic anemia; GI: N/V L1 (oral), L4 (high dose i.v.), diarrhea, mucositis, anorexia, and increased LFT values; PULM: pulmonary toxicity (pulmonary fibrosis and interstitial pneumonitis); OTHER: hypersensitivity reactions, secondary malignancies, and infertility.

Comments

  • Oral absorption is highly variable, with considerable patient-to-patient variability in systemic availability. Oral dosages may be adjusted on the basis of blood counts to achieve some level of myelosuppression to ensure that potentially therapeutic levels of the drug have been reached.
  • In an experimental mouse model, melphalan injection showed a lack of vesicant activity, although the melphalan solvent (acid or alcohol in propylene glycol) was ulcerogenic if injected undiluted (3).

MERCAPTOPURINE (PURINETHOL)

Mechanism of Action

Mercaptopurine is an antimetabolite.

U.S. Food and Drug Administration–Approved Indications

  • ALL: indicated in the remission induction and maintenance therapy of ALL. May be used as a single agent, but a higher complete remission rate is seen with combination chemotherapy.
  • AML

U.S. Food and Drug Administration–Approved Dosage

  • Induction: 2.5 mg per kg (to nearest 25 mg) PO once daily × 4 weeks, and then to be adjusted according to blood counts.
  • Maintenance: 1.5 to 2.5 mg per kg PO once daily.

Dose Modification Criteria

Renal impairment: dose reduction to be considered for modification; hepatic impairment: dose reduction to be considered for modification; myelosuppression: dose to be modified.

Adverse Reactions

DERM: rash and alopecia; GI: anorexia, N/V L1, mucositis, and hepatotoxicity; HEMAT: myelosuppression; OTHER: tumor lysis syndrome.

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Comments

  • Monitoring of LFT results, bilirubin at weekly intervals initially and then monthly intervals.
  • Usually, there is complete cross-resistance with thioguanine.
  • Oral mercaptopurine dose should be reduced to 25% to 33% of usual daily dose in patients receiving allopurinol concomitantly.
  • Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.

METHOTREXATE

Mechanism of Action

Methotrexate is an antimetabolite.

U.S. Food and Drug Administration–Approved Indications

  • Neoplastic disease indications: Gestational tumors (i.e., choriocarcinoma, chorioadenoma destruens, and hydatidiform mole), ALL (maintenance therapy in combination with other agents and in the prophylaxis of meningeal leukemia), treatment of meningeal leukemia, breast cancer, epidermoid cancers of the head or neck, advanced mycosis fungoides, lung cancers (particularly squamous cell and small cell types), advanced-stage non-Hodgkin lymphoma, lymphosarcoma, and nonmetastatic osteosarcoma (high-dose therapy followed by leucovorin rescue).
  • Other indications: psoriasis (i.e., severe, recalcitrant, and disabling); rheumatoid arthritis (severe).

U.S. Food and Drug Administration–Approved Dosage

  • Choriocarcinoma and similar trophoblastic diseases: 15 to 30 mg PO or i.m. daily × 5 days. Treatment courses are repeated 3 to 5 times, with rest periods of 1 or more weeks between courses to allow for toxic symptoms to subside. Current literature may be consulted.
  • ALL maintenance therapy (following induction): 15 mg per m2PO or i.m. twice weekly (total weekly dose of 30 mg per m2) or 2.5 mg per kg i.v. every 14 days (in combination with other agents). Current literature to be referred to for combination regimens for both induction and maintenance regimens in ALL.
  • Meningeal leukemia (intrathecal administration): in patients younger than 1 year, 6 mg intrathecally; 1 year to younger than 2 years, 8 mg intrathecally; 2 years to younger than 3 years, 10 mg intrathecally; older than 3 years, 12 mg intrathecally. Current literature may be consulted.
  • Mycosis fungoides: 2.5 to 10 mg PO daily × weeks to months or 50 mg i.m. weekly or 25 mg i.m. twice weekly. Current literature may be consulted.
  • Nonmetastatic osteosarcoma: 12 g per m2i.v. over 4 hours × one dose (with leucovorin rescue, vigorous hydration, and urinary alkalinization) given weekly (weeks 4, 5, 6, and 7 after surgery), and then weeks 11, 12, 15, 16, 29, 30, 44, and 45. Leucovorin doses should be adjusted on the basis of methotrexate concentrations. Methotrexate is usually given with other agents. Current literature may be consulted.
  • Other indications: Current literature may be consulted.

Dose Modification Criteria

Renal impairment: dose to be modified.

Adverse Reactions

CNS: acute chemical arachnoiditis (intrathecal), subacute myelopathy (intrathecal), chronic leukoencephalopathy (intrathecal), and acute neurotoxicity or encephalopathy (high-dose i.v. therapy); DERM: alopecia, rash, urticaria, telangiectasia, acne, photosensitivity, and severe

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dermatologic reactions; GI: N/V (≤50 mg per m2 L1, >50 to <250 mg per m2 L2, 250 to 1,000 mg per m2 L3, >1,000 mg per m2 L4), mucositis/stomatitis, diarrhea, increased LFT values, and acute and chronic hepatotoxicity; GU: renal failure (high-dose therapy) and cystitis; HEMAT: myelosuppression; PULM: interstitial pneumonitis; OTHER: fever, malaise, chills, fatigue, teratogenic, and tumor lysis syndrome.

Comments

  • Clearance is reduced in patients with impaired renal function or third-space fluid accumulations (e.g., ascites and pleural effusions). Methotrexate distributes to third-space fluid accumulations, with subsequent slow and delayed clearance, leading to prolonged terminal plasma half-life and toxicity.
  • Nonsteroidal anti-inflammatory drugs and acidic drugs inhibit methotrexate clearance. Multiple potential drug interactions; current literature may be reviewed.
  • Use vigorous hydration, urinary alkalinization, and leucovorin rescue with high-dose therapy.
  • Preservative-free product and diluents to be used when administering intrathecally or with high-dose i.v. regimens.

MITOMYCIN C (MUTAMYCIN)

Mechanism of Action

Mitomycin C induces DNA cross-links through alkylation; inhibits DNA and RNA synthesis.

U.S. Food and Drug Administration–Approved Indications

Disseminated gastric cancer or pancreatic cancer (in combination with other agents and as palliative treatment when other modalities have failed).

U.S. Food and Drug Administration–Approved Dosage

Single-agent therapy: 20 mg per m2 i.v. × 1 dose repeated every 6 to 8 weeks.

Current literature may be referred to for alternative dosing regimens and combination regimens.

Dose Modification Criteria

  • Renal impairment: dose to be modified; myelosuppression: dose to be modified.

Adverse Reactions

CV: CHF (patients with prior doxorubicin exposure); DERM: alopecia, pruritus, tissue damage or necrosis with extravasation; GI: anorexia, N/V L2, mucositis, and diarrhea; GU: increased Cr; HEMAT: myelosuppression (may be cumulative); PULM: nonproductive cough, dyspnea, and interstitial pneumonia; OTHER: fever, hemolytic uremic syndrome, malaise, and weakness.

Comments

Vesicant.

MITOTANE (LYSODREN)

Mechanism of Action

Mitotane is an adrenal cytotoxic agent.

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U.S. Food and Drug Administration–Approved Indications

Inoperable, functional, and nonfunctional adrenal cortical carcinoma.

U.S. Food and Drug Administration–Approved Dosage

Initial dose: 2 to 6 g PO per day in three to four divided doses. Doses are usually increased incrementally to 9 to 10 g per day or until maximum tolerated dose is achieved. Maximum tolerated dose range varies from 2 to 16 g per day but has usually been 9 to 10 g per day. Total daily doses should be administered in three to four divided doses.

Adverse Reactions

CNS: vertigo, depression, lethargy, somnolence, and dizziness; DERM: transient skin rashes; GI: anorexia, nausea, and diarrhea; OTHER: adrenal insufficiency.

Comments

  • Adrenal insufficiency precautions to be instituted.
  • Patients should be counseled regarding the common CNS side effects, and ambulatory patients should be cautioned about driving, operating machinery, and other hazardous pursuits requiring mental and physical alertness.

MITOXANTRONE (NOVANTRONE)

Mechanism of Action

Mitoxantrone interacts with DNA and is an intercalating agent and a topoisomerase-II inhibitor.

U.S. Food and Drug Administration–Approved Indications

  • ANLL (myelogenous, promyelocytic, monocytic, and erythroid acute leukemia) in adults (initial therapy in combination with other agents)
  • Advanced hormone-refractory prostate cancer (in combination with corticosteroids)
  • Other indications: Multiple sclerosis.

U.S. Food and Drug Administration–Approved Dosage

  • ANLL: Induction, 12 mg per m2i.v. daily × 3 days (days 1, 2, and 3) in combination with cytarabine; consolidation, 12 mg per m2 i.v. daily × 2 days (days 1 and 2) in combination with cytarabine.
  • Prostate cancer: 12 to 14 mg per m2i.v. × one dose every 21 days with prednisone or hydrocortisone.

Dose Modification Criteria

Renal impairment: no data available; hepatic impairment: to be used with caution; dose adjustment may be considered.

Adverse Reactions

CV: CHF (clinical risk increases after a lifetime cumulative dose of 140 mg per m2), tachycardia, electrocardiographic changes, and chest pain; DERM: rash, alopecia, urticaria, nail bed changes; GI: N/V (>15 mg per m2: L4, ≤15 mg per m2: L3), mucositis, constipation,

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anorexia, and increased LFT values; HEMAT: myelosuppression; PULM: dyspnea; OTHER: bluish green urine, sclera may turn bluish, phlebitis (irritant), fatigue, secondary leukemias, and tumor lysis syndrome.

Comments

  • Appropriate prophylaxis may be considered for tumor lysis syndrome when treating acute leukemias.

NILUTAMIDE (NILANDRON)

Mechanism of Action

Nilutamide is an antiandrogen.

U.S. Food and Drug Administration–Approved Indications

Metastatic prostate cancer (stage D2; in combination therapy with surgical castration). Dosing should begin on same day or day after surgical castration.

U.S. Food and Drug Administration–Approved Dosage

Give 300 mg PO daily × 30 days, and then 150 mg PO daily (with or without food).

Adverse Reactions

CNS: dizziness; CV: hypertension, and angina; ENDO: hot flashes, impotence, and decreased libido; GI: nausea, anorexia, increased LFT values (LFT results to be monitored periodically because of rare associations with cholestatic jaundice, hepatic necrosis, and encephalopathy), and constipation; OCULAR: visual disturbances and impaired adaptation to dark; PULM: interstitial pneumonitis and dyspnea.

Comments

  • Baseline chest x-ray to be obtained before initiating therapy (with consideration of baseline pulmonary function tests). Patients should be instructed to report any new or worsening shortness of breath and if symptoms occur, nilutamide should be immediately discontinued.
  • LFT results should be monitored at baseline and at regular intervals × 4 months and then periodically thereafter.

OXALIPLATIN (ELOXATIN)

Mechanism of Action

Oxaliplatin is an alkylating-like agent producing interstrand DNA cross-links.

U.S. Food and Drug Administration–Approved Indications

Advanced or metastatic colorectal cancer:

  • First-line therapy in combination with infusional fluorouracil and leucovorin in patients with advanced colorectal cancer.
  • Second-line therapy in combination with infusional fluorouracil and leucovorin in patients with metastatic colorectal cancer whose disease has recurred or progressed within 6 months of completion of first-line therapy with the combination of bolus fluorouracil/leucovorin and irinotecan.

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U.S. Food and Drug Administration–Approved Dosage

Combined therapy with infusional fluorouracil and leucovorin (FOLFOX regimen)

Day 1:

  • Oxaliplatin 85 mg per m2i.v. over 120 minutes × 1 dose given concurrently with
  • Leucovorin 200 mg per m2i.v. over 120 minutes × 1 dose followed by
  • Fluorouracil 400 mg per m2i.v. bolus over 2 to 4 minutes × 1 dose followed by
  • Fluorouracil 600 mg per m2i.v. continuous infusion over 22 hours.

Day 2:

  • Leucovorin 200 mg per m2i.v. over 120 minutes × 1 dose, followed by
  • Fluorouracil 400 mg per m2i.v. bolus over 2 to 4 minutes × 1 dose, followed by
  • Fluorouracil 600 mg per m2i.v. continuous infusion over 22 hours.

Cycles are repeated every 2 weeks.

Dose Modification Criteria

Renal impairment: no data available (to be used with caution); myelosuppression: dose to be modified; nonhematologic toxicity: dose to be modified.

Adverse Reactions

CNS: peripheral sensory neuropathies (details follow under “Comments”), headache; CV: edema, thromboembolic events; DERM: injection-site reactions; GI: N/V L3, diarrhea, mucositis or stomatitis, abdominal pain, anorexia, taste perversion, and elevated LFT values; GU: elevated serum creatinine; HEMAT: myelosuppression; PULM: pulmonary fibrosis, dyspnea, and cough; OTHER: fatigue, fever, back pain, pain, and hypersensitivity reaction.

Comments

  • Oxaliplatin is associated with two types of peripheral neuropathy:
  1. An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset (from within hours to 1 to 2 days of dosing), that resolves within 14 days, and that frequently recurs with further dosing. The symptoms include transient paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat. Symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects. Patients should be instructed to avoid cold drinks and use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.
  2. A persistent (>14 days), primarily peripheral, sensory neuropathy usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities. Dose modifications are recommended for persistent grade 2 neurotoxicity and discontinuation of therapy is recommended for persistent grade 3 neurotoxicity.

PACLITAXEL (TAXOL)

Mechanism of Action

Paclitaxel stabilizes microtubule assembly.

U.S. Food and Drug Administration–Approved Indications

  • Advanced ovarian cancer (first-line and subsequent therapy). As first-line therapy, paclitaxel is indicated in combination with cisplatin.
  • Breast cancer

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  • Adjuvant treatment of node-positive breast cancer (administered sequentially to standard doxorubicin-containing combination chemotherapy)
  • Second-line therapy for breast cancer (after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy)
  • NSCLC (first-line therapy in combination with cisplatin) in patients who are not candidates for potentially curative surgery and/or radiation therapy.
  • AIDS-related Kaposi sarcoma (second-line therapy).

U.S. Food and Drug Administration–Approved Dosage

  • Patients are to be premedicated with dexamethasone, diphenhydramine (or its equivalent), and H2antagonists (e.g., cimetidine or ranitidine) to prevent severe hypersensitivity reactions. Suggested package literature premedication regimen: dexamethasone 20 mg PO × two doses administered approximately 12 and 6 hours before paclitaxel; diphenhydramine 50 mg i.v. 30 to 60 minutes before paclitaxel; and cimetidine 300 mg i.v. or ranitidine 50 mg i.v. 30 to 60 minutes before paclitaxel. Current literature may be consulted for alternative premedication regimens.
  • First-line ovarian cancer: 135 mg per m2i.v. continuous infusion over 24 hours or 175 mg per m2 i.v. over 3 hours (followed by cisplatin 75 mg per m2 i.v.) every 3 weeks.
  • Second-line ovarian cancer: 135 mg per m2or 175 mg per m2 i.v. over 3 hours every 3 weeks. Current literature may be consulted for alternative regimens.
  • Adjuvant therapy of node-positive breast cancer: 175 mg per m2i.v. over 3 hours every 3 weeks × four cycles (administered sequentially with doxorubicin-containing chemotherapy).
  • Second-line breast cancer: 175 mg per m2i.v. over 3 hours every 3 weeks.
  • NSCLC: 135 mg per m2i.v. continuous infusion over 24 hours (followed by cisplatin 75 mg per m2 i.v.) every 3 weeks.
  • AIDS-related Kaposi sarcoma: 135 mg per m2i.v. over 3 hours every 3 weeks or 100 mg per m2 i.v. over 3 hours every 2 weeks. (Note: reduce the dose of dexamethasone premedication dose to 10 mg PO per dose instead of the suggested 20 mg PO dose).

Dose Modification Criteria

Hepatic impairment: dose to be modified; myelosuppression: dose to be modified; nonhematologic toxicity (neuropathy): dose to be modified.

Adverse Reactions

CNS: peripheral neurosensory toxicity (paresthesia, dysesthesia, and pain); CV: hypotension, bradycardia, and electrocardiographic changes; DERM: alopecia, onycholysis (more common with weekly dosing), and injection-site reactions; GI: N/V L2, diarrhea, and mucositis; HEMAT: myelosuppression; INFUS: acute hypersensitivity-type reactions; OTHER: arthralgia, and myalgia.

Comments

  • Use non-DEHP plasticized solution containers and administration sets.
  • Inline filtration (0.22-µ filter) required during administration.
  • Lower dose, weekly dosage regimens are commonly utilized. Current literature may be consulted for dose guidelines.

PEGASPARGASE (ONCASPAR)

Mechanism of Action

Pegaspargase is a modified (pegylated) version of the enzyme L-asparaginase. L-asparaginase depletes asparagine, an amino acid required by some leukemic cells.

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U.S. Food and Drug Administration–Approved Indications

Patients with ALL who are hypersensitive to native forms of L-asparaginase.

U.S. Food and Drug Administration–Approved Dosage

  • The preferred route is i.m.; i.v. administration should be over 1 to 2 hours.
  • Combination or sole induction therapy: Adults and children, with BSA ≥0.6 m2: 2,500 IU per m2i.m. or i.v. × one dose every 14 days.
  • Children with BSA <0.6 m2: 82.5 IU per kg i.m. or i.v. × 1 dose every 14 days.

Adverse Reactions

CNS: malaise, confusion, lethargy, and depression; CV: chest pain, hypertension, and hypotension; DERM: alopecia, itching, and injection-site reactions; ENDO: hyperglycemia; GI: anorexia; N/V L1-2, hepatotoxicity, increased LFT values, and pancreatitis; GU: increased BUN and Cr; HEMAT: hypofibrinogenemia; PULM: respiratory distress, cough, and epistaxis; OTHER: hypersensitivity reaction, fever, arthralgia, musculoskeletal pain, and tumor lysis syndrome.

Comments

Contraindications: active pancreatitis or history of pancreatitis, serious hemorrhagic episode with native L-asparaginase, serious allergic reactions (e.g., bronchospasm) to native L-asparaginase.

PEMETREXED (ALIMTA)

Mechanism of Action

Pemetrexed is an antimetabolite and also an antifolate that disrupts folate-dependent metabolic process essential for cell replication.

U.S. Food and Drug Administration–Approved Indications

Malignant pleural mesothelioma: in combination with cisplatin in patients whose disease is unresectable or who are otherwise ineligible for curative surgery.

U.S. Food and Drug Administration–Approved Dosage

Malignant pleural mesothelioma: 500 mg per m2 i.v. over 10 minutes on day 1 of each 21-day cycle. The recommended dose of cisplatin (in combination with pemetrexed) is 75 mg per m2 i.v. over 2 hours, beginning approximately 30 minutes after the end of pemetrexed. See comments section for premedication regimen for pemetrexed.

Dose Modification Criteria

Renal impairment (CrCl ≥45 mL per minute): no dose modification, renal impairment (CrCl <45 mL per minute): administration is not recommended; hepatic impairment: no data available; myelosuppression: dose to be modified; nonhematologic toxicity: dose to be modified.

Adverse Reactions

DERM: rash, desquamation; GI: N/V L2, mucositis, pharyngitis, diarrhea, anorexia, and increased LFT values; HEMAT: neutropenia, thrombocytopenia, and anemia; OTHER: fatigue, fever.

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Comments

  • Vitamin supplementation: Patients treated with pemetrexed must be instructed to take folic acid and vitamin B12as a prophylactic measure to reduce treatment-related hematologic and GI toxicity. Patients should receive at least five daily doses of folic acid (most common daily dose: 400 µg) during the 7-day period prior to the first dose of pemetrexed and dosing should continue during the full course of therapy and for 21 days after the last dose. Patients must also receive one intramuscular dose of vitamin B12 (1,000 µg) during the week prior to the first dose of pemetrexed and every three cycles (9 weeks) thereafter.
  • Corticosteroid premedication: Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reactions. Recommended regimen (product labeling): dexamethasone 4 mg PO b.i.d. × 3 days (six doses) beginning the day before each dose of pemetrexed (the day before, the day of, and the day after pemetrexed).
  • Pregnancy category D: Pemetrexed may cause fetal harm when administered to pregnant women. Pemetrexed is fetotoxic and teratogenic in mice; there are no studies of pemetrexed in pregnant women.

PENTOSTATIN (NIPENT)

Mechanism of Action

Pentostatin is an antimetabolite and an adenosine deaminase inhibitor.

U.S. Food and Drug Administration–Approved Indications

Hairy cell leukemia (first-line and in α-interferon-refractory disease)

U.S. Food and Drug Administration–Approved Dosage

4 mg per m2 i.v. every other week. The optimal treatment duration has not been determined. The package insert suggests continued treatment until a complete response has been achieved followed by two additional doses.

Dose Modification Criteria

Renal impairment: dose to be modified; myelosuppression: dose to be modified.

Adverse Reactions

DERM: rash; GI: N/V L3-4, and elevated LFT values; GU: mild transient rise in serum creatinine; HEMAT: leukopenia, anemia, and thrombocytopenia; OTHER: fever, infection, and fatigue.

Comments

  • A high incidence of fatal pulmonary toxicity was seen in a trial investigating the combination of fludarabine with pentostatin. The combined use of fludarabine and pentostatin is not recommended.
  • Patients should receive hydration (500 to 1,000 mL) before and after each pentostatin dose.

POLIFEPROSAN 20 WITH CARMUSTINE IMPLANT (GLIADEL WAFER)

Mechanism of Action

The polifeprosan 20 with carmustine implant is designed to deliver carmustine directly into the surgical cavity created when a brain tumor is resected. On exposure to the aqueous environment

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of the resection cavity, carmustine is released from the copolymer and diffuses into the surrounding brain tissue. Carmustine is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

  • High-grade malignant glioma (first-line therapy in newly diagnosed patients as an adjunct to surgery and radiation)
  • Recurrent glioblastoma multiforme as an adjunct to surgery.

U.S. Food and Drug Administration–Approved Dosage

Each wafer contains 7.7 mg of carmustine. Up to eight wafers should be implanted at time of surgery (eight wafers result in a dose of 61.6 mg).

Adverse Reactions

CNS: meningitis, abscess, and brain edema; GI: nausea; OTHER: abnormal healing, pain, and fever.

Comments

Wafers can be broken in half. Proper handling and disposal precautions should be observed.

PORFIMER (PHOTOFRIN)

Mechanism of Action

Porfimer is a photosensitizing agent.

U.S. Food and Drug Administration–Approved Indications

  • Esophageal cancer (palliation of complete or partial obstruction)
  • Endobronchial NSCLC
  • For reduction of obstruction and palliation of symptoms in patients with completely or partially obstructed endobronchial NSCLC.
  • For treatment of microinvasive endobronchial NSCLC in patients for whom surgery and radiotherapy are not indicated.
  • High-grade dysplasia in Barrett esophagus (ablation of high-grade dysplasia in patients who do not undergo esophagectomy).

U.S. Food and Drug Administration–Approved Dosage

2 mg per kg i.v. injection over 3 to 5 minutes × one dose followed by photodynamic therapy. For the treatment of esophageal and endobronchial cancer, patients may receive up to three additional courses; each course should be administered no sooner than 30 days after the previous course. For the ablation of high-grade dysplasia in Barrett esophagus, patients may receive up to three additional courses; each course should be administered no sooner than 90 days after the previous course.

Adverse Reactions

CNS: anxiety, confusion, and insomnia; CV: hypertension, hypotension, heart failure, chest pain, atrial fibrillation, and tachycardia; DERM: photosensitivity; HEMAT: anemia; GI: N/VL2, abdominal pain, anorexia, constipation, dysphagia, esophageal edema, and esophageal stricture;

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PULM: pleural effusion, dyspnea, pneumonia, pharyngitis, cough, respiratory insufficiency, and tracheoesophageal fistula; OTHER: fever.

Comments

Patients are photosensitive (including eyes) for at least 30 days after administration.

PROCARBAZINE (MATULANE)

Mechanism of Action

Mechanism of action of procarbazine is unknown. There is evidence that the drug may act by inhibition of protein, RNA, and DNA synthesis.

U.S. Food and Drug Administration–Approved Indications

Stages III and IV Hodgkin disease: first-line therapy in combination with other anticancer drugs. [Procarbazine is used as part of the MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy regimen.]

U.S. Food and Drug Administration–Approved Dosage

  • All doses based on actual body weight unless the patient is obese or there has been a spurious weight increase, in which case lean body weight (dry weight) should be used.
  • Doses may be given as a single daily dose or divided throughout the day.
  • MOPP regimen for Hodgkin disease: 100 mg per m2PO daily × 14 days (in combination with mechlorethamine, vincristine, and prednisone).
  • Adult single-agent therapy: 2 to 4 mg per kg PO daily × 7 days, and then 4 to 6 mg per kg PO daily until maximal response is obtained. Maintenance dose: 1 to 2 mg per kg PO daily.
  • Pediatric single-agent therapy: 50 mg per m2PO daily × 7 days, and then 100 mg per m2 PO daily until maximum response is obtained. Maintenance dose: 50 mg per m2 PO daily.

Adverse Reactions

CNS: paresthesias, confusion, lethargy, and mental depression; DERM: pruritus, hyperpigmentation, and alopecia; GI: anorexia, N/V L4, stomatitis, xerostomia, diarrhea, and constipation; HEMAT: myelosuppression; OTHER: fever, and myalgia.

Comments

  • Disulfiram-like (Antabuse) reaction can occur; alcoholic beverages are to be avoided while taking procarbazine.
  • Procarbazine is a weak monoamine oxidase inhibitor (MAOI); tyramine-rich foods as well as sympathomimetic drugs and tricyclic antidepressants are to be avoided.

RITUXIMAB (RITUXAN)

Mechanism of Action

Rituximab is a chimeric (murine, human) monoclonal antibody directed at the CD20 antigen found on the surface of normal and malignant B lymphocytes.

U.S. Food and Drug Administration–Approved Indications

Relapsed or refractory low-grade or follicular, CD20-positive, B cell, non-Hodgkin lymphoma.

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U.S. Food and Drug Administration–Approved Dosage

  • Premedication with acetaminophen and/or diphenhydramine should be considered before each infusion.
  • If patient experiences an infusion-related reaction, the infusion should be stopped, the patient managed symptomatically, and then the infusion should be restarted at half the rate once the symptoms have resolved.
  • 375 mg per m2i.v. weekly × four doses (days 1, 8, 15, 22) or eight doses.
  • First infusion: to start at 50 mg per hour, and then may increase by 50 mg per hour every 30 minutes up to a maximum of 400 mg per hour. Subsequent infusions if prior infusions tolerated: to start at 100 mg per hour, and then may increase by 100 mg per hour every 30 minutes up to a maximum of 400 mg per hour.

Adverse Reactions

CNS: headache, and dizziness; CV: hypotension, arrhythmias, and peripheral edema; DERM: rash, pruritus, urticaria, and severe mucocutaneous reactions; GI: N/V L1-2, and abdominal pain; HEMAT: angioedema, leukopenia, thrombocytopenia, and neutropenia; INFUS: fever, chills, rigors, hypoxia, pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock; OTHER: throat irritation, rhinitis, bronchospasm, hypersensitivity reaction, myalgia, back pain, and tumor lysis syndrome.

Comments

  • Tumor lysis syndrome has been reported within 12 to 24 hours after the infusion (high risk: high numbers of circulating malignant cells).
  • Mild-to-moderate infusion reactions consisting of fever, chills, and rigors occur in the majority of patients during the first infusion. The reactions resolve with slowing or interruption of the infusion and with supportive care measures. The incidence of infusion reactions declines with subsequent infusions.
  • A more severe infusion-related complex, usually reported with the first infusion (hypoxia, pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock) has resulted in fatalities.
  • Severe mucocutaneous reactions, some with fatal outcome, have been reported in association with rituximab treatment.
  • Rituximab is commonly combined with cytotoxic chemotherapy agents in various subtypes of B cell non-Hodgkin lymphoma. Current literature may be consulted for dosing regimens.

STREPTOZOTOCIN (ZANOSAR)

Mechanism of Action

Streptozotocin is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

Metastatic islet cell carcinoma of the pancreas (functional and nonfunctional carcinomas).

U.S. Food and Drug Administration–Approved Dosage

  • Daily schedule: 500 mg per m2i.v. daily × 5 days every 6 weeks until maximum benefit or treatment limiting toxicity is observed, or
  • Weekly schedule: Initial dose: 1 g per m2i.v. weekly for the first two courses (weeks). In subsequent courses, drug doses may be escalated in patients who have not achieved a

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therapeutic response and who have not experienced significant toxicity with the previous course of treatment. However, a single dose should not exceed 1,500 mg per m2.

Dose Modification Criteria

Renal impairment: to be used with caution, dose reduction may be considered.

Adverse Reactions

DERM: injection-site reactions (irritant); ELECTRO: hypophosphatemia; ENDO: dysglycemia, may lead to insulin-dependent diabetes; GI: N/V L5, increased LFT values, diarrhea; GU: azotemia, anuria, renal tubular acidosis, increased BUN and serum creatinine, glycosuria; HEMAT: myelosuppression.

Comments

  • Renal complications are dose related and cumulative. Mild proteinuria is usually an early sign of impending renal dysfunction. Serial urinalysis is important for the early detection of proteinuria and should be quantified with a 24-hour collection when proteinuria is detected. Adequate hydration may help reduce the risk of nephrotoxicity. Avoid other nephrotoxic agents.

TAMOXIFEN (NOLVADEX)

Mechanism of Action

Tamoxifen is a nonsteroidal antiestrogen.

U.S. Food and Drug Administration–Approved Indications

  • Breast cancer treatment
  • Treatment of metastatic breast cancer
  • Adjuvant treatment of node-positive and node-negative breast cancer following breast surgery and breast irradiation
  • Reduction in breast cancer incidence
  • Ductal carcinoma in situ(DCIS): to reduce the risk of invasive breast cancer following breast surgery and radiation.
  • High-risk women [women at least 35 years of age with a 5-year predicted risk of breast cancer ≥1.67% as calculated by the Gail model (package insert to be consulted)].

U.S. Food and Drug Administration–Approved Dosage

  • Breast cancer treatment: 20 mg PO daily or 10 to 20 mg PO twice daily (20 to 40 mg per day). Adjuvant therapy should be continued × 5 years. Doses >20 mg per day should be given in divided doses (morning and evening).
  • Breast cancer incidence reduction (DCIS and in high-risk women): 20 mg PO daily × 5 years.

Adverse Reactions

CV: thromboembolism, stroke, and pulmonary embolism; DERM: skin rash; ENDO: hot flashes; GI: nausea, anorexia; GU: menstrual irregularities, pruritus vulvae, and vaginal discharge or bleeding; HEMAT: bone marrow depression; OCULAR: vision disturbances and

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cataracts; PULM: dyspnea, chest pain, and hemoptysis; OTHER: dizziness, headaches, tumor or bone pain, pelvic pain, and uterine malignancies.

Comments

  • High risk is defined as the risk in women who are at least 35 years old, with a 5-year predicted risk of breast cancer of 1.67%, as predicted by the Gail risk model.
  • Serious and life-threatening events associated with tamoxifen in the risk reduction setting include uterine malignancies, stroke, and pulmonary embolism. Package insert may be consulted for additional information.

TEMOZOLOMIDE (TEMODAR)

Mechanism of Action

Temozolomide is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

Refractory anaplastic astrocytoma: Second-line therapy in adults (after a nitrosourea and procarbazine regimen).

U.S. Food and Drug Administration–Approved Dosage

Initial dose: 150 mg per m2 PO daily × 5 consecutive days every 28 days. If the initial dose leads to acceptable hematologic parameters at the nadir and on day of dosing (criteria in package insert to be verified), the temozolomide dose may be increased to 200 mg per m2 PO daily × 5 consecutive days per 28 day treatment cycle.

Dose Modification Criteria

Renal (severe impairment): to be used with caution; hepatic (severe impairment): to be used with caution; myelosuppression: dose to be modified.

Adverse Reactions

CNS: headache; HEMAT: myelosuppression; GI: N/V L2 (reduced by taking on an empty stomach); OTHER: asthenia, fatigue.

Comments

  • Capsules should be taken with water. Administer consistently with respect to food, and to reduce the risk of nausea and vomiting it is recommended that temozolomide be taken on an empty stomach. Bedtime administration may be advised.
  • Myelosuppression occurs late in the treatment cycle. The median nadirs in a study of 158 patients with anaplastic astrocytoma occurred at 26 days for platelets (range 21 to 40 days) and 28 days for neutrophils (range 1 to 44 days). The package insert recommends obtaining a complete blood count on day 22 (21 days after the first dose) and then weekly to ensure that the absolute neutrophil count (ANC) is higher than 1.5 × 109per L and the platelet count exceeds 100 × 109 per L. The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. Package insert may be consulted for dose modification guidelines.

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TENIPOSIDE (VUMON)

Mechanism of Action

Teniposide is a topoisomerase-II inhibitor.

U.S. Food and Drug Administration–Approved Indications

Refractory childhood ALL: induction therapy as a second-line therapy (in combination with other agents).

U.S. Food and Drug Administration–Approved Dosage

  • Current literature may be consulted for dosing regimens. The package insert cites two dosage regimens based on two different studies:
  • In combination with cytarabine: 165 mg per m2i.v. over 30 to 60 minutes twice weekly × eight to nine doses.
  • In combination with vincristine and prednisone: 250 mg per m2i.v. over 30 to 60 minutes weekly × four to eight doses.

Dose Modification Criteria

Renal impairment: to be used with caution, no guidelines available; hepatic impairment: to be used with caution, no guidelines available.

Adverse Reactions

CV: hypotension with rapid infusion; DERM: alopecia, thrombophlebitis, and tissue damage secondary to drug extravasation; GI: diarrhea, N/V L2, and mucositis; HEMAT: myelosuppression; OTHER: anaphylaxis, and hypersensitivity.

Comments

  • Observe patient for at least 60 minutes after dose.
  • Consider premedication with antihistamines and/or corticosteroids for retreatment (if indicated) after a hypersensitivity reaction.
  • Use non-DEHP plasticized solution containers and administration sets.

TESTOLACTONE (TESLAC)

Mechanism of Action

Testolactone is a synthetic derivative of testosterone that appears to inhibit steroid aromatase activity and consequently cause a reduction in estrone synthesis.

U.S. Food and Drug Administration–Approved Indications

  • Breast cancer: adjunctive therapy in the palliative treatment of advanced or disseminated breast cancer in postmenopausal women when hormonal therapy is indicated or in premenopausal women in whom ovarian function has been terminated.
  • Advanced or disseminated mammary cancer.

U.S. Food and Drug Administration–Approved Dosage

250 mg PO q.i.d. (4 times daily; total daily dose: 1,000 mg per day).

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Adverse Reactions

CNS: paresthesia; CV: hypertension, peripheral edema, DERM: maculopapular erythema, alopecia, and nail growth disturbance; GI: anorexia, nausea; OTHER: malaise, aches, and glossitis.

THIOGUANINE (TABLOID)

Mechanism of Action

Thioguanine is an antimetabolite.

U.S. Food and Drug Administration–Approved Indications

ANLL: remission induction, remission consolidation, and maintenance therapy

U.S. Food and Drug Administration–Approved Dosage

  • Combination therapy: current literature may be consulted.
  • Single-agent therapy: 2 mg per kg PO daily as a single daily dose. May increase to 3 mg per kg PO daily as a single daily dose after 4 weeks if no clinical improvement.

Adverse Reactions

GI: anorexia and stomatitis, N/V L1, increased LFT values, and increased bilirubin (cases of venoocclusive hepatic disease have been reported in patients receiving combination chemotherapy for leukemia); HEMAT: myelosuppression; OTHER: hyperuricemia and tumor lysis syndrome.

Comments

  • Cross-resistance with mercaptopurine.
  • Consider appropriate prophylaxis for tumor lysis syndrome when treating acute leukemias.

THIOTEPA (THIOPLEX)

Mechanism of Action

Thiotepa is an alkylating agent.

U.S. Food and Drug Administration–Approved Indications

Superficial papillary carcinoma of the bladder, controlling intracavitary effusions secondary to diffuse or localized neoplasms of the serosal cavities, breast cancer, ovarian cancer, Hodgkin disease, and lymphosarcoma.

U.S. Food and Drug Administration–Approved Dosage

  • Intravenous administration: 0.3 to 0.4 mg per kg i.v. × one dose repeated at 1 to 4 week intervals. Current literature may be consulted for alternative dosing regimens.
  • Intravesical administration: Patients with papillary carcinoma of the bladder are dehydrated for 8 to 12 hours before procedure. Then 60 mg of thiotepa in 30 to 60 mL of sodium chloride injection is instilled into the bladder. For maximum effect, the solution should be retained in the bladder for 2 hours. If desired, reposition patient every 15 minutes to maximize contact. Repeat administration weekly × 4 weeks. A course of treatment (four doses) may be repeated for up to two more courses if necessary, but with caution since bone marrow depression may be increased.

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  • Intracavitary administration: 0.6 to 0.8 mg per kg × one dose through tubing used to remove fluid from cavity.

Adverse Reactions

CNS: dizziness, headache, blurred vision, and conjunctivitis; DERM: alopecia and pain at the injection site; GI: anorexia, N/V L2, and mucositis at high doses; GU: amenorrhea, reduced spermatogenesis, dysuria, and chemical or hemorrhagic cystitis (intravesical); HEMAT: myelosuppression; OTHER: fever, hypersensitivity reactions, fatigue, weakness, and anaphylaxis.

TOPOTECAN (HYCAMTIN)

Mechanism of Action

Topotecan is a topoisomerase-I inhibitor.

U.S. Food and Drug Administration–Approved Indications

  • Metastatic ovarian cancer: second-line therapy after failure of initial or subsequent chemotherapy
  • SCLC: second-line therapy in sensitive disease after failure of first-line chemotherapy.

U.S. Food and Drug Administration–Approved Dosage

Ovarian or SCLC: 1.5 mg per m2 i.v. over 30 minutes daily × 5 days, starting on day 1 of a 21-day course.

Dose Modification Criteria

Renal (mild impairment, CrCl 40 to 60 mL per minute): no dose modification; renal (moderate impairment, CrCl 20 to 39 mL per minute): dose to be modified; renal (severe impairment, <20 mL per minute): no recorded experience with dosage; hepatic impairment (bilirubin, mild-to-moderate elevation): no dosage modification; myelosuppression: dose to be modified.

Adverse Reactions

CNS: headache; DERM: alopecia and injection-site reactions; HEMAT: myelosuppression; GI: N/V L2, diarrhea, constipation, abdominal pain, stomatitis, and anorexia; OTHER: fatigue and asthenia.

Comments

Concomitant filgrastim may worsen neutropenia. If used, start filgrastim at least 24 hours after last topotecan dose.

TOREMIFENE (FARNESTON)

Mechanism of Action

Toremifene is a nonsteroidal antiestrogen.

U.S. Food and Drug Administration–Approved Indications

Metastatic breast cancer in postmenopausal women with ER–positive or unknown tumors.

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U.S. Food and Drug Administration–Approved Dosage

60 mg PO daily.

Adverse Reactions

CV: thromboembolism, stroke, and pulmonary embolism; CNS: dizziness, depression; DERM: skin discoloration, dermatitis; ELECTRO: hypercalcemia; ENDO: hot flashes; GI: N/V L1, constipation and elevated LFT values; GU: vaginal discharge, vaginal bleeding; OCULAR: dry eyes, ocular changes, and cataracts; OTHER: sweating and tumor flare.

Comments

Not to be used in patients with a history of thromboembolic disease or endometrial hyperplasia.

TRASTUZUMAB (HERCEPTIN)

Mechanism of Action

Trastuzumab is a humanized monoclonal antibody directed at the human EGFR 2 protein (HER2).

U.S. Food and Drug Administration–Approved Indications

  • Metastatic breast cancer in patients whose tumor overexpresses the HER2 protein including:
  • First-line therapy in combination with paclitaxel
  • Second-line therapy as a single-agent therapy

U.S. Food and Drug Administration–Approved Dosage

Initial loading dose of 4 mg per kg i.v. infused over 90 minutes. Weekly maintenance dose of 2 mg per kg i.v. infused over 30 minutes (if first dose is tolerated).

Adverse Reactions

CNS: headache and dizziness (infusion reactions to be referred); CV: cardiomyopathy, ventricular dysfunction, CHF (incidence higher in patients receiving concurrent chemotherapy), and hypotension (infusion reactions); DERM: rash; HEMAT: myelosuppression (anemia and leukopenia with concurrent chemotherapy); GI: diarrhea, nausea, vomiting, and anorexia; INFUS: (first infusion) chills, fever, nausea, vomiting, pain (at tumor sites), rigors, headache, dizziness, dyspnea, rash, hypotension, and asthenia; PULM: cough, dyspnea, rhinitis, adult respiratory distress syndrome, bronchospasm, angioedema, wheezing, pleural effusions, pulmonary infiltrates, noncardiogenic pulmonary edema, pulmonary insufficiency, and hypoxia (some severe pulmonary reactions required supplemental oxygen or ventilatory support); OTHER: infection (higher incidence of mild upper respiratory infections and catheter infections observed in one randomized trial), asthenia, allergic reactions, and anaphylaxis.

Comments

  • Death within 24 hours of a trastuzumab infusion has been reported. The most severe reactions seem to occur in patients with considerable preexisting pulmonary compromise secondary to intrinsic lung disease and/or malignant pulmonary involvement.
  • Not to be administered as i.v. push or i.v. bolus.

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  • May use sterile water for injection for reconstitution if patient is allergic to benzyl alcohol (supplied diluent is bacteriostatic water for injection); product should be used immediately and unused portion discarded.
  • Alternative dosing regimens have been studied including dosing at longer dosing intervals; current literature to be consulted.

TRETINOIN (VESANOID)

Mechanism of Action

Tretinoin induces maturation, cytodifferentiation, and decreased proliferation of Acute Promyleocytic Leukemia cells.

U.S. Food and Drug Administration–Approved Indications

APL: Induction of remission in patients with APL (FAB M3, including the M3 variant), characterized by the t(15;17) translocation and/or the presence of the PML/RARα gene, who are refractory to or relapsed after anthracycline chemotherapy or for whom anthracycline therapy is contraindicated.

U.S. Food and Drug Administration–Approved Dosage

22.5 mg per m2 PO twice daily (total daily dose: 45 mg per m2) until complete remission is documented. Therapy should be discontinued 30 days after complete remission is obtained or after 90 days of treatment, whichever comes first.

Adverse Reactions

CNS: dizziness, anxiety, insomnia, headache, depression, confusion, intracranial hypertension, agitation, earaches, hearing loss, and pseudotumor cerebri; CV: hypertension, arrhythmias, flushing, and hyperlipidemia; DERM: dry skin or mucous membranes, rash, pruritus, alopecia, mucositis; GI: nausea, diarrhea, constipation, and dyspepsia; HEMAT: leukocytosis; OCULAR: visual changes; OTHER: dyspnea, fever, shivering, and retinoic acid–APL syndrome (RA-APL syndrome: fever, dyspnea, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusion).

Comments

  • Teratogenic; women must use effective contraception during and for 1 month after therapy.
  • RA-APL syndrome occurs in up to 25% of patients usually within first month. Early recognition helps palliation; and high-dose corticosteroids (dexamethasone 10 mg i.v. every 12 hours × 3 days or until the resolution of symptoms) have been used for management.
  • During tretinoin treatment approximately 40% of patients will develop rapidly evolving leukocytosis, which is associated with a higher risk of life-threatening complications. If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, high-dose corticosteroids should be initiated immediately. Chemotherapy is often combined with tretinoin in patients who present with leukocytosis (WBC count >5 × 109per L) or with rapidly evolving leukocytosis.
  • Current literature may be consulted for APL treatment regimens.

TRIPTORELIN (TRELSTAR)

Mechanism of Action

Triptorelin is an LHRH agonist; chronic administration leads to sustained suppression of pituitary gonadotropins and subsequent suppression of serum testosterone in men and serum estradiol in women.

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U.S. Food and Drug Administration–Approved Indications

Palliative treatment of advanced prostate cancer.

U.S. Food and Drug Administration–Approved Dosage

Trelstar Depot: 3.75 mg i.m. injection monthly.

Trelstar LA: 11.25 mg i.m. injection every 84 days.

Adverse Reactions

CV: hypertension and peripheral edema; ENDO: hot flashes, gynecomastia, breast pain, sexual dysfunction, and decreased erections; GU: erectile dysfunction, lower urinary tract symptoms, and testicular atrophy; OTHER: tumor flare in the first few weeks of therapy, bone pain, injection-site reactions, loss of bone mineral density, osteoporosis, bone fracture, and asthenia.

Comments

  • To be used with caution in patients at risk of developing ureteral obstruction or spinal cord compression.

VALRUBICIN (VALSTAR)

Mechanism of Action

Valrubicin is an intercalating agent and topoisomerase-II inhibitor.

U.S. Food and Drug Administration–Approved Indications

Carcinoma in situ of the urinary bladder: second-line intravesical treatment after bacille Calmette-Guérin (BCG) therapy in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.

U.S. Food and Drug Administration–Approved Dosage

800 mg to be administered intravesically weekly × 6 weeks. For each instillation, 800 mg of valrubicin is diluted with 0.9% sodium chloride to a total volume of 75 mL. Once instilled into the bladder, the patient should retain drug in bladder for 2 hours before voiding.

Adverse Reactions

GU: Irritable bladder symptoms: urinary frequency, dysuria, urinary urgency, hematuria, bladder spasm, bladder pain, urinary incontinence, cystitis, local burning symptoms related to the procedure, and red-tinged urine.

Comments

  • Patients should maintain adequate hydration after treatment.
  • Irritable bladder symptoms may occur during instillation and retention of valrubicin and for a limited period following voiding. For the first 24 hours following administration, red-tinged urine is typical. Patients should report prolonged irritable bladder symptoms or prolonged passage of red-colored urine immediately to their physician.
  • Non-DEHP plasticized solution containers and administration sets to be used.

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VINBLASTINE (VELBAN)

Mechanism of Action

Vinblastine inhibits microtubule formation.

U.S. Food and Drug Administration–Approved Indications

Palliative treatment of the following malignancies:

  • Frequently responsive malignancies: testicular cancer, Hodgkin disease, non-Hodgkin lymphoma, mycosis fungoides, Kaposi sarcoma, histiocytic lymphoma, and Letterer-Siwe disease (histiocytosis X).
  • Less frequently responsive malignancies: breast cancer, and resistant choriocarcinoma.

U.S. Food and Drug Administration–Approved Dosage

Initial (adults): 3.7 mg per m2 i.v. weekly. May increase weekly dose up to 18.5 mg per m2 to maintain WBC >3,000 cells per mm3 (package insert to be consulted for schema).

Initial (pediatric): 2.5 mg per m2 i.v. weekly. May increase weekly dose up to 12.5 mg per m2 to maintain WBC >3,000 cells per mm3(package insert to be consulted for schema).

Current literature may be consulted for alternative dosing regimens.

Dose Modification Criteria

Renal impairment: no dosage modification; hepatic impairment: dose to be modified; myelosuppression: dose to be modified.

Adverse Reactions

CNS: peripheral neuropathy, paresthesias, loss of deep tendon reflexes, and SIADH; CV: hypertension; DERM: alopecia, tissue damage or necrosis with extravasation; GI: N/V L1, stomatitis, constipation, and ileus; GU: urinary retention and polyuria; HEMAT: myelosuppression; OTHER: bone pain, jaw pain, tumor pain, weakness, malaise, and Raynaud phenomenon.

Comments

  • Vesicant.
  • To be administer only by the intravenous route. Fatalities have been reported when other vinca alkaloids have been given intrathecally.
  • Syringe to be labeled: “Administer only i.v.; fatal if given intrathecally.” Outer wrap (if used) should read: “Do not remove covering until moment of injection. Fatal if given intrathecally. For intravenous use only.”

VINCRISTINE (ONCOVIN AND OTHERS)

Mechanism of Action

Vincristine inhibits microtubule formation.

U.S. Food and Drug Administration–Approved Indications

  • Acute leukemia;
  • Vincristine has been shown to be useful in combination with other agents for Hodgkin disease, non-Hodgkin lymphoma, neuroblastoma, Wilms' tumor, rhabdomyosarcoma.

P.666

 

U.S. Food and Drug Administration–Approved Dosage

  • Adults: 1.4 mg per m2i.v. × one dose. Doses may be repeated at weekly intervals. Some clinicians will limit (“cap”) individual doses to a maximum of 2 mg.
  • Pediatrics: 1.5 to 2 mg per m2i.v. × one dose. For pediatric patients weighing 10 kg or less: 0.05 mg per kg i.v. × one dose. Doses may be repeated at weekly intervals. Some clinicians will limit (“cap”) individual doses to a maximum of 2 mg.

Dose Modification Criteria

Renal impairment: no dosage modification; hepatic impairment: dose to be modified.

Adverse Reactions

CNS: peripheral neuropathy, paresthesias, numbness, loss of deep tendon reflexes, and SIADH; DERM: alopecia, tissue damage or necrosis with extravasation; GI: N/V L1, stomatitis, anorexia, diarrhea, constipation, and ileus; GU: urinary retention, OCULAR: ophthalmoplegia, extraocular muscle paresis; PULM: pharyngitis; OTHER: jaw pain.

Comments

  • Vesicant.
  • To be administered only by the intravenous route. Fatalities have been reported when other vinca alkaloids have been given intrathecally.
  • Syringe to be labeled: “Administer only i.v.; fatal if given intrathecally.” Outer wrap (if used) should read: “Do not remove covering until moment of injection. Fatal if given intrathecally. For intravenous use only.”
  • A routine prophylactic regimen against constipation is recommended for all patients receiving vincristine.

VINORELBINE (NAVELBINE)

Mechanism of Action

Vinorelbine inhibits microtubule formation.

U.S. Food and Drug Administration–Approved Indications

NSCLC: First-line therapy as a single agent (stage IV) or in combination with cisplatin (stage III or IV) for ambulatory patients with unresectable, advanced NSCLC.

U.S. Food and Drug Administration–Approved Dosage

  • Single agent: 30 mg per m2i.v. over 6 to 10 minutes, weekly
  • Vinorelbine in combination with cisplatin:

Vinorelbine 25 mg per m2 i.v. over 6 to 10 minutes weekly, plus

Cisplatin 100 mg per m2 i.v. every 4 weeks

or

  • Vinorelbine 30 mg per m2i.v. over 6 to 10 minutes weekly, plus
  • cisplatin 120 mg per m2i.v. × one dose on days 1 and 29, then every 6 weeks
  • Line to be flushed with 75 to 125 mL of fluid (e.g., 0.9% sodium chloride) after administration of vinorelbine.

P.667

 

Dose Modification Criteria

Renal impairment: no dosage modification; hepatic impairment: dose to be modified; neurotoxicity: dose to be modified; myelosuppression: dose to be modified.

Adverse Reactions

CNS: peripheral neuropathy, and loss of deep tendon reflexes; CV: thromboembolic events, and chest pain; DERM: alopecia, vein discoloration, venous pain, chemical phlebitis, tissue damage or necrosis with extravasation; GI: N/V L1–2, stomatitis, anorexia, constipation, ileus, and elevated LFT values; HEMAT: myelosuppression (granulocytopenia greater than thrombocytopenia or anemia); PULM: interstitial pulmonary changes, and shortness of breath; OTHER: jaw pain, tumor pain, fatigue, and anaphylaxis.

Comments

  • Vesicant.
  • To be administered only by the intravenous route. Fatalities have been reported when other vinca alkaloids have been given intrathecally.

REFERENCES

  1. Kohler DR, Montello MJ, Green L, et al. Standardizing the expression and nomenclature of cancer treatment regimens. Am J Health Syst Pharm1998;55:137–144.
  2. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol1997;15:103–109.
  3. Dorr RT, Alberts DS, Soble M. Lack of experimental vesicant activity for the anticancer agents cisplatin, melphalan, and mitoxantrone.Cancer Chemother. Pharmacol. 1986;16(2):91–94.