Chapter 40: Drug Preparation and Administration

The following tables describe appropriate handling and storage, and drug product preparation and administration procedures for antineoplastics and other selected medications often used concomitantly. The tables describe drug use under a variety of commonly encountered conditions, but do not identify all applications or conditions of product stability and compatibility. Likewise, the tables are not an exhaustive list of marketed products and should not be construed as an endorsement for any manufacturer's products or discriminating against products that were not specifically identified. Clinicians are advised to refer to product labeling for more complete information about individual products and up-to-date reference sources for information about drug compatibility and stability

The information contained in this chapter is derived from contemporary product labeling approved by the U.S. Food and Drug Administration (FDA), pharmaceutical manufacturers' websites, and, in some cases, from published studies and personal communications with pharmaceutical manufacturers

Occasionally, the package insert component of product labeling for drugs that have received FDA approval for commercial use is prefaced by prominent precautionary and warning summaries circumscribed by a rectangular border, commonly referred to as black box warnings, or, simply, boxed warnings. The boxed warnings reproduced in this chapter faithfully recapitulate the most current versions of manufacturers' product labeling available lacking only referent citations to information located elsewhere within product labeling. Referents are replaced here by an ellipsis (…). Health care providers are urged to consult the most current versions of product labeling and primary medical publications for more information

In 2001, the FDA Office of Generic Drugs requested manufacturers of sixteen similarly named drug pairs to voluntarily revise the appearance of those established drug names by enhancing distinguishing elements of otherwise very similar (look-alike) names. The Name Differentiation Project of 2001 encouraged manufacturers to supplement their applications with revised labeling that incorporated "Tall Man" letters within drug names to aid visual differentiation between those drug names with a goal toward minimizing medication errors by inappropriate drug selection, ie, capitalizing letters that aid in distinguishing between similar generic and proprietary drug names. With the exception of section titles, labeled identities, compendial names, and boxed warnings, drug names appear in this chapter with the Tall Man names and conventions established and recommended by the FDA (URL: http://www.fda.gov/Drugs/DrugSafety/MedicationErrors/ucm164587.htm [accessed February 14, 2014]) and the Institute for Safe Medication Practices, Horsham, PA. (URL: www.ismp.org [accessed, February 14, 2014])

Key to Abbreviations

ado-Trastuzumab

KADCYLA™ (ado-trastuzumab emtansine) for injection, for intravenous use; product label, May 2013. Manufactured by: Genentech, Inc. A Member of the Roche Group, South San Francisco, CA

Do Not Substitute KADCYLA for or with Trastuzumab

WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin…

• Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function…

• Embryo-Fetal Toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception…

Boxed Warning for "KADCYLA™ (ado-trastuzumab emtansine) for injection, for intravenous use; May 2013 product label. Genentech, Inc., A Member of the Roche Group, South San Francisco, CA

Product Identification, Preparation, Storage, and Stability

• Ado-trastuzumab emtansine contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex

• The commercial product, KADCYLA™, is a sterile, white to off-white, preservative-free, lyophilized powder in individually packaged, single-use vials that contain ado-trastuzumab emtansine 100 mg (NDC 50242-088-01) or 160 mg (NDC 50242-087-01)

• Store intact vials under refrigeration at 2°–8°C (35.6°–46.4°F) until time of reconstitution

• Do not freeze or shake intact vials

Reconstitution:

• In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is KADCYLA™ (ado-trastuzumab emtansine), NOT trastuzumab

• Using a sterile syringe, slowly inject SWFI diluent into vials containing ado-trastuzumab emtansine as follows:

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  Vial Contents (ado-trastuzumab emtansine)	SWFI Volume for Reconstitution	ado-Trastuzumab Emtansine Concentration after Reconstitution
  100 mg	5 mL	20 mg/mL
  160 mg	8 mL

• Swirl vials gently until the drug substance is completely dissolved

  • Do not shake vials to aid dissolution to avoid foaming

• After reconstitution, each vial contains ado-trastuzumab emtansine 20 mg/mL, polysorbate 20 0.02% (w/v), sodium succinate 10 mmol/L, and sucrose 6% (w/v), with a pH = 5.0 and density = 1.026 g/mL

• Inspect the reconstituted drug product (20 mg/mL) for particulates and discoloration

  • The solution should be clear to slightly opalescent, free of visible particulates, and colorless to pale brown

  • Do not use the reconstituted solution if it contains visible particulates or is cloudy or discolored

• The reconstituted lyophilized drug product should be used immediately following reconstitution, or, if not used immediately, reconstituted product may be stored for up to 24 hours under refrigeration at 2°–8°C (35.6°–46.4°F). Do not freeze

• Discard all unused ado-trastuzumab emtansine stored under refrigeration after 24 hours

Note: The reconstituted product contains no preservative and is intended for single use only

Dilution:

• Calculate the volume of concentrated reconstituted ado-trastuzumab emtansine solution (20-mg/mL) needed to prepare a patient's dose

• With a syringe, aseptically transfer from one or more vials the volume needed to a parenteral product container prefilled with 250 mL 0.9% NS

  • Do not use 5% dextrose injection as a diluent/vehicle solution

• Mix the diluted drug product by repeated gentle inversion of the container to avoid foaming

• After dilution, ado-trastuzumab emtansine admixture should be used immediately, but if not used immediately, it may be stored under refrigeration (2°–8°C) for up to 24 hours prior to use

  • The time under refrigeration for storing diluted ado-trastuzumab emtansine (24 h) is in addition to the time allowed for storing the reconstituted concentrated solution (20 mg/mL) in vials (24 h)

• Do not freeze or shake the diluted drug product

Selected incompatibility:

• Do not mix ado-trastuzumab emtansine with other medicinal products in the same container

Recommendations for Drug Administration and Ancillary Care

General:

• In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is KADCYLA™ (ado-trastuzumab emtansine) NOT trastuzumab

  • In order to improve traceability of biological pharmaceutical products and prevent medication errors, the complete generic name or a distinguishing proprietary (brand) name of the administered product should be clearly recorded in a patient's medical records

Administration:

• Do not mix ado-trastuzumab emtansine with other medicinal products in the same container or during administration

• Do not substitute ado-trastuzumab emtansine for trastuzumab or trastuzumab for ado-trastuzumab emtansine

• The recommended dose of ado-trastuzumab emtansine is 3.6 mg/kg, given as an intravenous infusion every 3 weeks (21-day cycles)

  • Do not administer KADCYLA at dosages greater than 3.6 mg/kg

  • Do not administer ado-trastuzumab emtansine by intravenous injection or bolus

  • Do not re-escalate ado-trastuzumab emtansine dosages after a dosage reduction is made

• Administer ado-trastuzumab emtansine intravenously only with a 0.22-micrometer, in-line, polyethersulfone filter

• If a planned dose is delayed or missed, it should be administered as soon as possible

  • Do not wait until the next planned cycle

  • The schedule of administration should be adjusted to maintain a 3-week interval between doses

Notes:

• FDA-approved product labeling for ado-trastuzumab emtansine includes recommendations for treatment modifications for concomitant use with potentially interacting medications, co-morbid conditions, and adverse effects associated with treatment, including: increased serum liver transaminases (AST and ALT), hyperbilirubinemia or both conditions, and hepatic toxicity including nodular regenerative liver hyperplasia; left ventricular dysfunction, thrombocytopenia, pulmonary toxicity, and peripheral neuropathy (refer to current product labeling for detailed recommendations)

  • Management may require temporary delays, interruption, dose reduction, or treatment discontinuation

• Infusion-related reactions associated with ado-trastuzumab emtansine reported in clinical trials were characterized by one or more of the following: flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia, and one episode of a serious allergic/anaphylactic reaction

  • The overall frequency of infusion-related reactions reported in one randomized trial was 1.4%

  • In most patients, reactions resolved over the course of several hours to a day after ado-trastuzumab emtansine administration was discontinued

  • Interrupt ado-trastuzumab emtansine treatment in patients who develop severe infusion-related reactions

  • ado-Trastuzumab emtansine should be permanently discontinued in the event of life-threatening infusion-related reactions

Aldesleukin

PROLEUKIN^® (aldesleukin) for injection, for intravenous infusion; product label, July 2012. Manufactured by Prometheus Laboratories, Inc., San Diego, CA at Bayer HealthCare Pharmaceuticals, Emeryville, CA

WARNINGS

Therapy with Proleukin^® (aldesleukin) should be restricted to patients with normal cardiac and pulmonary functions as defined by thallium stress testing and formal pulmonary function testing. Extreme caution should be used in patients with a normal thallium stress test and a normal pulmonary function test who have a history of cardiac or pulmonary disease

Proleukin should be administered in a hospital setting under the supervision of a qualified physician experienced in the use of anticancer agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available

Proleukin administration has been associated with capillary leak syndrome (CLS) which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension and reduced organ perfusion which may be severe and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, and mental status changes

Proleukin treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Consequently, preexisting bacterial infections should be adequately treated prior to initiation of Proleukin therapy. Patients with indwelling central lines are particularly at risk for infection with gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated with a reduced incidence of staphylococcal infections

Proleukin administration should be withheld in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma

Boxed Warning for "PROLEUKIN^® (aldesleukin) for injection, for intravenous infusion"; July 2012 product label; Prometheus Laboratories, Inc., San Diego, CA

Product Identification, Preparation, Storage, and Stability

• Proleukin is supplied in individually boxed single-use vials containing aldesleukin 22 million IU as a sterile, white to off-white, preservative-free, lyophilized powder (equivalent to a protein mass of 1.3 mg). NDC 65483-116-07

  • Aldesleukin biologic potency is determined by a lymphocyte proliferation bioassay and is expressed in international units (IU) as established by the World Health Organization 1st International Standard for Interleukin-2 (human)

• Store intact vials and reconstituted and diluted aldesleukin under refrigeration at 2°C–8°C (35.6°F–46.4°F). Protect from light. Do not freeze aldesleukin

• Reconstitute the contents of a vial with 1.2 mL of SWFI to produce a clear, colorless to slightly yellow solution with a biologic potency of 18 million IU aldesleukin/mL (equivalent to 1.1 mg of aldesleukin protein per milliliter)

  • Each milliliter of the reconstituted product also contains 50 mg mannitol and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range: 7.2–7.8)

• During reconstitution, direct the stream of SWFI at the side wall of a vial rather than directly into the drug powder and gently swirl vials to avoid excessive foaming

• Do not shake vials to dissolve aldesleukin

• For intraVENous administration, dilute aldesleukin only with D5W to a final concentration between 0.5 and 1.1 million IU/mL (30–70 mcg/mL; see chart below). Drug delivery may be adversely affected by aldesleukin concentrations <30 mcg/mL or >70 mcg/mL

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  Aldesleukin (million IU)	Diluent Volume (D5W)
  5–11	10 mL
  7.5–16.5	15 mL
  12.5–27.5	25 mL
  25–55	50 mL
  50–110	100 mL

• If it is necessary to administer aldesleukin in a concentration <30 mcg/mL (>0.5 million IU/mL), the drug should be diluted in D5W that contains Albumin Human, USP, in a concentration of 0.1% (1 mg/mL)

• Either glass bottles or PVC bags are acceptable containers for aldesleukin, but plastic containers provide more consistent drug delivery than glass containers

• Reconstituted and diluted aldesleukin solutions are stable for up to 48 hours at 2°–25°C (35.6°–77°F), but the Proleukin product does not contain a preservative

• Store reconstituted and diluted solutions under refrigeration, but allow diluted aldesleukin to warm to room temperature before administering it to a patient

Selected incompatibility:

• Do not combine aldesleukin with other drugs in the same container

• Do not reconstitute or dilute aldesleukin with 0.9% NS or antimicrobially-preserved diluents, which may increase protein aggregation

Recommendations for Drug Administration and Ancillary Care

General:

• Dose modification for toxicity should be accomplished by withholding or interrupting a dose rather than reducing the dose to be administered

• See Chapter 41 for recommended use in renal dysfunction

• Bring aldesleukin solution to room temperature before administration

• Administer aldesleukin by intraVENous infusion over 15 minutes

• Do not filter aldesleukin either during preparation or administration

• Complete administration within 48 hours after reconstitution

Pharmacodynamic interactions:

• Aldesleukin may affect CNS function, which may be exacerbated by concomitant administration of drugs with psychotropic activity, for example, opioids, analgesics, antiemetics, sedatives, hypnotics

• Aldesleukin may increase the nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic effects of other drugs if given concurrently

• Impaired kidney and liver function associated with aldesleukin use may delay elimination and increase the risk of adverse events from concomitantly administered medications

• Hypersensitivity reactions that consisted of erythema, pruritus, and hypotension, have been reported in patients who received combination regimens containing sequential high-dose aldesleukin and antineoplastic agents, specifically: dacarbazine, CISplatin, tamoxifen, and interferon alfa. Adverse reactions occurred within hours after administration of chemotherapy, and required medical intervention in some patients¹

• In patients who received aldesleukin and interferon alfa concurrently:

  • The incidence of myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis, appears to be increased²

  • Exacerbation or initial presentation of autoimmune and inflammatory disorders has been observed, including: crescentic IgA glomerulonephritis, oculobulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome

• Glucocorticoids have been shown to reduce aldesleukin-induced side effects, including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, but concomitant use should be avoided to preclude compromising aldesleukin's antitumor effectiveness³

• Beta-blockers and other antihypertensives may potentiate aldesleukin's hypotensive effects

• Aldesleukin use followed by administration of iodinated radiographic contrast media is associated with acute, atypical adverse reactions, including fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria, with onset commonly within 1–4 hours after the administration of contrast media. In some cases, the reactions resemble the immediate side effects caused by aldesleukin administration; however, other than a temporal relationship between aldesleukin and iodinated contrast media administration the cause of aldesleukin-associated contrast reactions is not known. Although most events were reported to occur when contrast media was given within 4 weeks after the last dose of aldesleukin, events were also reported to occur when contrast media was given several months after aldesleukin^4,5,6,7,8,9

Alemtuzumab

CAMPATH^® (alemtuzumab) Injection for intravenous use; product label, August 2009. Manufactured and distributed by Genzyme Corporation, Cambridge, MA

WARNINGS

CYTOPENIAS, INFUSION REACTIONS, and INFECTIONS

Cytopenias: Serious, including fatal, pancytopenia/marrow hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia can occur in patients receiving Campath. Single doses of Campath greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia…

Infusion Reactions: Campath administration can result in serious, including fatal, infusion reactions. Carefully monitor patients during infusions and withhold Campath for Grade 3 or 4 infusion reactions. Gradually escalate Campath to the recommended dose at the initiation of therapy and after interruption of therapy for 7 or more days…

Infections: Serious, including fatal, bacterial, viral, fungal, and protozoan infections can occur in patients receiving Campath. Administer prophylaxis against Pneumocystis jirovecii pneumonia (PCP) [sic] and herpes virus infections…

Boxed Warning for "Campath^® (alemtuzumab)", Injection for intravenous use"; August 2009 product label; Genzyme Corporation, Cambridge, MA

Change in Product Availability

• As of September 4, 2012, Campath (alemtuzumab) injection for treatment of B-cell chronic lymphocytic leukemia was withdrawn from commercial availability in the United States

• Genzyme Corporation, the American distributor, announced activation of the "US Campath Distribution Program," which "…was developed to ensure continued access to Campath (alemtuzumab) for appropriate patients"

• An announcement at http://www.campath.com/advises visitors, "Campath will no longer be available commercially, but will be provided through the Campath Distribution Program free of charge. In order to receive Campath, the healthcare provider is required to document and comply with certain requirements."

• The website provides contact telephone numbers for more information:

  • Campath Distribution Program: 1-877-422-6728

  • Genzyme Medical Information: 1-800-745-4447, Option #2

  • URL: http://www.campath.com/ (Last accessed October 7, 2013)

Product Identification, Preparation, Storage, and Stability

• Campath is packaged in clear, glass, single-use vials containing 30 mg alemtuzumab/mL NDC 58468-0357-3 (3 vials per carton). NDC 58468-0357-1 (single vial per carton)

  • Campath is a sterile, clear, colorless, isotonic solution for injection containing alemtuzumab 30 mg/mL at pH 6.8–7.4

  • Each milliliter of the commercial product also contains 8 mg sodium chloride, 1.44 mg dibasic sodium phosphate, 0.2 mg potassium chloride, 0.2 mg monobasic potassium phosphate, 0.1 mg polysorbate 80, and 0.0187 mg disodium edetate dihydrate

• Store intact vials under refrigeration at 2°–8°C (35.6°–46.4°F); protect vials from direct sunlight

• Do not freeze alemtuzumab. If the product is accidentally frozen, thaw at 2°–8°C before use

• Do not shake vials before use

  1. Withdraw from a vial into a syringe an amount of alemtuzumab needed to prepare a patient's dose

     1. 0.1 mL Campath solution for a 1-mg dose

     2. 0.33 mL Campath solution for a 10-mg dose

     3. 1 mL Campath solution for a 30-mg dose

  2. Inject the amount of drug needed to prepare a patient's dose into 100 mL of 0.9% NS or D5W in a plastic parenteral product container

  3. Gently invert the bag to mix the solution

• Diluted alemtuzumab solutions may be stored at room temperature (15°C–30°C; 59°F–86°F) or under refrigeration

• The commercial drug product contains no antimicrobial preservatives. Use the product within 8 hours after dilution

Selected incompatibility:

• Alemtuzumab is compatible with PVC bags, PVC- or polyethylene-lined PVC administration sets

• No data are available concerning the compatibility of alemtuzumab with other drugs. Do not add or simultaneously infuse other drugs through the same intraVENous line with alemtuzumab

Recommendations for Drug Administration and Ancillary Care

General:

• Administer alemtuzumab only by intraVENous infusion over ≥2 hours

• Do not administer alemtuzumab by direct intraVENous injection or bolus injection

Infusion reactions and dose escalation:

• Alemtuzumab administration can result in serious infusion reactions commonly including: pyrexia, chills, hypotension, urticaria, and dyspnea

  • G3 and G4 pyrexia and/or chills occurred in approximately 10% of previously untreated patients and in approximately 35% of previously treated patients

  • The occurrence of infusion reactions was greatest during the initial week of treatment and decreased with subsequent doses

  • All patients were pretreated with antipyretics and antihistamines; additionally, 43% of previously untreated patients received glucocorticoid prior to alemtuzumab

• Gradual escalation to the recommended maintenance dose/schedule is required when initiating therapy and after treatment interruptions ≥7 days. Generally, escalation to a 30-mg dose can be accomplished in 3–7 days as follows:

  1. Initiate treatment with alemtuzumab 3 mg intraVENously over 2 hours

  2. After a 3-mg DAILY dose is tolerated (ie, infusion-related toxicities are grades ≤2), escalate DAILY dose to 10 mg/day and continue until tolerated

  3. After a 10-mg DAILY dose is tolerated (infusion-related toxicities grades ≤2), escalate to a maintenance dose and schedule of alemtuzumab 30 mg/dose on 3 nonconsecutive days for 3 doses per week (eg, Monday, Wednesday, and Friday) for a total treatment duration of 12 weeks, including the period of dose escalation

Concomitant medications:

• Give premedication 30 minutes before the first alemtuzumab dose, before dose escalations, and as clinically indicated, with:

  • DiphenhydrAMINE 50 mg orally or intraVENously

  • Acetaminophen 500–1000 mg orally

• Treat severe infusion-related events with:

  • Hydrocortisone intraVENously (anaphylactoid reactions)

  • Meperidine intraVENously (chills, rigors)

  • Epinephrine 1:1000 (1 mg/mL) intraMUSCularly (preferred) or SUBCUTaneously (anaphylactoid reactions)

  • Epinephrine 1:10,000 (0.1 mg/mL) intraVENously with cardiac monitoring (airway edema, severe bronchospasm, hypotension)

• Give antibacterial and antiviral primary prophylaxis during treatment and continue for at least 2 months after the last dose of alemtuzumab is administered or until CD4+ lymphocyte counts are ≥200/mm³, whichever event occurs later, with:

  • Cotrimoxazole (trimethoprim 160 mg + sulfamethoxazole 800 mg) orally, twice daily for 3 days/week (or equivalent anti-PCP prophylaxis)

  • Famciclovir 250 mg orally twice daily (or equivalent anti-herpesvirus prophylaxis)

Amifostine

AMIFOSTINE FOR INJECTION; product label, May 2013. Manufactured by MedImmune Pharma B.V., Nijmegen, The Netherlands. Distributed by Bedford Laboratories, Bedford, OH

Product Identification, Preparation, Storage, and Stability

• Amifostine is packaged in 10-mL (capacity) single-use vials containing 500 mg (on an anhydrous basis) of amifostine trihydrate as a sterile lyophilized powder. NDC 55390-308-03 (3 vials per carton)

• Store intact vials at controlled room temperature, 20°–25°C (68°–77°F)

• Reconstitute amifostine with 9.7 mL of 0.9% NS to produce a solution with concentration of 500 mg amifostine/10 mL

• Amifostine may be further diluted in PVC containers with 0.9% NS to concentrations ranging from 5 to 40 mg/mL

• The reconstituted drug product (500 mg/mL) and diluted amifostine solutions are chemically stable for up to 5 hours at approximately 25°C and for up to 24 hours under refrigeration (2°–8°C; 35.6°–46.4°F)

Selected incompatibility:

• Product labeling advises admixture with solutions other than 0.9% NS with or without other (unspecified) additives is not recommended

Recommendations for Drug Administration and Ancillary Care

General:

• Administer intraVENously (see indication-specific recommendations below)

• Provide adequate hydration before amifostine infusion

• Administer antiemetic primary prophylaxis before amifostine

  • Emetic risk is related to amifostine dosage: low risk, ≤300 mg/m²; moderate risk, >300 mg/m² (NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines^®]: Antiemesis, V.1.2014. National Comprehensive Cancer Network, Inc., 2013. [Accessed October 8, 2013, at http://www.nccn.org.])

• Monitor a patient's blood pressure every 5 minutes during amifostine administration, and thereafter as clinically indicated

• Keep patients in a supine position during the amifostine infusion. Interrupt amifostine administration if systolic blood pressure (SBP) decreases significantly from baseline as follows:

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  Baseline SBP (mm Hg)	Decrease in SBP That Warrants Interrupting Amifostine Infusion
  <100	20 mm Hg
  100–119	25 mm Hg
  120–139	30 mm Hg
  140–179	40 mm Hg
  ≥180	50 mm Hg

  • If BP returns to normal within 5 minutes and the patient is asymptomatic, resume administration to complete the planned dose

  • If the planned dose cannot be administered, decrease the amifostine dosage during subsequent chemotherapy cycles from 910 mg/m² to 740 mg/m²

To reduce cumulative renal toxicity with chemotherapy:

• Administer antiemetic primary prophylaxis before amifostine, including dexamethasone 20 mg intraVENously, a serotonin receptor (5-HT₃ subtype) antagonist, plus additional antiemetics as appropriate for the chemotherapy utilized

• Administer amifostine 910 mg/m² once daily by intraVENous infusion over 15 minutes, starting 30 minutes before chemotherapy

  • A 15-minute infusion is better tolerated than longer infusions

To decrease moderate-to-severe xerostomia from head and neck radiation:

• Administer antiemetic primary prophylaxis before amifostine, for example, a 5-HT₃ antagonist ± additional antiemetics if clinically appropriate

• Administer amifostine 200 mg/m² once daily by intraVENous infusion over 3 minutes, 15–30 minutes before standard-fraction radiation therapy (ie, 1.8–2 Gy/fraction)

• Monitor blood pressure at least before and immediately after the infusion, and thereafter as clinically indicated

Arsenic Trioxide

TRISENOX^® (arsenic trioxide) injection, for intravenous use only; product label, June 2010. Manufactured for Cephalon Inc., Frazer, PA

WARNINGS

Experienced Physician and Institution: TRISENOX (arsenic trioxide) injection should be administered under the supervision of a physician who is experienced in the management of patients with acute leukemia

APL Differentiation Syndrome: Some patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called the retinoic-acid-Acute Promyelocytic Leukemia (RA-APL) or APL differentiation syndrome, characterized by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. The management of the syndrome has not been fully studied, but high-dose steroids have been used at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intraVENously BID) should be immediately initiated, irrespective of the leukocyte count, and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy during treatment of the APL differentiation syndrome

ECG Abnormalities: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with arsenic trioxide

ECG and Electrolyte Monitoring Recommendations: Prior to initiating therapy with TRISENOX, a 12-lead ECG should be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine should be assessed; preexisting electrolyte abnormalities should be corrected and, if possible, drugs that are known to prolong the QT interval should be discontinued. For QTc greater than 500 msec, corrective measures should be completed and the QTc reassessed with serial ECGs prior to considering using TRISENOX. During therapy with TRISENOX, potassium concentrations should be kept above 4 mEq/L and magnesium concentrations should be kept above 1.8 mg/dL. Patients who reach an absolute QT interval value >500 msec should be reassessed and immediate action should be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. If syncope, rapid or irregular heartbeat develops, the patient should be hospitalized for monitoring, serum electrolytes should be assessed, TRISENOX therapy should be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of TRISENOX on the QTc interval during the infusion

Boxed Warning for "Trisenox^® (arsenic trioxide) injection, For Intravenous Use Only"; June 2010 product label; Cephalon Inc., Frazer, PA

Product Identification, Preparation, Storage, and Stability

• Trisenox^® is packaged in 10-mL, glass, single-use ampules containing 10 mg of arsenic trioxide (1 mg/mL). NDC 63459-600-10 (package of 10 ampules)

  • Trisenox^® is formulated as a sterile, nonpyrogenic, clear, colorless, preservative-free solution of arsenic trioxide in water for injection. Sodium hydroxide and hydrochloric acid are used to adjust the pH to 7.5–8.5

• Store intact ampules at 25°C (77°F). Temperature excursions are permitted to 15°–30°C (59°–86°F)

• Dilute arsenic trioxide in 100–250 mL of 0.9% NS or D5W immediately after withdrawing the drug product from an ampule. Unused drug should be discarded in a manner appropriate for hazardous drugs

• Diluted arsenic trioxide solutions are chemically and physically stable for 24 hours when stored at room temperature and for up to 48 hours under refrigeration

Selected incompatibility:

Arsenic trioxide should not be mixed with other drugs

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in renal and hepatic dysfunction

• Administer arsenic trioxide by intraVENous infusion over 1–2 hours. The duration of administration may be extended to 4 hours for patients who experience acute vasomotor reactions

• A central VAD is not required for administering arsenic trioxide

ECG changes:

• QT/QTc prolongation should be expected during treatment with arsenic trioxide, and torsade de pointes and complete heart block have been reported

• In >460 ECG tracings from 40 patients evaluated for QTc prolongation, 16 patients (40%) demonstrated at least 1 QTc interval >500 msec

• QTc prolongation was observed between 1 and 5 weeks after arsenic trioxide administration, and then returned towards baseline by the end of 8 weeks after arsenic trioxide administration

• Neither sex nor age factors correlated with QT prolongation events

• Complete AV block has also been reported in association with arsenic trioxide treatment, including a case in a patient with acute promyelocytic leukemia

Asparaginase, Erwinia Chrysanthemi Source

Asparaginase Erwinia chrysanthemi ERWINAZE™ for injection, intramuscular use; product label, November 2011. Manufactured by EUSA Pharma (USA), Inc., Langhorne, PA

Product Identification, Preparation, Storage, and Stability

Erwinaze™ is a sterile, white lyophilized powder supplied in clear, 3-mL, glass vials. Each carton of the commercial product contains 5 vials (NDC 57902-249-05). Each vial (NDC 57902-249-01) contains 10,000 IU of asparaginase Erwinia chrysanthemi

• Store intact vials and cartons under refrigeration at 2°–8°C (35.6°–46.4°F)

• Protect intact vials and the reconstituted drug product from light

Preparation for intraMUSCular use:

• Asparaginase Erwinia chrysanthemi is reconstituted by slowly injecting 1 or 2 mL of preservative-free 0.9% NS against the inner vial wall

• DO NOT forcefully inject the diluent solution directly into the drug powder

• Dissolve the drug powder by gentle mixing or swirling after adding preservative-free 0.9% NS diluent. DO NOT shake or invert vials to solubilize the drug product

• After reconstitution, asparaginase Erwinia chrysanthemi should be a clear, colorless solution

• Discard the reconstituted product if visible particles or protein aggregates are present

• DO NOT freeze or refrigerate asparaginase Erwinia chrysanthemi solutions

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in hepatic dysfunction

IntraMUSCular administration:

• Asparaginase Erwinia chrysanthemi is administered ONLY by intraMUSCular injection

• Volumes for injection >2 mL should be distributed among 2 or more injection sites

• Withdraw from a vial into a polypropylene syringe within 15 minutes after reconstitution a volume of reconstituted asparaginase Erwinia chrysanthemi appropriate for a calculated dose

• Administer asparaginase Erwinia chrysanthemi within 4 hours after reconstitution

To substitute asparaginase Erwinia chrysanthemi for a dose of pegaspargase:

• For each planned dose of pegaspargase, the recommended dose of asparaginase Erwinia chrysanthemi is 25,000 IU/m² administered intraMUSCularly 3 times per week (eg, Monday, Wednesday, and Friday) for 6 doses

To substitute asparaginase Erwinia chrysanthemi for a dose of Escherichia coli asparaginase:

• The recommended dose is a single dose of asparaginase Erwinia chrysanthemi 25,000 IU/m² administered intraMUSCularly

Asparaginase, Escherichia Coli Source

ELSPAR (asparaginase) for injection, intravenous or intramuscular, product label, April 2010. Lundbeck, Inc, Deerfield, IL

Note: Information at http://www.lundbeck.com/us/products/customer-support [accessed January 11, 2014] states: As of January 18, 2013, Elspar was sold to Recordati Rare Diseases (Recordati). For access to Recordati's website for Elspar, go to http://www.recordatirarediseases.com/

Product Identification, Preparation, Storage, and Stability

Elspar^® is packaged in individually boxed single-use vials containing asparaginase 10,000 IU as a sterile, white lyophilized plug or powder for intraVENous or intraMUSCular injection after reconstitution. NDC 67386-411-51

• Elspar^® contains the enzyme l-asparagine amidohydrolase, type EC-2, derived from Escherichia coli and 80 mg of mannitol

  • One International Unit of asparaginase is defined as that amount of enzyme required to generate 1 μmol of ammonia per minute at pH 7.3 and 37°C

  • The product's specific activity is at least 225 IU/mg of protein

• Store intact vials under refrigeration at 2°–8°C (35.6°–46.4°F)

• After reconstitution, Elspar^® is a clear, colorless solution

• Unused, reconstituted asparaginase should be stored at 2°–8°C and discarded after 8 hours or sooner if the reconstituted product becomes cloudy

• Asparaginase stability is dependent on solution pH and storage temperature¹⁰

  • Asparaginase is relatively stable at pH = 4.5–11; drug activity is lost at greater extremes of pH

  • Asparaginase also has a high stability to changes in temperature (37°–60°C), but both solution pH and storage temperature affect stability

  • Asparaginase activity was preserved for at least 7 days after dilution in 0.9% NS and storage under refrigeration (8°C) in polyolefin or polyethylene containers

  • Administer asparaginase by either intraVENous or intraMUSCular routes

For intraVENous use:

• Reconstitute vials containing asparaginase 10,000 IU with 5 mL of SWFI or 0.9% NS to produce a solution with concentration = 2000 IU/mL. Ordinary shaking during reconstitution does not inactivate the enzyme, but may cause foaming

• The reconstituted solution is suitable for direct intraVENous injection or may be diluted with 0.9% NS or LRI

• Asparaginase should be administered intraVENously over a period not less than 30 minutes

• Administer asparaginase within 8 hours after preparation and only if the solution remains clear

  1. Occasionally, a small number of gelatinous fiber-like particles may develop on standing

  2. Filtration through a 5-μm filter during administration removes the particles with no resultant loss in potency

  3. SOME LOSS OF POTENCY has been observed with the use of a 0.2-μm filter

For intraMUSCular use:

• Add 2 mL of 0.9% NS to a vial containing asparaginase 10,000 IU to produce a solution with concentration = 5000 IU/mL

• If a volume >2 mL is to be administered, 2 injection sites should be used

• Administer asparaginase within 8 hours and only if the solution remains clear

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in hepatic dysfunction

Intradermal skin test:

• Asparaginase administration is associated with allergic reactions. An intradermal skin test may be performed before initial administration and when asparaginase is given after an interval ≥1 week has elapsed between doses

• Observe a skin test site for at least 1 hour for a wheal or erythema; either sign indicates a positive reaction

Note: A negative skin test reaction does not preclude the possibility of an allergic reaction to asparaginase treatment; that is, be wary of false-negative results

Prepare a skin test solution as follows:

1. Reconstitute asparaginase 10,000 IU with 5 mL of 0.9% NS

2. From the solution prepared in the previous step (containing 2000 IU/mL), withdraw 0.1 mL and inject it into a vial containing 9.9 mL of 0.9% NS, yielding a skin test solution of approximately 20 IU/mL

3. Inject intradermally 0.1 mL of the skin test solution (approximately 2 IU)

Note: In patients who demonstrate hypersensitivity by skin testing, and in any patient who previously completed a course of asparaginase, retreatment should be instituted only after successful desensitization

Desensitization should be performed before administering a first dose of asparaginase in positive reactors, and before retreating patients who have not received asparaginase for a period >1 week

Desensitization^11,12:

• Rapid intraVENous desensitization may be attempted with progressively increasing amounts of asparaginase if adequate precautions are taken to treat an acute allergic reaction should it occur

• The following schedule begins with a total of 1 IU, intraVENously and, provided no reaction has occurred, doubles the dose every 10 minutes, until the accumulated total amount given equals the planned dose for that day

ELSPAR^® (ASPARAGINASE) product label, December 2005. Merck & Co., Inc., Whitehouse Station, NJ

IntraVENous administration:

• Infuse over at least 30 minutes through the side arm of a running infusion of 0.9% NS or D5W

IntraMUSCular administration:

• Limit the volume at a single injection site to ≤2 mL

Azacitidine

VIDAZA^® (azacitidine for injection) for SC or IV use; product label, December 2012. Manufactured by Ben Venue Laboratories, Inc., Bedford, OH, or Baxter Oncology GmbH, Halle/Westfalen, Germany, or BSP Pharmaceuticals S.r.l., Latina Scalo, Italy. Manufactured for Celgene Corporation, Summit, NJ

Product Identification, Preparation, Storage, and Stability

• Vidaza^® is packaged in cartons with one single-use vial containing azaCITIDine 100 mg with 100 mg mannitol as a sterile, lyophilized, white to off-white powder for reconstitution as a suspension for SUBCUTaneous injection or as a solution for intraVENous infusion. NDC 59572-102-01

  • Store intact vials at 25°C (77°F); temperature excursions are permitted to 15°–30°C (59°–86°F)

Preparation for SUBCUTaneous administration:

1. Reconstitute lyophilized azaCITIDine powder by slowly injecting 4 mL of SWFI into a vial

2. Vigorously shake or roll the vial until a uniform cloudy suspension is formed. The resulting suspension contains 25 mg azaCITIDine per milliliter

Preparation for immediate SUBCUTaneous administration:

1. Divide doses >4 mL (>100 mg) equally into two syringes

2. Store reconstituted azaCITIDine suspension for up to 1 hour at room temperature, but the product must be administered within 1 hour after reconstitution

Preparation for delayed SUBCUTaneous administration:

1. Reconstituted azaCITIDine may be kept in the vial or drawn into a syringe

2. Divide doses >4 mL (>100 mg) equally into 2 syringes

3. Immediately place the product under refrigeration (2°–8°C; 35.6°–46.4°F) where it may be maintained for up to 8 hours

   1. If refrigerated SWFI was used in reconstituting azaCITIDine, the reconstituted product may be stored under refrigeration (2°–8°C) for up to 22 hours

   2. If non-refrigerated SWFI was used in reconstituting azaCITIDine, the reconstituted product may be stored under refrigeration (2°–8°C) for up to 8 hours, or for one hour if stored at room temperature (25°C [77°F])

4. After removal from refrigeration, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes before administration

Preparation for delayed intraVENous administration:

1. Reconstitute an appropriate number of vials to achieve the desired dose. Inject 10 mL SWFI into each vial and vigorously shake or roll the vial until all solids are dissolved. The resulting solution should be clear and will contain azaCITIDine 10 mg/mL

2. Withdraw a volume of azaCITIDine solution appropriate to deliver the desired dose and inject it into 50–100 mL of 0.9% NS or LRI

3. After reconstitution for intraVENous administration, azaCITIDine may be stored at 25°C, but administration must be completed within 1 hour after reconstitution

Selected incompatibilities:

• D5W, Hespan^® (6% hetastarch [hydroxyethyl starch] in 0.9% NS), and solutions that contain bicarbonate have the potential to increase the rate of azaCITIDine degradation and should be avoided

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in renal and hepatic dysfunction

• If patients experience an unexplained decrease in serum bicarbonate concentration to <20 mEq/L during or after treatment with azaCITIDine, the dosage should be decreased by 50% during the next treatment cycle

• If patients experience an unexplained increase in BUN or serum creatinine during treatment, the next cycle should be delayed until laboratory values return to normal or baseline and azaCITIDine dosage should be decreased by 50% on the next treatment course

• AzaCITIDine and its metabolites are substantially renally excreted. Elderly individuals and other patients with impaired renal function may be at increased risk of toxicity from azaCITIDine

For SUBCUTaneous administration only:

• Doses >4 mL (>100 mg) should be divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or upper arm)

• New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, red, or hard

• For azaCITIDine suspension that is not administered immediately after preparation:

  • After removal from refrigeration, allow the suspension to equilibrate to room temperature for up to 30 minutes before administration

  • Resuspend the product before administration to provide a homogeneous suspension by vigorously shaking a vial or rolling syringes between the palms until a uniform cloudy suspension is formed

For IntraVENous administration:

• After reconstitution and further dilution, administer the total azaCITIDine dose over a period of 10–40 minutes

• Administration must be completed within 1 hour after initial reconstitution

Bendamustine Hydrochloride

TREANDA^® (bendamustine hydrochloride) for Injection for Intravenous Infusion, product label, August 2013. Distributed by Teva Pharmaceuticals USA, Inc., North Wales, PA

TREANDA^® (bendamustine hydrochloride) Injection for Intravenous Infusion; product label, September 2013. Distributed by Teva Pharmaceuticals USA, Inc., North Wales, PA

Note: Although "TREANDA^® (bendamustine hydrochloride) Injection…" (product formulated in solution) received FDA approval in September 2013, it is not commercially available within the USA as of January 2014

Product Identification, Preparation, Storage, and Stability

Bendamustine HCl Injection (lyophilized product for reconstitution)

• TREANDA^® is available in single-use, individually packaged, amber glass vials containing a sterile, non-pyrogenic, white to off-white, lyophilized powder available in two presentations:

  • 25 mg bendamustine HCl with 42.5 mg mannitol, USP; NDC 63459-390-08; and

  • 100 mg bendamustine HCl with 170 mg mannitol, USP; NDC 63459-391-20

• Store intact vials at temperatures up to 25°C (77°F); temperature excursions are permitted up to 30°C (86°F)

• Vials should be stored in the original packaging carton to protect bendamustine HCl from light

• Reconstitute the commercial products only with SWFI as follows:

  Table Graphic Jump Location

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  Bendamustine HCl Content	SWFI (diluent) Volume	Resulting Bendamustine HCl Concentration
  25 mg	5 mL	5 mg/mL
  100 mg	20 mL

  • Shake well to yield a clear and colorless to pale yellow solution with pH of 2.5–3.5

  • The lyophilized powder should completely dissolve within 5 minutes. If particulate matter is observed, the reconstituted product should not be used

• Within 30 minutes after reconstitution, transfer an amount of bendamustine HCl sufficient to prepare a patient's dose to a parenteral product container with a volume of 0.9% NS or D2.5W/0.45% NaCl sufficient to produce a clear and colorless to slightly yellow solution with a concentration within the range of 0.2–0.6 mg/mL

• Thoroughly mix the diluted product

• After reconstitution and dilution as described, the drug product is stable for 24 hours if stored under refrigeration (2°–8°C [35.6°–46.4°F]), or for 3 hours if stored at room temperature (15°–30°C [59°–86°F]) and exposed to room light

• Administration must be completed within the duration of known product stability

  • TREANDA^® contains no antimicrobial preservatives. The admixture should be prepared as close as possible to the time of use

Bendamustine HCl Injection (product in solution)

• TREANDA^® is packaged in single-use, individually cartoned, amber glass vials containing a clear, colorless-to-yellow solution of bendamustine HCl with a concentration of 90 mg/mL. The commercial product is available in two presentations:

  • Bendamustine HCl 45 mg/0.5 mL with propylene glycol, USP, 162 mg and 293 mg of N,N-dimethylacetamide, EP 293 mg; NDC 63459-395-02, or

  • Bendamustine HCl 180 mg/2 mL with propylene glycol, USP, 648 mg and 1172 mg of N,N-dimethylacetamide, EP 293 mg; NDC 63459-396-02

  • Each vial contains 0.2 mL of excess drug (overfill)

• Store intact vials under refrigeration at 2°–8°C (35.6°–46.4°F) in the original packaging carton to protect bendamustine HCl from light

• Aseptically transfer a volume of concentrated bendamustine HCl solution sufficient to prepare a patient's dose to a parenteral product container already containing a volume of 0.9% NS or D2.5W/0.45% NaCl sufficient to produce a clear colorless-to-yellow solution with a concentration within the range 0.2–0.7 mg/mL

• Thoroughly mix the diluted product

• After dilution, the admixture is stable for 24 hours if stored under refrigeration (2°–8°C), or for 2 hours if stored at room temperature (15°–30°C [59°–86°F]) and exposed to room light

• Administration must be completed within the duration of known product stability

  • TREANDA^® contains no antimicrobial preservatives. The admixture should be prepared as close as possible to the time of use

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in renal and hepatic dysfunction

• Dosages and administration rates vary between FDA-approved indications:

  • In treatment for chronic lymphocytic leukemia, administer bendamustine HCl (100 mg/m² per day for 2 consecutive days, days 1 and 2, during a 28-day cycle) by intraVENous infusion over 30 minutes

  • In treatment for non-Hodgkin lymphoma, administer bendamustine HCl (120 mg/m² per day for 2 consecutive days, days 1 and 2, during a 21-day cycle) by intraVENous infusion over 60 minutes

Potential drug interactions:

• CYP1A2 catalyzes bendamustine metabolism to its active metabolites, γ-hydroxy-bendamustine (M3) and N-desmethyl-bendamustine (M4)

  • CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) have a potential to increase bendamustine concentration and decrease concentrations of its active metabolites in plasma

  • Conversely, CYP1A2 inducers (eg, omeprazole, tobacco use) potentially may decrease plasma concentrations of bendamustine and its active metabolites

• In vitro studies suggest that P-glycoprotein (MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2, MXR1), and other efflux transporters may have a role in bendamustine transport

• Based on in vitro data, bendamustine is not likely to inhibit metabolism via human CYP1A2, CYP2C9/10, CYP2D6, CYP2E1, or CYP3A4/5, or induce the metabolism of cytochrome P450 substrates

Bevacizumab

AVASTIN^® (bevacizumab) Solution for intravenous infusion; product label, December 2013. Manufactured by Genentech, Inc., A Member of the Roche Group, South San Francisco, CA

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Gastrointestinal Perforations

The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation…

Surgery and Wound Healing Complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed…

Hemorrhage

Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis…

Boxed Warning for "AVASTIN^® (bevacizumab) Solution for intravenous infusion"; December 2013 product label. Genentech, Inc., A Member of the Roche Group, South San Francisco, CA

Product Identification, Preparation, Storage, and Stability

• Avastin^® is packaged in individually boxed, single-use, glass vials in 2 presentations containing either 100 mg or 400 mg bevacizumab preservative-free solution in a uniform concentration of 25 mg/mL. NDC 50242-060-01 (100 mg/4 mL). NDC 50242-061-01 (400 mg/16 mL)

• Store intact vials under refrigeration at 2°–8°C (35.6°–46.4°F) in the original carton to protect them from light

• Do not freeze or shake Avastin^®

• The commercial product contains a clear to slightly opalescent, colorless to pale brown, sterile, solution of bevacizumab with pH = 6.2

  • The 100-mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and SWFI

  • The 400-mg product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and SWFI

• Withdraw from a vial an amount of bevacizumab sufficient to prepare a patient's dose and add it to a volume of 0.9% NS sufficient to produce a total volume of (Q.S.) 100 mL in a PVC or polyolefin container. Gently invert the container to mix diluted bevacizumab solution. Discard any unused bevacizumab that remains in a vial

• Do not mix bevacizumab with dextrose solutions

• After dilution, bevacizumab solutions may be stored at 2°–8°C for up to 8 hours

• After dilution in 0.9% NS, bevacizumab was stable for up to 24 hours under the following conditions:

Selected incompatibility:

• Do not mix bevacizumab with dextrose solutions

Recommendations for Drug Administration and Ancillary Care

General:

• Do not administer bevacizumab by direct intraVENous injection or bolus injection

• Administer bevacizumab by intraVENous infusion after chemotherapy. The INITIAL DOSE is given over 90 minutes. If a dose given over 9 minutes was well tolerated, the administration duration may be decreased to 60 minutes during a subsequent infusion. If a 60-minute infusion was well tolerated, subsequent treatments may be administered over 30 minutes

• Do not administer, mix, or flush bevacizumab with dextrose solutions

Bleomycin Sulfate

Bleomycin for Injection, USP; product label, July 2012. Product of Australia. Hospira, Inc. Lake Forest, IL

Bleomycin—bleomycin sulfate injection, powder, lyophilized, for solution; product label, April 2012. Manufactured by Teva Parenteral Medicines, Inc., Irvine, CA

WARNINGS

It is recommended that Bleomycin for Injection, USP, be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available

Pulmonary fibrosis is the most severe toxicity associated with bleomycin

The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total [cumulative] dose, but pulmonary toxicity has been observed in young patients and those treated with low doses

A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin

Boxed Warning for "Bleomycin—bleomycin sulfate injection, powder, lyophilized, for solution"; April 2012 product label; Teva Parenteral Medicines, Inc., Irvine, CA

Product Identification, Preparation, Storage, and Stability

• Bleomycin is generically available as a lyophilized powder for reconstitution for injection in individually packaged vials

• Each vial contains sterile bleomycin sulfate equivalent to 15 units or 30 units of bleomycin

  • Sulfuric acid or sodium hydroxide are used, if necessary to adjust product pH

• Store intact vials under refrigeration at 2°–8°C (35.6°–46.4°F)

• One unit of bleomycin activity corresponds to 1 mg of bleomycin activity

  • Commercial products are a mixture of bleomycin glycopeptides. Measurement in activity units is a more precise indication of drug potency

• Reconstitute with 0.9% NS, SWFI, or BWFI as follows:

  Table Graphic Jump Location

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  	Diluent Volumes
  Bleomycin Content/Vial	0.9% NS for IntraVENous or Intrapleural Administration		0.9% NS, SWFI, or BWFI for SUBCUTaneous or IntraMUSCular Administration
  15 units	5 mL	Bleomycin concentration = 3 units/mL	1 mL	Bleomycin concentration = 15 units/mL
  30 units	10 mL		2 mL

• For intrapleural administration as a sclerosing agent, further dilute bleomycin 60 units in 50–100 mL of 0.9% NS

• Do not reconstitute or dilute bleomycin with dextrose-containing solutions

  • Bleomycins A₂ and B₂ potencies decrease after reconstitution or dilution in dextrose-containing solutions, which does not occur in 0.9% NS¹³

• After reconstitution in 0.9% NS, bleomycin is stable for 24 hours at room temperature

• Bleomycin is compatible with glass, PVC, and high-density polyethylene containers¹³, and with polyethylene, PVC, and polybutadiene administration sets¹⁴

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal dysfunction

• Bleomycin is given by slow intraVENous injection over 10 minutes; by intraVENous infusion; and by the intraMUSCular, intrapleural, and SUBCUTaneous routes

• Bleomycin may be filtered during administration with filter membranes composed of cellulose ester^14,15, cellulose nitrate/cellulose acetate ester¹⁶, or tetrafluoroethylene polymer (Teflon^® [DuPont]), without a significant loss of drug potency

Idiosyncratic reactions:

• In approximately 1% of patients with lymphoma treated with bleomycin, a severe idiosyncratic reaction, similar to anaphylaxis, has been reported, consisting of: hypotension, mental confusion, fever, chills, and wheezing. Treatment is symptomatic including volume expansion, vasopressors, antihistamines, and glucocorticoids. The reaction may be immediate or delayed for several hours, and usually occurs after a first or second dose

  • Consequently, current FDA approved product labeling recommends because of the possibility of an anaphylactoid reaction, patients with lymphoma should receive not more than 2 units of bleomycin for the first 2 doses. If no acute reaction occurs, then the regular dosage schedule may be followed

    • The absence of hypersensitivity to test doses (≤2 units bleomycin) does not preclude hypersensitivity phenomena during subsequent administration at full treatment dosages

• Renal insufficiency markedly alters bleomycin elimination. Bleomycin terminal elimination half-life increases exponentially as creatinine clearance decreases

  • Patients with impaired renal function should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Bleomycin dosage reduction may be required in renally impaired patients

  • See Chapter 41 for modifying bleomycin dosage in renal impairment

For intrapleural administration:

• Administer bleomycin through a thoracostomy tube after excess pleural fluid drainage and confirming complete lung expansion. The thoracostomy tube is clamped after bleomycin instillation. The patient is moved from the supine to the left and right lateral positions several times during the next 4 hours. The clamp is then removed and thoracostomy tube suction is reestablished. The amount of time a thoracostomy tube remains in place following sclerosis is dictated by the clinical situation

Bortezomib

VELCADE^® (bortezomib) for Injection, for subcutaneous or intravenous use; product label, October 2012. Distributed and marketed by Millennium Pharmaceuticals, Inc., Cambridge, MA

Product Identification, Preparation, Storage, and Stability

• VELCADE^® is packaged in individually packaged, single-use, 10-mL vials containing bortezomib 3.5 mg as a white to off-white, sterile, lyophilized cake or powder. NDC 63020-049-01

  • Each vial also contains 35 mg mannitol, USP

• Store unopened vials at controlled room temperature 25°C (77°F); temperature excursions are permitted from 15°–30°C (59°–86°F). Retain the product in its original packaging to protect it from light

Preparation for intraVENous injection (1 mg/mL solution)

• Reconstitute bortezomib powder with 3.5 mL of 0.9% NS to produce a clear, colorless solution with concentration = 1 mg bortezomib/mL

Preparation for SUBCUTaneous Injection (2.5 mg/mL solution)

• Reconstitute bortezomib powder with 1.4 mL of 0.9% NS to produce a clear, colorless solution with concentration = 2.5 mg bortezomib/mL

• The reconstituted product may be stored in its original vial or a syringe at 25°C (excursions are permitted from 15°–30°C), and should be administered within 8 hours after preparation

• Bortezomib solution must be used within 8 hours after reconstitution if the product is exposed to normal indoor lighting

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

Caution:

• Exercise caution in calculating the volume of bortezomib to be administered

  • Different volumes of 0.9% NS diluent are used to reconstitute the product for the different routes of administration

  • The concentration of reconstituted bortezomib for SUBCUTaneous administration (2.5 mg/mL) is greater than the concentration of reconstituted bortezomib for intraVENous administration (1 mg/mL)

• Stickers that identify the intended route of administration are provided with commercial VELCADE^®, and should be placed on syringes containing prepared doses as a safeguard against administration via an unintended route

• The reconstituted product is suitable for direct injection

IntraVENous Administration:

• For administration by intraVENous injection over 3–5 seconds

SUBCUTaneous Administration:

• When administered SUBCUTaneously, rotate injection sites (thigh or abdomen). Administer repeated injections at least 1 inch from a previously injected site, and never where a site is tender, bruised, erythematous, or indurated

• If local injection site reactions occur after SUBCUTaneous administration of bortezomib prepared in a concentration of 2.5 mg/mL, a less-concentrated solution (1 mg/mL) may be administered SUBCUTaneously. Alternatively, consider intraVENous administration

Potential for drug interactions:

• Bortezomib is a substrate for metabolism by CYP3A4, CYP2C19, and CYP1A2

  • Concomitant administration with potent inhibitors or inducers of CYP3A subfamily enzymes has been shown to alter bortezomib's pharmacokinetic behavior

  • Avoid use of bortezomib with potent inhibitors or inducers of CYP3A subfamily enzymes

Brentuximab Vedotin

ADCETRIS^™ (brentuximab vedotin) for Injection, For intravenous infusion; product label, September 2013. Manufactured by Seattle Genetics, Inc., Bothell, WA

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS…

Boxed Warning for "ADCETRIS™ (brentuximab vedotin) for Injection, For intravenous infusion"; September 2013 product label; Seattle Genetics, Inc., Bothell, WA

Product Identification, Preparation, Storage, and Stability

• ADCETRIS^™ (brentuximab vedotin) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized cake or powder in individually boxed single-use vials containing 50 mg brentuximab vedotin. NDC 51144-050-01

  • The reconstituted product contains a solution of brentuximab vedotin 5 mg/mL with 70 mg/mL trehalose dihydrate, 5.6 mg/mL sodium citrate dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80 and water for injection. The pH is approximately 6.6

• Store intact vials at 2°–8°C (35.6°–46.4°F) in the original carton to protect brentuximab vedotin from light

• Caution: Calculate a patient's dose and the number of ADCETRIS^™ vials required to prepare a dose. A dose for patients weighing >100 kg should be calculated based on a weight of 100 kg

• Reconstitution

  1. Reconstitute brentuximab vedotin with 10.5 mL of SWFI, to produce a solution containing 5 mg brentuximab vedotin/mL

  2. Direct the stream of SWFI toward the vial wall, not directly into the drug product

  3. Gently swirl vial to aid drug dissolution. Do not shake a vial to aid dissolution

  4. The reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates. Following reconstitution, dilute brentuximab vedotin immediately, or store the solution at 2°–8°C and use it within 24 hours after reconstitution. Do not freeze brentuximab vedotin

  5. Discard any unused portion of brentuximab vedotin left in a vial

• Dilution

  1. Immediately add reconstituted brentuximab vedotin (5 mg/mL) to a parenteral product container containing a minimum volume of 100 mL 0.9% NS, D5W, or LRI to achieve a final diluted concentration within the range, 0.4–1.8 mg/mL brentuximab vedotin

  2. Gently invert the product container to mix the solution

  3. Following dilution, administer brentuximab vedotin solution immediately, or store the solution at 2°–8°C and use the product within 24 hours after reconstitution. Do not freeze brentuximab vedotin

Recommendations for Drug Administration and Ancillary Care

General:

• The recommended initial dosage is brentuximab vedotin 1.8 mg/kg body weight administered intraVENously over 30 minutes every 3 weeks

  • Doses for patients whose body weight is >100 kg should be calculated based on a weight of 100 kg; that is, the maximum single brentuximab vedotin dose is 180 mg

  • Do not administer brentuximab vedotin by direct intraVENous injection or over a period <30 minutes

Cautions:

• In vitro, the binding of monomethyl auristatin E (MMAE, the microtubule disrupting portion of brentuximab vedotin) to human plasma proteins ranged from 68–82%. MMAE is not likely to displace or to be displaced by highly protein-bound drugs

• In vitro, MMAE was a substrate but was not a potent inhibitor of the P-glycoprotein transport protein (P-gp, ABCB1, MDR1)

  • Avoid concomitant use of brentuximab vedotin with moderate and more potent inhibitors of the ABCB1 transport protein

• In vitro data indicate that MMAE is largely eliminated in urine and feces as unchanged drug; however, a small portion of MMAE is a substrate for metabolism by CYP3A4/5. In vitro studies using human liver microsomes indicate MMAE inhibits CYP3A4/5 but not other CYP isoforms

  • Avoid concomitant use of brentuximab vedotin with potent inhibitors and inducers of CYP3A subfamily enzymes

• Concomitant use of brentuximab vedotin and bleomycin is contraindicated because of a greater incidence rate of noninfectious pulmonary toxicity with concurrent use than a historical comparison of the incidence of pulmonary toxicity reported with the ABVD (DOXOrubicin, bleomycin, vinBLAStine, dacarbazine) regimen

  • Patients typically reported cough and dyspnea. Interstitial infiltration and inflammation were observed on chest radiographs and CT. Most patients responded to steroids

Adverse events:

• Infusion-related reactions, including anaphylaxis, have occurred with brentuximab vedotin. Continually monitor patients during drug administration

  • If anaphylaxis occurs, immediately and permanently discontinue brentuximab vedotin administration and administer appropriate medical therapy

  • In the event of less-severe manageable infusion-related reactions, interrupt brentuximab vedotin administration and institute appropriate medical management

    • Patients who experience an infusion-related hypersensitivity reaction should receive prophylaxis against hypersensitivity reactions before retreatment with brentuximab vedotin

    • Medications for hypersensitivity prophylaxis may include acetaminophen, an antihistamine, and a glucocorticoid

• Peripheral neuropathy should be managed using a combination of dose delay and dosage reduction to 1.2 mg/kg

  • For new or worsening G2 or G3 neuropathy, withhold brentuximab vedotin until neuropathy improves to G1 or baseline, then restart treatment with brentuximab vedotin 1.2 mg/kg per dose

  • Discontinue brentuximab vedotin treatment for G4 peripheral neuropathy

• JC virus infection resulting in PML and death has been reported in patients treated with brentuximab vedotin

  • Other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression

  • Consider a diagnosis of PML in any patient presenting with new-onset signs and symptoms of CNS abnormalities

  • Evaluation for PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy

  • Withhold brentuximab vedotin for any suspected case of PML and discontinue use if a diagnosis of PML is confirmed

• Neutropenia should be managed by dose delay and dosage reduction

  • Withhold brentuximab vedotin for neutropenia G ≥3 until ANC resolves to baseline or G ≤2 neutropenia

  • Hematopoietic growth factor support should be considered for subsequent cycles in patients who experience neutropenia G ≥3

  • Also consider dosage reduction to brentuximab vedotin 1.2 mg/kg in patients with recurrent G4 neutropenia despite the use of hematopoietic growth factors

Busulfan

BUSULFEX^® (busulfan) injection; product label, May 2011. Manufactured by DSM Pharmaceuticals, Inc., Greenville, NC. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD

WARNINGS

BUSULFEX^® (busulfan) Injection is a potent cytotoxic drug that causes profound myelosuppression at the recommended dosage. It should be administered under the supervision of a qualified physician who is experienced in allogeneic hematopoietic stem cell transplantation, the use of cancer chemotherapeutic drugs and the management of patients with severe pancytopenia. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available…

Boxed Warning for "BUSULFEX^® (busulfan) Injection"; May 2011 product label; Otsuka America Pharmaceutical, Inc., Rockville, MD

Product Identification, Preparation, Storage, and Stability

• BUSULFEX^® (busulfan) injection is supplied as a clear, colorless, sterile solution in 10-mL, single-use, clear, glass vials each containing busulfan 60 mg/10 mL (6 mg/mL) dissolved in N,N-dimethylacetamide (DMA) 33% (v/v) and polyethylene glycol 400, 67% (v/v). NDC 59148-070-90

• BUSULFEX^® is distributed as a unit carton containing 8 vials. NDC 59148-070-91

• Store intact vials under refrigeration at 2°–8°C (35.6°–46.4°F)

Dilution for clinical use:

• The solubility of busulfan in water is 100 mg/L and the pH of BUSULFEX^® diluted to approximately 0.5 mg busulfan/mL in 0.9% NS or D5W as recommended reflects the pH of the diluent used, and ranges from 3.4 to 3.9

• BUSULFEX^® must be diluted for clinical use with either 0.9% NS or D5W

  • The volume of diluent should be 10-times the volume of BUSULFEX^® solution, such that the final concentration of busulfan for clinical use is approximately 0.5 mg/mL

• Mix busulfan thoroughly by inverting the product container several times

• After dilution in 0.9% NS or D5W, BUSULFEX^® is stable at room temperature, 25°C (77°F), for up to 8 hours, but administration must be completed within that time¹⁷

• After dilution in 0.9% NS, BUSULFEX^® is stable under refrigeration at 2°–8°C for up to 12 hours, but administration must be completed within that time

Preparation and administration precautions:

• Do not use polycarbonate syringes or polycarbonate filter needles in transferring or administering busulfan solutions

• Do not inject BUSULFEX^® solution (6 mg/mL) into a parenteral product container that does not contain 0.9% NS or D5W

  • Always add BUSULFEX^® to a diluent (vehicle) solution, not the reverse

Selected incompatibility:

• Do not mix BUSULFEX^® with another solution unless compatibility is known

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with hepatic dysfunction

• Select an administration set with minimal intraluminal priming volume (≤5 mL) to administer busulfan

• Prime the administration set tubing with diluted busulfan solution to allow accurate determination of the start of busulfan administration

  • It is important to accurately identify administration starting and completion times in order to modify busulfan dosage based on its pharmacokinetic behavior in individual patients

• A rate-controlling device (infusion pump) should be used to administer diluted busulfan by intraVENous infusion via a central VAD over 2 hours

  • More rapid administration has not been tested and is not recommended

• Before starting and after completing busulfan administration, flush the patient's VAD with approximately 5 mL of 0.9% NS or D5W. Do not mix BUSULFEX^® with another solution unless compatibility is known

  • Flushing is particularly important if blood samples for pharmacokinetically guided busulfan dose adjustment must be acquired from the same VAD used to administer the drug

Concomitant drug use:

• Busulfan crosses the blood–brain barrier and induces seizures. All patients should receive anticonvulsant prophylaxis with phenytoin prior to starting busulfan

  • Although phenytoin decreases busulfan AUC_plasma by 15%, other anticonvulsants may increase busulfan AUC_plasma, and increase the risk of venoocclusive disease or seizures

  • Busulfan pharmacokinetics were studied in patients treated with phenytoin, and its clearance at the recommended dose may be less and exposure (AUC) greater in patients not treated with phenytoin

  • Plasma busulfan exposure should be monitored in cases where other anticonvulsants must be used

• Acetaminophen use should be avoided within 72 hours before and concurrently with busulfan use

  • Busulfan is eliminated via conjugation with glutathione. Acetaminophen is known to decrease glutathione concentrations in blood and tissues. Concurrent use with busulfan may result in reduced busulfan clearance, potentially prolonged systemic exposure to busulfan, and enhanced adverse effects

Busulfan dosage as a component of the "BuCy" conditioning regimen before hematopoietic stem cell transplantation:

• The usual adult dosage is based on the lesser of either ideal or actual body weight, and is 0.8 mg/kg per dose, every 6 hours, for a total of 16 doses (total daily dosage = 3.2 mg/kg per day for 4 consecutive days, or a total dosage/4-day course = 12.8 mg/kg)

• Busulfan clearance is best predicted when doses are based on adjusted ideal body weight (AIBW)

  • Dose calculations based on actual body weight, ideal body weight, or other factors can produce significant differences in busulfan clearance among lean, normal, and obese patients

• Busulfan dosage in obese patients is based on adjusted ideal body weight as follows:

Ideal body weight and adjusted ideal body weight calculations (IBW and AIBW, respectively):

• IBW for men (kg) = 50 + 0.91 × ([height in cm] − 152)

• IBW for women (kg) = 45 + 0.91 × ([height in cm] − 152)

• AIBW men and women (kg) = IBW + 0.25 3 ([actual body weight] − IBW)

• Where available, pharmacokinetic monitoring may be considered to optimize therapeutic targeting

  • Therapeutic target AUC_plasma = 1125 μmol · min

Cabazitaxel

JEVTANA^® (cabazitaxel) injection, 60 mg/1.5 mL, for intravenous infusion only; product label May 2013. sanofi-aventis U.S. LLC, Bridgewater, NJ

WARNING

Neutropenic deaths have been reported. In order to monitor the occurrence of neutropenia, frequent blood cell counts should be performed on all patients receiving JEVTANA. JEVTANA should not be given to patients with neutrophil counts of ≤1,500 cells/mm³

Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of the JEVTANA infusion and administration of appropriate therapy… Patients should receive premedication… JEVTANA must not be given to patients who have a history of severe hypersensitivity reactions to JEVTANA or to other drugs formulated with polysorbate 80…

Boxed Warning for "JEVTANA^® (cabazitaxel) Injection, 60 mg/1.5 mL, for intravenous infusion only"; May 2013 product label; sanofi-aventis U.S. LLC, Bridgewater, NJ

Product Identification, Preparation, Storage, and Stability

• JEVTANA^® (cabazitaxel) injection 60 mg/1.5 mL (NDC 0024-5824-11) is supplied as a kit consisting of 2 vials in a blister pack in 1 carton, including:

  • one single-use vial contains 60 mg of cabazitaxel (anhydrous and solvent-free) in 1.5 mL of polysorbate 80 (1.56 g) as a sterile, nonpyrogenic, clear yellow to brownish-yellow, viscous solution. Each milliliter of the concentrated drug product contains cabazitaxel (anhydrous) 40 mg and 1.04 g of polysorbate 80

  • one vial contains Diluent for JEVTANA^®, a clear, colorless, sterile, nonpyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL

• Both the JEVTANA^® injection and Diluent for JEVTANA^® vials contain excess drug and diluent solutions (overfill), respectively, to compensate for volume lost during preparation

• Store JEVTANA^® injection and Diluent for JEVTANA^® at 25°C (77°F); temperature excursions are permitted between 15°–30°C (59°–86°F)

• Do not refrigerate JEVTANA^® Injection and Diluent for JEVTANA^®

• JEVTANA^® requires 2 dilutions before it may be administered to patients:

  • The concentrated drug product should be diluted only with the supplied Diluent for JEVTANA^®, followed by dilution in either 0.9% NS or D5W

  • Do not use PVC infusion containers or polyurethane administration sets during preparation or administration of JEVTANA^®

Initial dilution:

1. With a syringe, aseptically withdraw the entire contents of a Diluent for JEVTANA^® vial and inject it into a vial containing the JEVTANA^® drug product

   1. When transferring the diluent, direct the needle onto the inside wall of the drug product vial and inject slowly to limit foaming

2. Remove the syringe and needle and gently mix the initially diluted solution by repeated inversions for at least 45 seconds to assure a homogeneous mixture of the drug and diluent. Do not shake initially diluted JEVTANA^® to avoid foaming

3. Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter

   1. It is not required that all foam dissipate prior to continuing preparation

   2. The resulting initially diluted JEVTANA^® solution (10 mg cabazitaxel/mL) requires further dilution before it may be given to patients

Caution: Secondary dilution must be completed within 30 minutes after completing initial dilution to obtain a product appropriate for administration to patients

Secondary dilution:

1. With a syringe, aseptically withdraw an amount of the initially diluted JEVTANA^® solution (10 mg cabazitaxel/mL) appropriate for a patient's dose and transfer it to a volume of 0.9% NS or D5W to produce a cabazitaxel concentration within the range 0.1–0.26 mg/mL

   1. Product concentrations must not exceed 0.26 mg cabazitaxel/mL. Discard any unused portion of the initially diluted JEVTANA^® solution

2. Thoroughly mix the secondarily diluted product by manual rotation and by gently inverting the container

3. After the second dilution in either 0.9% NS or D5W, JEVTANA^® should be used within 8 hours if maintained at ambient temperatures (including the 1-hour administration time), or may be used within 24 hours after preparation (including the 1-hour administration time) if stored under refrigeration at 2°–8°C (35.6°–46.4°F)

Cautions: JEVTANA^® should not be mixed with any other drugs

Chemical and physical stability of cabazitaxel solution has been demonstrated for 24 hours under refrigerated conditions; however, both the initially diluted and secondarily diluted solutions are supersaturated. Consequently, if crystals or particulates appear in either solution, the solutions must not be used and should be discarded

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

• Cabazitaxel is administered intraVENously over 60 minutes in combination with predniSONE 10 mg/day administered orally, continually throughout treatment with cabazitaxel

Primary prophylaxis against hypersensitivity reactions:

• At least 30 minutes before each dose of cabazitaxel give the following medications intraVENously to decrease the risk or severity of hypersensitivity:

  • A histamine H1-subtype receptor antagonist, for example, dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent antihistamine, plus

  • A glucocorticoid, for example, dexamethasone 8 mg, or another steroid at a glucocorticoid-equivalent dose, plus

  • A histamine H₂-subtype receptor antagonist, for example, ranitidine 50 mg or equivalent

• After secondary dilution, JEVTANA^® solution (concentration 0.1–0.26 mg cabazitaxel/mL) should be administered intraVENously over 60 minutes at room temperature through an in-line filter with nominal pore size of 0.22 μm

• Although it is recommended the secondarily diluted solution should be used immediately, storage time can be longer under specific conditions:

  • Up to 8 hours after preparation if maintained at ambient temperatures (including the 1-hour administration time), or

  • Up to 24 hours after preparation (including the 1-hour administration time) if stored under refrigeration at 2°–8°C

Caution with medications given concomitantly:

• Cabazitaxel is a substrate for metabolism catalyzed by CYP3A subfamily enzymes

  • Avoid concomitant use of moderate and more potent CYP3A subfamily enzyme inhibitors, which may increase systemic exposure to cabazitaxel (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

  • Avoid concomitant use of strong CYP3A subfamily enzyme inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort), which may be expected to decrease cabazitaxel concentrations

• Cabazitaxel is a substrate of P-glycoprotein (P-gp, MDR1, ABCB1) in vitro, but is not a substrate of MRP1, MRP2, or the breast cancer resistance protein (BCRP, ABCG2, MXR1)

  • In vitro, cabazitaxel inhibited the transport of P-gp and BRCP, at concentrations at least 38-fold greater than what is observed clinically

• A risk of cabazitaxel perturbing the pharmacokinetic behavior of concurrently used medications by inhibiting P-gp or BCRP is unlikely at clinically used dosages

Carboplatin

Carboplatin injection; product label, August 2007. Hospira, Inc., Lake Forest, IL

CARBOPLATIN–carboplatin injection, solution (50-, 150-, and 450-mg multidose vials); product label, October 2011. Manufactured by Pharmachemie B.V., Haarlem, The Netherlands. Manufactured for Teva Pharmaceuticals USA, Sellersville, PA, and

CARBOPLATIN INJECTION; product label, January 2008. APP Pharmaceuticals LLC, Schaumburg, IL

WARNINGS

Carboplatin injection should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available

Bone marrow suppression is dose related and may be severe, resulting in infection and/or bleeding. Anemia may be cumulative and may require transfusion support. Vomiting is another frequent drug-related side effect

Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of carboplatin injection administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms

Boxed Warnings for "Carboplatin Injection"; August 2007 product label; Hospira, Inc., Lake Forest, IL

Product Identification, Preparation, Storage, and Stability

• CARBOplatin is marketed as branded and generic products from several manufacturers in multidose (or multiuse) vials containing 50 mg, 150 mg, 450 mg, or 600 mg CARBOplatin per vial

• CARBOplatin injection is a sterile aqueous solution of CARBOplatin at a concentration of 10 mg/mL (1%); the pH of a 1% solution of CARBOplatin is 5–7

• Store unopened vials under temperature conditions indicated for individual products, generally within a range between 20°C and 25°C (68°F and 77°F). Available products often indicate temperature excursions to 15°–30°C (59°–86°F) are permitted. Protect unopened vials from light

• CARBOplatin injection in multidose vials maintain microbial, chemical, and physical stability for up to 14 days (Teva Pharmaceuticals USA product) or 15 days (Hospira, Inc. product) at 25°C following multiple needle entries

• CARBOplatin injection may be further diluted to concentrations as low as 0.5 mg/mL with either D5W or 0.9% NS. After dilution, CARBOplatin may be stored at room temperature (25°C [77°F]) for up to 8 hours before use

Selected incompatibility:

• Avoid admixture with solutions with pH >6.5 (eg, solutions containing fluorouracil or sodium bicarbonate)

• Avoid admixture with mesna

• Aluminum reacts with CARBOplatin, causing precipitation and loss of drug potency. Do not prepare or administer CARBOplatin with needles or administration sets that contain aluminum parts that may come into contact with the drug

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal dysfunction

• Administer CARBOplatin intraVENously over at least 15 minutes. Pre- or post-treatment hydration and forced diuresis are not required

• Prescriptions and medication orders should identify the drug by its complete generic name, "CARBOplatin", to prevent confusion with other platinum compounds

Carfilzomib

KYPROLIS^™ (carfilzomib) for Injection, for intravenous use; product label, July 2012. Manufactured by Onyx Pharmaceuticals, Inc., South San Francisco, CA

Product Identification, Preparation, Storage, and Stability

• KYPROLIS^™ (carfilzomib) for injection is supplied in individually cartoned single-use vials containing carfilzomib 60 mg as a sterile, white to off-white, lyophilized cake or powder with sulfobutylether beta-cyclodextrin 3000 mg, citric acid 57.7 mg, and sodium hydroxide sufficient to adjust the product pH to 3.5. NDC 76075-101-01

• Store unopened vials under refrigeration between 2°C and 8°C (35.6°F and 46.4°F) in the original packaging to protect carfilzomib from light

• Preparation:

  1. Remove a vial from refrigeration just prior to use

  2. Slowly inject 29 mL of SWFI by directing the solution onto the inside vial wall, not into the drug product to minimize foaming

  3. Gently swirl or slowly and repeatedly invert the vial for approximately 1 minute, or until the drug cake or powder has completely dissolved. DO NOT SHAKE carfilzomib to avoid generating foam

  4. If foaming occurs, set the vial aside for approximately 2–5 minutes, to allow the foam to dissipate

  5. After reconstitution, the resulting solution should be clear and colorless and contains carfilzomib at a concentration of 2 mg/mL

• Carfilzomib stability

  Table Graphic Jump Location

  | Download (.pdf) | Print

  Storage Conditions After Reconstitution (Carfilzomib 2 mg/mL)	Stability as a Function of Product Container✫
  	Vial	Syringe	Diluted with D5W and Stored in a Plastic Container (Bag)
  Refrigeration (2°–8°C)	24 hours
  Room temperature (15°–30°C [59°–86°F])	4 hours
  ✫Total time from reconstitution to administration should not exceed 24 hours

  • 6. Dilute carfilzomib in a parenteral product container with 50 mL of D5W

  • 7. Discard vials containing unused drug solution

Recommendations for Drug Administration and Ancillary Care

Supportive Care:

Hydration

• Prior to administering carfilzomib, evaluate a patient's fluid status to ensure they are well hydrated

• Patients should receive hydration with carfilzomib to reduce the risk of developing renal toxicity and tumor lysis syndrome (TLS)

  • Overall, TLS occurred in <1% of patients, but patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS

  • Monitor for evidence of TLS during treatment, and manage promptly

  • Interrupt carfilzomib treatments until TLS is resolved

• Maintain patients' fluid volume status and monitor blood chemistries closely throughout treatment with carfilzomib

  • During cycle 1:

    • Give 250–500 mL 0.9% NS or another fluid intraVENously as clinically appropriate before each carfilzomib dose

    • Give an additional 250–500 mL of fluids intraVENously as needed after completing each carfilzomib dose

  • During repeated treatment cycles, continue intraVENous hydration as needed

  • Monitor patients for fluid overload

  Prophylaxis against hypersensitivity/infusion-related reactions

  • Hypersensitivity reactions may occur immediately after or during the first 24 hours after carfilzomib administration

  • Infusion-related reactions may be characterized by any of the following: fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, angina

  • To mitigate the incidence and severity of infusion reactions, administer dexamethasone 4 mg orally or intraVENously prior to each carfilzomib dose during cycle 1 and prior to each carfilzomib dose during the cycle in which carfilzomib dosage is escalated to 27 mg/m²

  • Continue or resume prophylaxis with dexamethasone 4 mg orally or intraVENously if symptoms develop or reappear during subsequent cycles

   

  General:

  • Carfilzomib is administered only by intraVENous infusion over 2–10 minutes, on 2 consecutive days, weekly, for three consecutive weeks every 28 days, that is administration on days 1, 2, 8, 9, 15, and 16, during a 28-day treatment cycle

  • Flush with 0.9% NS or D5W the administration set tubing and VAD through which carfilzomib is given immediately before beginning and after completing carfilzomib administration

  • Do not mix carfilzomib with other medicinal products or administer it through the same intraVENous VAD with other medicinal products

   

  Carfilzomib dose calculation:

  • Carfilzomib dose is calculated using a patient's actual BSA calculated at baseline. Patients with a BSA >2.2 m² should receive a dose based upon a BSA of exactly 2.2 m²

  • There is no need to make dose adjustments for changes in body weight ≤20%

   

  Carfilzomib dosage escalation:

  • During cycle 1, carfilzomib is administered at a dosage of 20 mg/m² each day of treatment

  • If carfilzomib is well tolerated at 20 mg/m² per dose, the dosage during cycle 2 may be escalated to 27 mg/m² for each day of treatment, and continued at 27 mg/m² per dose during subsequent cycles

Carmustine

BiCNU^® (carmustine for injection); product label, May 2011. BiCNU^® manufactured by Ben Venue Laboratories, Inc., Bedford, OH, or Emcure Pharmaceuticals Ltd., Hinjwadi, Pune 411057, INDIA. Diluent manufactured by Luitpold Pharmaceuticals, Inc., Shirley, NY. Distributed by Bristol-Myers Squibb Company, Princeton, NJ

WARNINGS

BiCNU^® (carmustine for injection) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents

Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of BiCNU…

Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose… At the recommended dosage, courses of BiCNU should not be given more frequently than every 6 weeks

The bone marrow toxicity of BiCNU is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose…

Pulmonary toxicity from BiCNU appears to be dose related. Patients receiving greater than 1400 mg/m² cumulative dose are at significantly higher risk than those receiving less

Delayed pulmonary toxicity can occur years after treatment, and can result in death, particularly in patients treated in childhood…

Boxed Warning for "BiCNU^® (carmustine for injection)"; May 2011 product label; Bristol-Myers Squibb Company, Princeton, NJ

Product Identification, Preparation, Storage, and Stability¹⁸

• BiCNU^®, NDC 0015-3012-60, packaging includes 2 containers, including:

  • One vial containing 100 mg of carmustine as sterile, lyophilized, pale-yellow flakes or a congealed mass

  • An ampule containing 3 mL of sterile dehydrated alcohol injection, USP, which is used to initially dissolve carmustine before attempting further dilution with aqueous media

• Dehydrated alcohol injection, USP, may be stored at room temperature 15°–30°C (59°–86°F) or under refrigeration at 2°–8°C (35.6°–46.4°F)

• Intact vials containing the drug product, carmustine, are stable for at least 3 years if stored under refrigeration at 2°–8°C, but for only 7 days if stored at room temperature (up to 25°C [≤77°F]). The lyophilized formulation does not contain a preservative and is intended for a single use

  • Caution: BiCNU^® has a low melting point (30.5°–32°C [86.9°–89.6°F])

    • Exposure of the drug to this or greater temperatures will cause the drug to liquefy, becoming an oily film on the interior surface of a vial; a sign of decomposition indicating affected vials should be discarded

    • If upon receipt appropriate storage during transportation is in question, immediately examine the vial containing carmustine in each individual carton by holding it to a bright light for inspection

    • If carmustine appears as a very small amount of dry flakes or a dry congealed mass, the product is suitable for use and should be refrigerated immediately

Preparation

1. Dissolve carmustine with 3 mL of the supplied diluent (dehydrated alcohol injection, USP)

2. Only after the drug product has been completely dissolved, aseptically add 27 mL of SWFI

   1. The resulting solution is clear, colorless to yellowish, and contains 3.3 mg carmustine/mL in 10% ethanol

      • After reconstitution as recommended, carmustine is stable for 8 hours at room temperature (25°C) if it is protected from light exposure, and for at least 24 hours if stored under refrigeration and protected from light

        • Reconstituted vials should be examined for crystal formation prior to use

        • If crystals are observed, they may be re-dissolved by warming the vial to room temperature with agitation

Administration

• For administration to patients, carmustine should be further diluted to a concentration of 0.2 mg/mL with D5W and stored only in glass or polyolefin parenteral product containers¹⁹

• Carmustine adsorption to PVC, ethylene vinyl acetate (EVA), and polyurethane containers results in substantial drug loss as a result of drug adsorption to the container material

Stability as a Function of Carmustine Concentration and Storage Temperature^{20, 21}

• Initial solubilization with ethanol produces a carmustine solution that can be very irritating to vascular endothelium during intraVENous administration. Consequently, several investigators have evaluated alternative preparation schemes to decrease or eliminate ethanol from carmustine for intraVENous administration. Although these methods are not advocated by the product manufacturer, and may present some logistical challenges with respect to material resources, 2 methods for producing an ethanol-free solution for intraVENous administration are described below

Alternative Preparation Schemes

Method 1²²:

• To a vial containing 100 mg carmustine, add 30 mL of preservative-free D5W

• Heat the vial to 60°C (140°F) in a water bath for 5 minutes, and, during heating, vigorously shake the vial 3 times

• The preparation scheme produces a solution with a carmustine concentration of 3.3 mg/mL and a stability half-life of 46 hours

  • The investigators demonstrated an 8% loss in concentration after product filtration

  • Although carmustine must be diluted before it is administered to patients, the investigators did not describe secondary dilution

Method 2²³:

• To a vial containing 100 mg carmustine, add 25 mL of preservative-free D5W warmed to 37°C (98.6°F)

• Shake the vial by hand or in a water bath warmed to 37°C for approximately 5 minutes

• The preparation scheme produces a solution with a carmustine concentration of ~4 mg/mL and a mean stability half-life of 6.8 hours

  • When prepared with ethanol according to the manufacturer's instruction, carmustine must be diluted before it is administered to patients. Tepe et al. did not describe secondary dilution

Selected incompatibility:

• Avoid admixture with solutions of pH >6 (eg, solutions containing sodium bicarbonate)²⁴

• Photodegradation occurs after exposure to strong light sources (>500 Lux; >46 foot-candles)

Recommendations for Drug Administration and Ancillary Care²⁵

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

• Administer by intraVENous infusion over at least 1–2 hours

  • Carmustine is irritating to vascular endothelium largely because of the ethanol used to initially dissolve the drug. Administration over <1 hour may produce sensations of intense pain and burning at the site of administration

• Use only polyethylene or polyethylene-lined administration sets

  • A substantial amount of carmustine may be lost from solution as a result of adsorption to the surfaces of ethylene vinyl acetate, PVC, and polyurethane product containers and administration sets

• Do not mix carmustine with solutions containing sodium bicarbonate

• Carmustine should not be given more frequently than every 6 weeks

Cetuximab

ERBITUX^® (cetuximab) injection, for intravenous infusion; product label, August 2013. Manufactured by ImClone LLC, a wholly owned subsidiary of Eli Lilly and Company, Branchburg, NJ. Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ. Comarketed by Eli Lilly and Company, Indianapolis, IN

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000… Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions…

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration…

Boxed Warning for "ERBITUX^® (cetuximab) injection, for intravenous infusion"; August 2013 product label; Co-marketed by Bristol-Myers Squibb Company, Princeton, NJ, and Eli Lilly and Company, Indianapolis, IN

Product Identification, Preparation, Storage, and Stability

• ERBITUX^® is supplied in individually packaged, single-use vials containing cetuximab 100 mg/50 mL (NDC 66733-948-23) or 200 mg/100 mL (NDC 66733-958-23) as a sterile, preservative-free, clear and colorless, injectable liquid with pH = 7.0–7.4

  • The commercial product contains cetuximab 2 mg/mL with 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium phosphate monobasic monohydrate, and SWFI

• Store vials under refrigeration at 2°–8°C (35.6°–46.4°F). Do not freeze the product

• The product may contain a small amount of easily visible, white, amorphous cetuximab particulates

  • Increased particulate formation may occur at temperatures ≤0°C (≤32°F)

• Cetuximab stored in parenteral product containers is chemically and physically stable for up to 12 hours at 2°–8°C and for up to 8 hours at controlled room temperature (20°–25°C; 68°–77°F)

  • Discard any unused cetuximab within 8 hours or within 12 hours after preparation for products maintained at controlled room temperature or under refrigeration (2°– 8°C), respectively

  • Discard any unused portions of cetuximab remaining in a vial

• Do not shake or dilute cetuximab solution

Recommendations for Drug Administration and Ancillary Care

General:

• Administer cetuximab by intraVENous infusion with an infusion pump or syringe pump

• Do not administer cetuximab by direct intraVENous injection or bolus injection

Premedication:

• Give primary prophylaxis against infusion-related reactions with an antihistamine (H₁-receptor) antagonist (eg, diphenhydrAMINE 50 mg IV, or equivalent H₁ antagonist) 30–60 minutes before a first dose of cetuximab

  • Infusion reactions have occurred in 15–21% of patients across studies, and included: pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension

    • Grades 3 and 4 infusion reactions occurred in 2–5% of patients, and were fatal in 1 patient

  • Premedication for subsequent cetuximab doses should be based upon clinical judgment and the presence and severity of infusion reactions during prior doses

Administration:

• Administer cetuximab through a low protein binding, 0.22-μm, inline filter (placed as proximal to the patient as practical)

• Administer cetuximab 400 mg/m² doses over 2 hours (120 min); administer 250 mg/m² doses over 1 hour (60 min)

  • The MAXIMUM INFUSION RATE should be ≤5 mL/min (≤10 mg/min), which is ≤300 mL/hour (≤600 mg/hour)

  • Use 0.9% NS to flush the line at the end of infusion

Patient monitoring:

• A 1-hour observation period is recommended after completing cetuximab administration in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, bronchodilators, oxygen, and parenteral steroids and antihistamines)

  • Continue monitoring to confirm resolution of an acute event in patients who required treatment for infusion reactions

  • Longer observation periods may be required in patients who experience infusion reactions

• Patients should be periodically monitored for hypomagnesemia, hypocalcemia, and hypokalemia, during and following cetuximab administration. The same electrolyte analyses should be continually monitored for approximately 8 weeks after the last dose administered, that is, a period of time commensurate with the half-life and persistence of cetuximab

• The onset of electrolyte abnormalities has been reported to occur from days to months after cetuximab administration. Electrolyte supplementation may be necessary in some patients and, in severe cases, intraVENous replacement may be required. The time to resolution of electrolyte abnormalities is not known

Patient counseling:

Advise patients:

• To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems

• Of the potential risks of using cetuximab during pregnancy or breast-feeding and of the need to use adequate contraception in both males and females during treatment, and for 6 months following the last dose of cetuximab

• That breast-feeding is not recommended during, and for 2 months following the last dose of cetuximab therapy

• To limit sun exposure (use sunscreen, wear hats) while receiving cetuximab and for 2 months following the last dose of cetuximab

Cisplatin

CISPLATIN INJECTION; product label, January 2008. APP Pharmaceuticals, LLC, Schaumburg, IL

PLATINOL–cisplatin injection, powder, lyophilized, for solution; product label, October 2010. Made in Italy. Manufactured for Bristol-Myers Squibb Company Princeton, NJ

CISPLATIN–cisplatin injection, solution; product label, February 2012 Teva Parenteral Medicines, Inc. Manufactured in The Netherlands by Pharmachemie B.V., Haarlem, The Netherlands. Manufactured for Teva Pharmaceuticals USA, Sellersville, PA

WARNINGS

[CISplatin] …should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available

Cumulative renal toxicity associated with cisplatin is severe. Other major dose-related toxicities are myelosuppression, nausea, and vomiting

Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus, and/or loss of high frequency hearing and occasionally deafness, is significant

Anaphylactic-like reactions to [CISplatin] …have been reported. Facial edema, bronchoconstriction, tachycardia, and hypotension may occur within minutes of [CISplatin] …administration. Epinephrine, corticosteroids, and antihistamines have been effectively employed to alleviate symptoms…

Exercise caution to prevent inadvertent [CISplatin] …overdose. Doses greater than 100 mg/m²/cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid inadvertent [CISplatin] …overdose due to confusion with… carboplatin …or prescribing practices that fail to differentiate daily doses from total dose per cycle

Boxed Warnings for "CISPLATIN INJECTION"; January 2008 product label; APP Pharmaceuticals, LLC, Schaumburg, IL; "PLATINOL—cisplatin injection, powder, lyophilized, for solution"; October 2010 product label; Bristol-Myers Squibb Company Princeton, NJ; and "CISPLATIN—cisplatin injection, solution"; February 2012 product label; Teva Pharmaceuticals USA, Sellersville, PA

• Prescriptions and medication orders should identify the drug by its complete generic name, "CISPLATIN", to prevent confusion with other platinum compounds

• Product labeling advises pharmacists to contact health care providers who prescribe CISplatin dosages >100 mg/m² per cycle for dose confirmation

Product Identification, Preparation, Storage, and Stability

• CISplatin is generically available from several manufacturers in multiuse vials in at least 2 presentations, including:

  • A sterile, clear, light yellow, aqueous solution for injection (CISplatin injection)

    • Commercially available products contain 50 mg, 100 mg, or 200 mg CISplatin in individually packaged, multiple-dose, amber vials

      • Each milliliter contains CISplatin 1 mg and sodium chloride 9 mg

      • Additional excipients may be present in some product formulations

    • CISplatin Injection (1 mg/mL) must be diluted before it is administered to patients

  • A white to light yellow lyophilized powder for reconstitution (CISplatin for injection)

    • Commercially available products contain 50 mg CISplatin in individually packaged, multiple-dose, amber vials

    • Reconstitute lyophilized CISplatin with 50 mL of SWFI to obtain a solution containing 1 mg CISplatin and sodium chloride 9 mg/mL

      • Additional excipients may be present in some formulations

    • Reconstituted CISplatin (1 mg/mL) must be diluted before it is administered to patients

• Consult product labeling for manufacturer recommendations about acceptable storage temperatures for intact vials

  • Acceptable storage temperatures for products in solution (CISplatin injection) vary within a range from 15°C (59°F) or 20°C (68°) for a lower temperature limit to an upper limit of 25°C (77°F)

  • At least 1 commercial product formulated as a lyophilized powder for reconstitution (CISplatin for injection) specifies storage at controlled room temperature (25°C [77°F])

• Do not store CISplatin in solution (1 mg/mL) under refrigeration, under which condition it is more likely to precipitate

• Protect unopened containers from light

• Dilute CISplatin in a convenient volume of fluid. The diluting fluid MUST CONTAIN a chloride concentration ≥0.225% sodium chloride (≥38.5 mEq/L), for example, 0.45% NaCl, 0.9% NS, 3% NaCl, and saline and dextrose solutions with chloride concentrations >0.225%²⁶

• Mannitol is compatible and may be added to diluted CISplatin solutions

• Protect CISplatin solutions that are not used within 6 hours after preparation from exposure to light

• CISplatin that remains in an amber vial after initial entry is stable for 28 days if protected from light or for 7 days under fluorescent room lighting

Selected incompatibility:

• Aluminum reacts with CISplatin causing precipitation and loss of drug potency

  • Do not prepare or administer CISplatin with needles or administration sets that contain aluminum parts that may come into contact with the drug

• Do not dilute CISplatin in solutions with chloride content less than the concentration found in 0.225% NaCl, that is, not less than 38.5 mEq/L

• CISplatin is incompatible in admixtures with mesna

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal dysfunction

• Hydration with 1000–2000 mL of fluid administered intraVENously is recommended starting at least 2 hours before CISplatin administration commences

  • Consider continuing hydration during and after CISplatin administration is completed, particularly in patients who receive a diuretic before, during, or after CISplatin to augment urine formation

  • Maintain increased hydration via oral, parenteral, or both routes, and urine output for at least 24 hours after CISplatin administration

• Administer CISplatin intraVENously. Infusion duration generally is within a range of 15–120 minutes, but may be prolonged in some regimens (8–24 hours)

Cladribine

CLADRIBINE INJECTION for intravenous infusion only; product label, January 2008. APP Pharmaceuticals, LLP, Schaumburg, IL

LEUSTATIN^® (cladribine) injection, PRODUCT INFORMATION; product label, August 2, 2012. Janssen-Cilag Pty Ltd., Macquarie Park NSW, Australia

CLADRIBINE injection, Rx only, for intravenous infusion only; product label, August 2006. Manufactured by Ben Venue Laboratories, Inc., Bedford, OH. Manufactured for Bedford Laboratories, Bedford, OH

WARNINGS

Cladribine Injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Serious neurological toxicity (including irreversible paraparesis and quadraparesis) has been reported in patients who received cladribine injection by continuous infusion at high doses (four to nine times the recommended dose for Hairy Cell Leukemia). Neurologic toxicity appears to demonstrate a dose relationship; however, severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens

Acute nephrotoxicity has been observed with high doses of cladribine (four to nine times the recommended dose for Hairy Cell Leukemia), especially when given concomitantly with other nephrotoxic agents/therapies

Boxed Warning for "CLADRIBINE INJECTION For Intravenous Infusion Only"; January 2008 product label; APP Pharmaceuticals, LLP, Schaumburg, IL

Product Identification, Preparation, Storage, and Stability

• Cladribine injection is generically available packaged in single-use, clear flint glass, 20-mL (capacity) vials containing cladribine 10 mg/10 mL (1 mg/mL) as a sterile, clear, colorless, preservative-free, isotonic solution

  • Each milliliter of commercially available products also contains 1 mg cladribine and 9 mg (0.15 mEq) of sodium chloride

  • The solution has a pH in the range of 5.5–8.0. Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the pH to 6.3 ± 0.3

• Presentations vary among manufacturers with respect to product packaging: vials may be packaged individually or in cases containing multiple vials

• Store intact vials under refrigeration 2°–8°C (35.6°–46.4°F) and protected from light during storage

• Cladribine must be diluted before administration

24-Hour drug supply (daily bag exchanges):

• Dilute in 500 mL of 0.9% NS an amount of cladribine needed to provide treatment for a single day

  • Compared with dilution in 0.9% NS, dilution in D5W increases the rate of cladribine degradation and is not recommended

  • Cladribine admixtures in 0.9% NS in PVC containers (eg, Viaflex Container, Baxter Healthcare Corporation, Deerfield, IL) are chemically and physically stable for at least 24 hours at room temperature under normal fluorescent lighting

7-Day drug supply:

• A 7-day infusion solution should only be prepared with B0.9% NS (preserved with 0.9% benzyl alcohol) as follows:

  1. Add to a plastic container an amount of cladribine needed for a 7-day supply of medication

  2. Add to the same plastic container a calculated amount of B0.9% NS sufficient to produce a total volume of (Q.S.) 100 mL

     1. Both cladribine and the diluent solution should be transferred into a parenteral product container through a sterile, disposable, hydrophilic syringe filter with pore size ≤0.22 μm to minimize the risk of microbial contamination

     2. Inject cladribine through the filter first followed by the B0.9% NS vehicle solution to flush into the product container any cladribine remaining in the filter

        • Solutions prepared with B0.9% NS for individuals weighing >85 kg may have reduced preservative effectiveness because of displacement of the benzyl alcohol-containing diluent by the volume of drug, that is, >53.6 mg in a total volume to deliver of 100 mL

        • Admixtures prepared with antimicrobially preserved diluent have demonstrated acceptable chemical and physical stability for at least 7 days in a SIMS Deltec, Inc., Medication Cassette Reservoir

  3. Aseptically connect to the drug product container (reservoir) any tubing that will be used to connect the reservoir to a patient's VAD during drug administration

  4. Aseptically remove air from the product container and any connected tubing

  5. Aseptically cap with a sterile Luer locking cap, closure, or seal any tubing attached to the drug reservoir for storage if the product is not immediately connected to a patient's VAD after preparation is completed

• Cladribine may precipitate when exposed to low temperatures, but can be resolubilized by warming at ambient room temperature and vigorous shaking

• Do not attempt to resolubilize cladribine by heating or microwaving

• Freezing does not adversely affect the solution. If freezing occurs, thaw at room temperature, but do not thaw cladribine by radiant thermal or microwave heating

• After thawing, vials are stable until the expiration date on the product label if stored under refrigeration

• Do not refreeze cladribine

• Any unused portion of cladribine remaining in a single-use vial should be discarded

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

• Administer only by intraVENous infusion over 2–24 hours

• Cladribine should be administered promptly, or, after dilution, stored under refrigeration (2°–8°C [35.6°–46.4°F]) for not more than 8 hours before starting administration

• Cladribine should not be mixed with other drugs or additives or administered simultaneously with other drugs via a common intraVENous line

Clofarabine

Clolar^® (clofarabine) injection for intravenous use; product label, April 2013. Manufactured by Teva Pharmachemie, Haarlem, The Netherlands. Manufactured for Genzyme Corporation, Cambridge, MA. Distributed by Genzyme Corporation, Cambridge, MA

Product Identification, Preparation, Storage, and Stability

• Clolar^® is packaged in 20-mL-capacity, flint glass, single-use vials containing 20 mL of a clear, practically colorless, preservative-free solution of clofarabine 1 mg/mL (20 mg/20 mL) (NDC 0024-5860-01)

  • The commercial product is formulated in 20 mL of unbuffered 0.9% NS. The pH range of the solution is 4.5–7.5

• Store intact vials at 25°C (77°F). Temperature excursions are permitted to 15°–30°C (59°–86°F)

• Clofarabine solution must be filtered before dilution. Use a sterile filter with a pore size equal to 0.2 μm either when aspirating the drug into a syringe or when expelling drug from the syringe into a diluent solution

• Dilute clofarabine with a volume of 0.9% NS or D5W sufficient to produce a concentration between 0.15 and 0.4 mg/mL before administering it to patients

• Diluted solutions may be stored at 15°–30°C, but must be used within 24 hours after preparation

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for comments about use in patients with renal and hepatic dysfunction

• Administer diluted clofarabine solutions by intraVENous infusion over 2 hours

• Provide supportive care, such as intraVENous fluids, allopurinol, and alkalinize urine throughout a 5-day treatment course to reduce the effects of tumor lysis and other adverse events

• Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during clofarabine administration

  • Avoid medications that produce or exacerbate hypotension during the days on which clofarabine is administered

• Evaluate and monitor patients receiving clofarabine treatment for signs and symptoms of cytokine release (eg, tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS), capillary leak syndrome, and organ dysfunction

• Immediately discontinue clofarabine in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome and provide appropriate supportive measures, which may include steroids, diuretics, and albumin

  • Glucocorticoid prophylaxis (eg, hydrocortisone 100 mg/m² per day for 3 days [days 1–3]) may prevent signs or symptoms of SIRS or capillary leak syndrome

• Monitor renal and hepatic function closely during a 5-day treatment course with clofarabine

  • Although clofarabine has not been studied in patients with renal or hepatic impairment, 49–60% of a dose was renally eliminated as unchanged drug within 24 hours after administration to pediatric patients

  • Avoid medications that adversely affect kidney and liver function during the days on which clofarabine is administered

  • Clofarabine should be immediately discontinued if Grades ≥3 increases in serum creatinine or bilirubin are observed during treatment

    • Clofarabine treatment may resume after a patient's condition has stabilized and organ function has returned to baseline, generally with a 25% reduction in clofarabine dose

• Discontinue clofarabine administration if a Grade 4 noninfectious nonhematologic adverse event occurs

Selected incompatibility:

• Do not administer other medications through the same intraVENous line as clofarabine

  • Clofarabine compatibility with other drugs is not yet known

Cyclophosphamide

Cyclophosphamide for injection, USP; product label, February 2013. Product made in Germany. Manufactured by Baxter Healthcare Corporation, Deerfield, IL

Product Identification, Preparation, Storage, and Stability

• Cyclophosphamide is available as a sterile white powder for reconstitution for injection in individually packaged single-use vials containing 500 mg (NDC 10019-955-01), 1000 mg (NDC 10019-956-01), or 2000 mg (NDC 10019-957-01) of cyclophosphamide monohydrate

• Store cyclophosphamide at temperatures ≤25°C (≤77°F)

• Cyclophosphamide may melt if exposed to high temperatures during transportation or storage

  • Melted cyclophosphamide appears as a clear or yellowish viscous liquid usually found in connection with portions of the drug that have remained in powdered form, or as droplets that have become separated from a portion of the drug that remains in powdered form

  • Do not use cyclophosphamide that exhibits signs of melting

• Commercially marketed cyclophosphamide products may not contain an antimicrobial preservative

• Reconstitute cyclophosphamide with 0.9% NS^✫ or SWFI^†, as follows:

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  Cyclophosphamide Content per Vial	Diluent Volume	Cyclophosphamide Concentration After Reconstitution
  500 mg	25 mL	20 mg/mL
  1000 mg	50 mL
  2000 mg	100 mL
  ✫After reconstitution with 0.9% NS, cyclophosphamide is suitable for direct intravenous, intraMUSCular, intraperitoneal, or intrapleural injection †Reconstitution with SWFI yields a hypotonic product, which should not be administered by intraVENous injection, but may be administered by intraVENous infusion after further dilution with 1 of the following solutions: D5W, 0.45% NaCl, 0.9% NS, D5W/RI, D5W/0.9% NS, LRI, sodium lactate injection, USP (1/6 molar sodium lactate)

• After reconstituting cyclophosphamide with SWFI, the resulting solution is hypotonic. Reconstitution with SWFI and 0.9% NS to a concentration of 20 mg/mL yields solutions with the following osmolarity:

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  Cyclophosphamide and Diluent	Osmolarity
  100 mg cyclophosphamide in 5 mL of SWFI	74 mOsm/L
  100 mg cyclophosphamide in 5 mL of 0.9% NS	374 mOsm/L

• After adding a diluent solution, shake cyclophosphamide vials vigorously to dissolve the drug powder

  • If cyclophosphamide does not readily and completely dissolve, allow the vials to stand for a few minutes and, if necessary, resuming shaking

• Reconstitution to a concentration of 20 mg cyclophosphamide/mL yields a product that is chemically and physically stable for 24 hours at room temperature or for 6 days under refrigeration (2°–8°C [35.6°–46.4°F])

• After reconstitution with 0.9% NS or SWFI to a concentration of 20 mg cyclophosphamide per milliliter, the reconstituted solution may be further diluted

  • Product labeling identifies cyclophosphamide stability diluted with three vehicle solutions as follows:

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    	Storage Temperature
    Solution	Room Temperature	Refrigeration
    0.45% NaCl	up to 24 hours	up to 6 days
    D5W	up to 24 hours	up to 36 hours
    D5W/0.9% NS	up to 24 hours	up to 36 hours

Recommendations for Drug Administration and Ancillary Care

General:

• After reconstitution with 0.9% NS to a concentration of 20 mg cyclophosphamide/mL the drug product is suitable for administration by direct intraVENous injection, intraVENous infusion, intraMUSCular intraperitoneal, or intrapleural injection

• Solutions prepared by reconstituting cyclophosphamide with SWFI are hypotonic, and are not recommended for intraVENous injection, but may be administered by intraVENous infusion if further diluted with any of the following solutions: D5W, 0.45% NaCl, 0.9% NS, D5W/RI, D5W/0.9% NS, LRI, sodium lactate injection, USP

Cytarabine

Cytarabine injection for intravenous, intrathecal and subcutaneous use only; product label, April 2012. Manufactured by Zydus Hospira Oncology Private Ltd., Gujarat, India. Manufactured for Hospira, Inc. Lake Forest, IL

Cytarabine injection NOT FOR INTRATHECAL USE—CONTAINS BENZYL ALCOHOL FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY; product label, April 2012. Manufactured by Zydus Hospira Oncology Private Ltd., Gujarat, India. Manufactured for Hospira, Inc. Lake Forest, IL

Cytarabine injection PHARMACY BULK PACKAGE—NOT FOR DIRECT INFUSION; product label, April 2012. Manufactured by Zydus Hospira Oncology Private Ltd., Gujarat, India. Manufactured for Hospira, Inc. Lake Forest, IL

Cytarabine for injection USP, for intravenous, intrathecal, or subcutaneous use only; product label, September 2008. Manufactured by Ben Venue Laboratories, Inc., Bedford, OH. Manufactured for Bedford Laboratories, Bedford, OH

WARNING

Only physicians experienced in cancer chemotherapy should use Cytarabine Injection

For induction therapy patients should be treated in a facility with laboratory and supportive resources sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The main toxic effect of Cytarabine Injection is bone marrow suppression with leukopenia, thrombocytopenia and anemia. Less serious toxicity includes nausea, vomiting, diarrhea and abdominal pain, oral ulceration, and hepatic dysfunction

The physician must judge possible benefit to the patient against known toxic effects of this drug in considering the advisability of therapy with Cytarabine Injection. Before making this judgment or beginning treatment, the physician should be familiar with… [all other elements of product labeling]

Boxed Warning for "Cytarabine Injection For Intravenous, Intrathecal and Subcutaneous Use Only"; April 2012 product label; Hospira, Inc., Lake Forest, IL

Product Identification, Preparation, Storage, and Stability

• Cytarabine is generically available from several manufacturers. Products are available in lyophilized (powdered) or solution formulations. Presentations include products packaged for a single use or multiple doses, and for pharmaceutical admixture and compounding (eg, Pharmacy Bulk Package)

  Cautions: Among products in solution (ie, "cytarabine injection…"):

  • Cytarabine concentrations are not consistently the same among available products

  • Products may or may not contain an antimicrobial preservative

• In general, cytarabine products are stored at controlled room temperatures around 20°–25°C (68°–77°F), with temperature excursions permitted to 15°–30°C (59°–86°F)

  • Acceptable storage temperatures vary among products from different manufacturers

  • Refer to product packaging and labeling for storage conditions appropriate for different products

• Do not use bacteriostatically preserved drug and diluent products for intraTHECAL use and for preparing cytarabine for high-dose treatments (dosages ≥1000 mg/m²)

• Refer to product packaging and labeling for storage conditions appropriate for different products

• Reconstitute lyophilized cytarabine as follows

  • Diluent selection depends on route of administration (see below):

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    Cytarabine Content per Vial	Diluent Volume	Reconstituted Cytarabine Concentration
    100 mg	5 mL	20 mg/mL
    500 mg	10 mL	50 mg/mL
    1000 mg	10 mL	100 mg/mL
    2000 mg	20 mL	100 mg/mL

• Promptly use reconstituted cytarabine solutions that do not contain an antimicrobial preservative and those in which the concentration of preservatives is not adequate to inhibit microbial growth

• Solutions reconstituted with BWFI may be stored at controlled room temperature, 15°–30°C (59°–86°F), for up to 48 hours

• Discard solutions in which a slight haze develops

For intraVENous or SUBCUTaneous use:

• Reconstitute cytarabine for injection with 0.9% NS, SWFI, or BWFI preserved with benzyl alcohol

  • Do not use bacteriostatically preserved diluents when preparing cytarabine doses ≥1000 mg/m²

• The reconstituted product may be further diluted to a convenient volume in 0.9% NS or D5W

For intraTHECAL use:

• Reconstitute cytarabine only with PRESERVATIVE-FREE 0.9% NS to produce a solution with concentration ≤20 mg/mL. Typical administration volumes range from 5 to 10 mL, and should closely approximate the volume of cerebrospinal fluid removed

• Admixtures with hydrocortisone sodium succinate for intraTHECAL administration (with or without methotrexate) should be prepared just before use and administered as soon as possible (within minutes) after preparation because of the instability of the hydrocortisone component

Caution: Do not use an antimicrobially preserved diluent to prepare cytarabine for intraTHECAL use

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

• Administer by intraVENous, intraTHECAL, or SUBCUTaneous routes

  • Use products prepared for intraTHECAL administration immediately after they are prepared

• If cytarabine is given intraMUSCularly, administration sites should be rotated

• Although the amount of drug administered is a modulating factor, patients generally can tolerate higher total doses given by rapid intraVENous injection than by slow infusion because of cytarabine's rapid inactivation and the relatively brief cellular exposure to cytotoxic concentrations that occur after rapid administration

Cytarabine Liposome Injection

DepoCyt^®–cytarabine injection, lipid complex, for intrathecal use only DEPOCYT^® (cytarabine liposome injection) for intrathecal use only, 50 mg vial; product label, September 2011. Manufactured by Pacira Pharmaceuticals, Inc. San Diego, CA. Distributed by Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD

WARNINGS

DepoCyt® (cytarabine liposome injection) should be administered only under the supervision of a qualified physician experienced in the use of intrathecal cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. In all clinical studies, chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache and fever, was a common adverse event. If left untreated, chemical arachnoiditis may be fatal. The incidence and severity of chemical arachnoiditis can be reduced by coadministration of dexamethasone… Patients receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis…

Boxed Warning (excerpt) for "DepoCyt^® - cytarabine injection, lipid complex, For Intrathecal Use Only DEPOCYT^® (cytarabine liposome injection) For Intrathecal Use Only, 50 mg vial"; September 2011 product label; Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD

Product Identification, Preparation, Storage, and Stability

• DepoCyt^® is packaged in individually packaged, glass, 5-mL, single-use, vials containing a sterile, nonpyrogenic, white to off-white, ready-to-use, preservative-free suspension of cytarabine encapsulated into multivesicular lipid-based particles (liposomes). NDC 57665-331-01

  • The liposome particles are suspended in sodium chloride 0.9% (w/v) in SWFI

  • Cytarabine 50 mg is present at a concentration of 10 mg/mL. Inactive ingredients at their respective approximate concentrations, include cholesterol 4.4 mg/mL, triolein 1.2 mg/mL, dioleoylphosphatidylcholine 5.7 mg/mL, and dipalmitoylphosphatidylglycerol 1 mg/mL. The product pH is within the range 5.5–8.5

• The drug product does not contain a preservative and should be stored under refrigeration at 2°–8°C (35.6°–46.4°F). Protect DepoCyt^® from freezing

• DepoCyt® is intended for direct administration without further dilution

• Allow vials to warm to room temperature before use

• Gently agitate or repeatedly invert a vial to resuspend drug particles before transferring its contents to a syringe. Avoid aggressively agitating the drug product

  • DepoCyt^® drug particles are denser than the solution in which they are suspended, and tend to settle with time and must be resuspended before use

• Administer a dose immediately after withdrawing the product from a vial. If treatment is delayed, do not use DepoCyt^® more than 4 hours after withdrawing the product from a vial

• Any portion of vial contents not used to prepare a dose should be discarded

Selected incompatibility:

• Do not mix DepoCyt^® with other medications

Recommendations for Drug Administration and Ancillary Care

General:

• Patients should receive dexamethasone 4 mg either orally or intraVENously twice daily for 5 days, beginning on the day of DepoCyt^® injection to mitigate the symptoms of chemical arachnoiditis

• Inject DepoCyt^® 50 mg slowly, over a period of 1–5 minutes directly into the cerebrospinal fluid via an intraventricular reservoir or by direct injection into the lumbar sac

  • Do not use inline filters when administering DepoCyt^®

• Patients should be instructed to lie flat for 1 hour after DepoCyt^® administration by lumbar puncture

• Continually monitor patients for immediate adverse reactions after DepoCyt^® injection

  • If drug-related neurotoxicity develops, the dose should be reduced to 25 mg. If it persists, discontinue DepoCyt^® treatment

• Advise patients about the expected adverse events of headache, nausea, vomiting, and fever, and about the early signs and symptoms of neurotoxicity

  • Emphasize at the initiation of each treatment cycle the importance of concurrent dexamethasone use

  • Patients should be instructed to seek medical attention if signs or symptoms of neurotoxicity develop, or if oral dexamethasone is not well tolerated

Note: DepoCyt^® particles are similar in size and appearance to white blood cells: care must be taken in interpreting CSF examinations following DepoCyt^® administration

Dacarbazine

DACARBAZINE for injection, USP; product label, September 2007. Manufactured by Ben Venue Laboratories, Inc., Bedford, OH. Manufactured for Bedford Laboratories, Bedford, OH

Dacarbazine for injection, USP; product label, July 2007. Hospira Inc., Lake Forest, IL

DACARBAZINE for injection, USP; product label, January 2008. APP Pharmaceuticals LLC, Schaumburg, IL

WARNINGS

It is recommended that dacarbazine be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents

1. Hemopoietic depression is the most common toxicity with dacarbazine…

2. Hepatic necrosis has been reported…

3. Studies have demonstrated this agent to have a carcinogenic and teratogenic effect when used in animals

4. In treatment of each patient, the physician must weigh carefully the possibility of achieving therapeutic benefit against the risk of toxicity

Boxed Warning (excerpt) for "Dacarbazine for Injection, USP", labeling for products from:

 Bedford Laboratories™, Bedford, OH (dated, September 2007)

 Hospira Inc., Lake Forest, IL (dated, July 2007)

 APP Pharmaceuticals LLC, Schaumburg, IL (dated, January 2008)

Product Identification, Preparation, Storage, and Stability

• Dacarbazine is generically available from several manufacturers. In general, the drug is packaged in single-use, amber glass vials, containing either 100 mg or 200 mg dacarbazine per vial

  • Commercial formulations also include mannitol and citric acid

  • Packaging varies among manufacturers' products, including: individually packaged vials and boxes containing 10 vials

• Dacarbazine is a white to pale yellow solid that is sensitive to light

• Store intact vials under refrigeration at 2°–8°C (35.6°–46.4°F) and protect from light exposure

• Reconstitute dacarbazine with SWFI as follows:

  Table Graphic Jump Location

  | Download (.pdf) | Print

  Dacarbazine Content per Vial	Diluent (SWFI) Volume	Dacarbazine Concentration After Reconstitution
  100 mg	9.9 mL	10 mg/mL
  200 mg	19.7 mL

• The resulting clear, yellowish solution has a pH from 3.0 to 4.0, and is highly sensitive to degradation as a result of exposure to light²⁷

• The reconstituted solution is suitable for intraVENous injection, or it may be further diluted in up to 250 mL of D5W or 0.9% NS and given by intravenous infusion

• Product labeling includes the following stability information:

  • After reconstitution, dacarbazine solution (10 mg/mL) may be stored in the product vial at 4°C (39.2°F) for up to 72 hours or at normal room temperature and (fluorescent) lighting conditions for up to 8 hours²⁸

  • After dilution in D5W or 0.9% NS, the resulting product may be stored at 4°C (39.2°F) for up to 24 hours or under normal room conditions (ambient temperature and artificial lighting) for up to 8 hours²⁸

  • See comments under "Dacarbazine Degradation," below

• Change in solution color from pale yellow or ivory to pink or red is a sign of decomposition

  • Dacarbazine solutions that exhibit changes in color toward pink or red should not be used

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

• Administer dacarbazine only by intraVENous routes:

  • By intraVENous injection over 1 minute or by intraVENous infusion over 15–30 minutes

• Cover parenteral product containers containing dacarbazine solutions with light-opaque materials (bags, aluminum foil)

• Use opaque or light-resistant (light-shielded) VAD to administer dacarbazine, or cover VAD used to administer dacarbazine to protect the drug from light; eg, with opaque sleeves or by wrapping tubing with aluminum foil

Dacarbazine degradation:

• Dacarbazine degrades to active and potentially toxic products, including 2-azahypoxanthine by photolysis^27,29 and hydrolysis

  • Photodegradation products are associated with adverse effects encountered during dacarbazine administration, including local venous pain, nausea, and vomiting

    • In small case series, venous pain ± other symptoms and signs of toxicity were eliminated or reduced during administration in a room illuminated by a red photographic lamp³⁰ and when the drug in vials and VAD tubing was protected from light exposure³¹

• Dacarbazine degradation is accelerated by light exposure and storage temperature

  • Sunlight causes more rapid photolysis than fluorescent lighting³²

  • For dacarbazine exposed to sunlight during preparation or administration:

    • Cover parenteral containers with opaque material or foil during administration^32,33

    • Use light-resistant or opaque administration sets, or wrap tubing with opaque material or foil during administration^32,33

  • Prepare dacarbazine just before it is used, or store reconstituted and diluted products under refrigeration and protected from light until used^28,32

Dactinomycin

Cosmegen^® for Injection (dactinomycin for injection) (Actinomycin D); product label, February 2013. Manufactured by Baxter Oncology GmbH, Halle/Westfalen, Germany. Manufactured for Recordati Rare Diseases Inc., Lebanon, NJ

DACTINOMYCIN FOR INJECTION USP; product label, August 2012. Manufactured by Ben Venue Laboratories, Inc. Manufactured for Bedford Laboratories, Bedford, OH

WARNING

COSMEGEN^® (dactinomycin for injection) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. Due to the toxic properties of dactinomycin (eg, corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently. Dactinomycin is extremely corrosive to soft tissue. If extravasation occurs during intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms

Boxed warning for: Cosmegen^® for Injection (dactinomycin for injection) (Actinomycin D); product label, February 2013. Manufactured by Baxter Oncology GmbH, Halle/Westfalen, Germany. Manufactured for Recordati Rare Diseases Inc., Lebanon, NJ

Product Identification, Preparation, Storage, and Stability

• DACTINomycin is marketed in individually packaged, single-use vials containing DACTINomycin 500 mcg (0.5 mg) and 20 mg mannitol as a sterile, yellow to orange, lyophilized powder. NDC 67386-811-55

• Store intact vials at 20°–25°C (68°–77°F). Temperature excursions to 15°–30°C (59°–86°F) are permitted. Protect vials from light and humidity

• Reconstitute the drug product by injecting 1.1 mL of SWFI (without preservative) into a vial to produce a clear, gold-colored solution that contains approximately 500 mcg (0.5 mg) DACTINomycin per milliliter

  • Reconstituted DACTINomycin is chemically stable, but the product does not contain an antimicrobial preservative

  • Diluents preserved with benzyl alcohol or parabens may cause drug precipitation and should not be used to reconstitute DACTINomycin

• Do not filter DACTINomycin during preparation. Filtration through cellulose ester filters may remove DACTINomycin from the solution being filtered

• DACTINomycin may be added to the tubing or side arm of a rapidly flowing intraVENous infusion of D5W or 0.9% NS. Alternatively, it may be prepared as an admixture in the same solutions for administration by intraVENous infusion or isolation perfusion techniques

  • DACTINomycin may be prepared as an admixture in 0.9 NS or D5W to concentrations ≥10 mcg/mL (≥0.01 mg/mL) in glass or PVC containers for intraVENous infusion

  • DACTINomycin is reported to be most stable at pH 5–7³⁴

• Use a "2-needle technique" if DACTINomycin is to be injected percutaneously directly into a vein

  • DACTINomycin is corrosive to skin, irritating to the eyes and respiratory tract mucosa, highly toxic by the oral route, and a vesicant if extravasated

  • The "2-needle technique" prevents soft-tissue exposure to DACTINomycin that remains on the external surfaces of needles used to reconstitute the drug product

Two-needle technique for preparing DACTINomycin for percutaneous administration:

1. Use 1 sterile needle to reconstitute and withdraw from a vial a measured amount of DACTINomycin needed to deliver a patient's dose

2. Aspirate all drug solution from the needle and needle hub into the syringe, and replace the first needle with a second sterile needle

3. With a second sterile needle on the syringe, carefully express air without expelling drug from the tip of the needle and inject DACTINomycin through an injection port into the tubing of a rapidly running intravenously administered solution

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with hepatic dysfunction

• For intraVENous administration only, by direct intraVENous injection over approximately 1 minute or intraVENous infusion over 15–30 minutes

• When diluted at concentrations of ≥10 mcg/mL in SWFI, 0.9% NS, or D5W in glass or PVC containers, DACTINomycin is chemically stable for up to 10 hours when stored at ambient room temperature

  • DACTINomycin should be diluted only with 0.9% NS or D5W for intraVENous infusion

  • Caution: After initial reconstitution with SWFI, further dilution with SWFI decreases DACTINomycin osmolality, which may result in an extremely hypotonic solution. Depending on administration rate and blood flow, administration of hypotonic solutions may result in some degree of intravascular hemolysis

• The dosage for DACTINomycin is calculated in micrograms (mcg)

  • The dose intensity per 2-week cycle for adults or children should not exceed 15 mcg/kg per day or 400–600 mcg/m² per day intraVENously for 5 days

  • Dosage calculations for obese or edematous patients should be performed on the basis of body surface area to more closely relate dosage to lean body mass

• Please review the 2-needle technique for direct intraVENous injection (see above). The procedure prevents soft-tissue exposure to DACTINomycin that remains on the external surfaces of needles used during drug preparation

• Do not filter DACTINomycin during administration

  • Filtration through 0.22-μm pore size filter membranes composed of cellulose ester (cellulose nitrate/cellulose acetate) or polytetrafluoroethylene (PTFE, Teflon) were shown to remove a substantial portion of DACTINomycin from the solution being filtered^16,35

  • Filtration through a 0.22-μm pore size cellulose ester filter membranes resulted in approximately 13% of the total amount of filtered DACTINomycin bound by the filter³⁶

Caution: DACTINomycin is a vesicant and may cause severe local soft-tissue necrosis if administered by injection into soft tissues or extravasated

Daunorubicin Hydrochloride

CERUBIDINE (Daunorubicin HCl) FOR INJECTION; product label, February 2008. Manufactured by Ben Venue Laboratories, Inc., Bedford, OH. Manufactured for Bedford Laboratories, Bedford, OH

DAUNORUBICIN HYDROCHLORIDE injection; product label, June 2013. Manufactured by Ben Venue Laboratories, Inc., Bedford, OH. Manufactured for Bedford Laboratories, Bedford, OH

DAUNORUBICIN HYDROCHLORIDE–daunorubicin hydrochloride injection, solution; product label, September 2012. Manufactured by Teva Parenteral Medicines, Inc., Irvine, CA

WARNINGS

1. Daunorubicin hydrochloride injection must be given into a rapidly flowing intravenous infusion. It must never be given by the intramuscular or subcutaneous route. Severe local tissue necrosis will occur if there is extravasation during administration

2. Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure may occur either during therapy or months to years after termination of therapy. The incidence of myocardial toxicity increases after a total cumulative dose exceeding 400 to 550 mg/m² in adults, 300 mg/m² in children more than 2 years of age, or 10 mg/kg in children less than 2 years of age

3. Severe myelosuppression occurs when used in therapeutic doses; this may lead to infection or hemorrhage

4. It is recommended that daunorubicin hydrochloride be administered only by physicians who are experienced in leukemia chemotherapy and in facilities with laboratory and supportive resources adequate to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The physician and institution must be capable of responding rapidly and completely to severe hemorrhagic conditions and/or overwhelming infection

5. Dosage should be reduced in patients with impaired hepatic or renal function

Boxed Warning for "Daunorubicin Hydrochloride Injection"; September 2012 product label; Teva Parenteral Medicines, Inc., Irvine, CA; and "Daunorubicin Hydrochloride Injection"; July 1999 product label; Bedford Laboratories™, Bedford, OH

Product Identification, Preparation, Storage, and Stability

• DAUNOrubicin HCl injection (solution) and DAUNOrubicin HCl for injection (lyophilized powder) are generically available from several manufacturers. DAUNOrubicin is a sterile, deep red to red-orange product packaged in glass single-use vials

• Products are formulated either as a sterile, deep red to red-orange solution, or hygroscopic, crystalline lyophilized powder packaged in glass single-use vials

  • DAUNOrubicin HCl injection (solution) is available in vials containing 20 mg/4 mL (packaged in cartons containing 10 vials) or 50 mg (individually packaged) DAUNOrubicin base per milliliter

  • DAUNOrubicin HCl for Injection (lyophilized powder) is packaged in cartons containing 10 vials each containing 20 mg of DAUNOrubicin base

• Storage:

  • Store unreconstituted DAUNOrubicin HCl for injection (lyophilized powder) at controlled room temperature, 15°–30°C (59°–86°F)

  • Store DAUNOrubicin HCl injection (solution) under refrigeration at 2°–8°C (35.6°–46.4°F)

• Protect DAUNOrubicin from exposure to light by storing unused vials in their packaging carton

Reconstitution for lyophilized DAUNOrubicin:

• Reconstitute DAUNOrubicin HCl lyophilized powder with 4 mL of SWFI to produce a solution with concentration equal to 5 mg DAUNOrubicin base per milliliter

Stability (solution and lyophilized formulations):

• After reconstitution, DAUNOrubicin HCl (lyophilized powder formulation) is stable for 24 hours at 15°–30°C (59°–86°F) and 48 hours under refrigeration (2°–8°C [35.6°–46.4°F])

• DAUNOrubicin HCl injection (formulations already in solution) are stable for 24 hours at 15°–30°C (59°–86°F)

• DAUNOrubicin HCl diluted with D5W (pH = 4.36) or 0.9% NS (pH = 5.20 or 6.47) to a concentration of 98 μg/mL (estimated) in PVC containers stored at 25°C, 4°C or –20°C was stable for 43 days under all conditions evaluated³⁷

  • DAUNOrubicin HCl for injection reconstituted with SWFI and diluted with 0.9% NS or D5W to an estimated concentration of 98 μg/mL stored in PVC containers for 43 days did not degrade during or after 11 repeated cycles of freezing (–20°C) and thawing at ambient temperature (25°C)³⁷

• DAUNOrubicin HCl for injection reconstituted with SWFI to a concentration of 2 mg/mL was stable for at least 43 days when stored in polypropylene syringes at 4°C³⁷

• DAUNOrubicin solutions undergo photodegradation

  • The rate and extent of photodegradation are inversely related to DAUNOrubicin concentrations in solution³⁸

    • At DAUNOrubicin concentrations ≥100 μg/mL (≥0.1 mg/mL) stored at 25°C for 168 h under artificial room lighting (four 65/80-Watt fluorescent tubes mounted approximately 1 m above the samples), little or no photodegradation occurred in clear or amber glass or opaque polyethylene containers³⁸

    • At DAUNOrubicin concentrations ≥500 μg/mL (≥0.5 mg/mL), no special precautions are necessary to protect freshly prepared solutions from exposure to artificial light or sunlight³⁸

Selected incompatibility:

• Product labeling recommends not mixing DAUNOrubicin with heparin or other drugs

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

• A calculated dose is withdrawn into a syringe with 10–15 mL of 0.9% NS for intraVENous injection

• Inject DAUNOrubicin into the tubing or side-arm of a rapidly flowing intraVENous infusion of D5W or 0.9% NS

• Severe hepatic or renal impairment may enhance adverse effects associated with DAUNOrubicin

  • Clinical laboratory evaluation of hepatic and renal function should be completed before administering DAUNOrubicin. Consult recommendations for modifying DAUNOrubicin dosage and schedule in hepatic or renal impairment

Caution: DAUNOrubicin is a vesicant and can produce severe local soft-tissue necrosis if extravasation occurs. NEVER inject DAUNOrubicin by the intraMUSCular, SUBCUTaneous, or intraTHECAL routes

• The current standard of care for managing anthracycline extravasation, including extravasation of DAUNOrubicin, is a 3-day course of intraVENously administered dexrazoxane (Totect, Savene)

• Advise patients DAUNOrubicin HCl may transiently impart a red discoloration to urine after administration

Daunorubicin Citrate Liposome Injection

DaunoXome^® (daunorubicin citrate liposome injection); product label, December 2011. Manufactured for Galen US Inc, Souderton, PA

WARNINGS

1. Cardiac function should be monitored regularly in patients receiving DaunoXome (daunorubicin citrate liposome injection) because of the potential risk for cardiac toxicity and congestive heart failure. Cardiac monitoring is advised especially in those patients who have received prior anthracyclines or who have pre-existing cardiac disease or who have had prior radiotherapy encompassing the heart

2. Severe myelosuppression may occur

3. DaunoXome should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents

4. Dosage should be reduced in patients with impaired hepatic function…

5. A triad of back pain, flushing, and chest tightness has been reported in 13.8% of the patients (16/116) treated with DaunoXome in the Phase III clinical trial, and in 2.7% of treatment cycles (27/994). This triad generally occurs during the first five minutes of the infusion, subsides with interruption of the infusion, and generally does not recur if the infusion is then resumed at a slower rate

Boxed Warning (excerpt) for "DaunoXome® (daunorubicin citrate liposome injection)"; December 2011 product label; Galen US Inc, Souderton, PA

Product Identification, Preparation, Storage, and Stability

• DaunoXome^® is a translucent, red, liposomal dispersion of DAUNOrubicin citrate equivalent to 50 mg DAUNOrubicin base in 25 mL (2 mg/mL) packaged in single-use vials (NDC 10885-001-01)

• Store DaunoXome^® under refrigeration at 2°–8°C (35.6°–46.4°F). Do not freeze DaunoXome. Protect it from exposure to light

• Withdraw the calculated volume of DaunoXome^® needed for a patient's dose from a vial into a syringe, and transfer it into a sterile parenteral product container containing an equivalent volume of D5W (1:1 dilution) to produce a concentration after dilution = 1 mg DAUNOrubicin per milliliter of solution

• The product does not contain a preservative or bacteriostatic agent. Partially used vials should be discarded as hazardous waste

• If diluted DaunoXome^® is not used immediately, it should be refrigerated at 2°–8°C (35.6°–46.4°F) for a maximum of 6 hours

Caution: The only fluid with which DaunoXome^® may be mixed is D5W

Selected incompatibility:

• Do not mix DaunoXome^® with any solution other than D5W

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

• Administer DaunoXome® intraVENously over 60 minutes immediately after dilution

• Do not filter DaunoXome^® during administration

• Do not mix DaunoXome^® with other drugs

Decitabine

DACOGEN^® (decitabine) for INJECTION; product label, March 2010. Manufactured by Pharmachemie B.V. Haarlem, The Netherlands. Manufactured for Eisai Inc., Woodcliff Lake, NJ

Product Identification, Preparation, Storage, and Stability

• Decitabine is a sterile, lyophilized, white to almost-white powder, individually packaged in clear, colorless, single-use, 20-mL, glass vials containing 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate), and 11.6 mg sodium hydroxide. NDC 62856-600-01

• Store intact vials at 25°C (77°F); temperature excursions are permitted to 15°–30°C (59°–86°F)

• Caution: BEFORE BEGINNING reconstitution, evaluate whether decitabine administration will begin within 15 minutes after the lyophilized product is reconstituted

  • Decitabine hydrolyzes spontaneously after reconstitution

  • If drug administration commences within 15 minutes after reconstitution began, there is no need to used prechilled diluents, but preparation should not commence until just before the drug is needed

  • If drug administration begins >15 minutes to within 7 hours after reconstitution, use prechilled solutions (2°–8°C [35.6°–46.4°F]) to reconstitute and dilute decitabine

• Reconstitution with 10 mL of SWFI produces a solution with concentration of 5 mg decitabine/mL at pH 6.7–7.3

• After powdered decitabine is completely dissolved, immediately withdraw with a syringe the calculated volume of drug needed for a patient's dose from a vial and transfer it into a sterile plastic or glass parenteral product container containing a volume of 0.9% NS, D5W, or LRI sufficient to produce a decitabine concentration between 0.1–1.0 mg/mL

  • If decitabine cannot be used within 15 minutes after diluent was introduced into a vial, the product should be promptly refrigerated and may be stored for up to 7 hours after reconstitution

  • Reconstituted and diluted products that have not been used within the time limits identified above and all materials potentially contaminated with decitabine during product preparation should be discarded as hazardous waste

• If a decitabine-containing solution was prepared and refrigerated as described (above) and used within 7 hours after reconstitution, administration should be completed within 3 hours after the product was transferred from refrigeration to room temperature conditions

Recommendations for Drug Administration and Ancillary Care

General:

• See Chapter 41 for recommended use in patients with renal and hepatic dysfunction

• If decitabine is not prepared with chilled solutions and promptly refrigerated after preparation, administration MUST BEGIN within 15 minutes after reconstitution

• If decitabine was prepared with chilled solutions and stored under refrigeration promptly after preparation, administration MAY BEGIN up to 7 hours after reconstitution

  • Drug administration should begin promptly after stored products are transferred from refrigeration to room temperature conditions

• Administer decitabine by intraVENous infusion over 3 hours

Denileukin Diftitox

ONTAK^® (denileukin diftitox) Injection for intravenous infusion; product label August 2011. Manufactured and Distributed by Eisai Inc., Woodcliff Lake, NJ

WARNING

SERIOUS INFUSION REACTIONS, CAPILLARY LEAK SYNDROME AND LOSS OF VISUAL ACUITY

The following adverse reactions have been reported:

• Serious and fatal infusion reactions. Administer Ontak in a facility equipped and staffed for cardiopulmonary resuscitation. Immediately stop and permanently discontinue Ontak for serious infusion reactions…

• Capillary leak syndrome resulting in death. Monitor weight, edema, blood pressure and serum albumin levels prior to and during Ontak treatment…

• Loss of visual acuity and color vision…

Boxed Warning (excerpt) for "ONTAK^® (denileukin diftitox) Injection for intravenous infusion"; August 2011 product label, Eisai Inc., Woodcliff Lake, NJ

Product Identification, Preparation, Storage, and Stability

• ONTAK^® is supplied in single-use vials as a sterile, frozen solution intended for intraVENous administration (6 vials/package; NDC 62856-603-01)

• Each vial contains 300 mcg of recombinant denileukin diftitox in 2 mL (150 mcg/mL) in a sterile solution of citric acid 20 mmol/L, EDTA 0.05 mmol/L, and polysorbate 20 (<1%) in SWFI. The solution has a pH range of 6.9–7.2

• Store ONTAK^® at ≤ −10°C (≤14°F)

• Thaw vials either:

  1. Under refrigeration at 2°–8°C (35.6°–46.4°F) for not more than 24 hours, or

  2. At room temperature for 1–2 hours

     • Do not heat ONTAK^® to thaw the product

     • Do not refreeze ONTAK^® after thawing

• Allow ONTAK^® to equilibrate with room temperature (up to 25°C [77°F]) before preparing a dose

• Mix ONTAK^® solution in a vial by gentle swirling. Do not shake ONTAK^® solution

  • After thawing, a haze may be visible. The haze should clear when the solution is at room temperature. Do not use the solution unless it is clear, colorless, and without visible particulate matter

• Prepare and contain diluted denileukin diftitox in plastic syringes or soft plastic parenteral product containers

  1. Do not use glass containers because an unpredictable portion of the drug may be lost because of adsorption to glass surfaces

  2. With a syringe, withdraw from 1 or more vials the amount of denileukin diftitox needed to prepare a patient's dose and inject it into an empty plastic parenteral product container (bag or syringe)

     • Denileukin diftitox concentration must be ≥15 mcg/mL during all preparation steps

  3. Add to the product container no more than 9 mL of preservative-free 0.9% NS for each 1 mL of denileukin diftitox in the container

• Do not mix denileukin diftitox with other drugs

• Partially used vials should be discarded immediately

Selected incompatibility:

• Product labeling recommends not mixing denileukin diftitox with other drugs

Recommendations for Drug Administration and Ancillary Care

Premedication:

• Premedicate with acetaminophen and an antihistamine (H₁-receptor antagonist) before each denileukin diftitox infusion

General:

• Withhold denileukin diftitox administration in a patient whose serum albumin is <3 g/dL

• Administer denileukin diftitox intraVENously over 30–60 minutes within 6 hours after preparation was completed

  • There is no clinical experience with prolonged infusion times (>80 minutes)

  • Do not administer denileukin diftitox by rapid or "bolus" intraVENous injection

• If infusion-related adverse events occur, denileukin diftitox administration should be discontinued, or the delivery rate should be decreased depending on the severity of the reaction

  • Immediately stop and permanently discontinue denileukin diftitox administration for serious infusion reactions

  • Resuscitative equipment should be available during denileukin diftitox administration

• Do not mix denileukin diftitox with other drugs

• Do not filter denileukin diftitox during administration

Dexrazoxane

Utilized as a Cardioprotectant

Zinecard^® (dexrazoxane for injection); product label, June 2012. Distributed by Pharmacia & Upjohn Company, Division of Pfizer Inc., New York, NY

Dexrazoxane for injection; product label, June 2005. Manufactured by Ben Venue Laboratories, Inc., Bedford, OH. Manufactured for Bedford Laboratories, Bedford, OH

DEXRAZOXANE HYDROCHLORIDE; product label, September 2012. Manufactured by Gland Pharma Limited, Hyderabad-500 043, India. Manufactured for Mylan Institutional LLC, Rockford, IL

Product Identification, Preparation, Storage, and Stability

Recommendations for Dexrazoxane Utilization as a Cardioprotectant

General:

• See Chapter 41 for recommended use in patients with hepatic dysfunction

Administration:

• DOXOrubicin administration must be completed within 30 minutes after dexrazoxane administration began

• Recommended dosage ratios of dexrazoxane to DOXOrubicin:

  • Patients with creatinine clearance ≥40 mL/min (≥0.66 mL/s), dexrazoxane to DOXOrubicin ratio is 10 : 1; eg, 500 mg dexrazoxane/m²: 50 mg DOXOrubicin/m²

  • Patients with creatinine clearance <40 mL/min (<0.66 mL/s), dexrazoxane to DOXOrubicin ratio is 5 : 1; eg, 250 mg dexrazoxane/m²: 50 mg DOXOrubicin/m²

Dexrazoxane

Utilized in Treating Anthracycline Extravasation

TOTECT^® Kit (dexrazoxane) for injection, for intravenous infusion only; product label, May 2011. Manufactured by Ben Venue Laboratories, Inc., Bedford, OH, and Hameln Pharmaceuticals GmbH, Hameln, Germany. Manufactured for Topotarget A/S, Copenhagen, Denmark. Distributed by Integrated Commercialization Solutions, Brooks, KY. Marketed by Topotarget USA Inc., Rockaway, NJ

Savene 20 mg/mL powder for concentrate and diluent for solution for infusion. Summary of Product Characteristics, August 16, 2011. Last accessed: April 7, 2012, at: http://www.ema.europa.eu. Marketing authorization holder is SpePharm Holding B.V., Amsterdam, The Netherlands

Notes: On April 2, 2013, BIOCODEX USA (San Bruno, CA) announced acquisition of Totect^® (at http://www.totect.com/ [accessed January 7, 2014]), and Totect^® currently is not available

Norgine BV (Amsterdam, The Netherlands) has acquired the distribution rights of the product portfolio of SpePharm Holding, including Savene^® (at: http://www.spepharm.com/ [accessed January 7, 2014])

Product Identification, Preparation, Storage, and Stability

• TOTECT^® is packaged as a kit (NDC 38423-110-01) containing twenty 50-mL Type I glass vials, including:

  • 10 single-use vials, each containing 589 mg dexrazoxane hydrochloride (equivalent to 500 mg dexrazoxane) as a lyophilized powder, plus

  • 10 Vials each containing 50 mL of sodium lactate injection, USP, 0.167 mol/L (0.167 M, 1/6 M, M/6) diluent for reconstituting dexrazoxane hydrochloride

• Store the unreconstituted product in its carton to protect it from light at 25°C (77°F). Temperature excursions are permitted to 15°–30°C (59°–86°F)

• Add 50 mL of 0.167 M sodium lactate injection, USP, to each vial of lyophilized dexrazoxane to produce a slightly yellow solution with dexrazoxane concentration of 10 mg/mL

  • The manufacturer recommends using reconstituted dexrazoxane solution within 2 hours after reconstitution

• Dilute the reconstituted product by injecting a volume of dexrazoxane appropriate for a patient's dose into 1000 mL of 0.9% NS

• After dilution, TOTECT^® is stable for 4 hours when stored at temperatures <25°C (<77°F)

• Discard any unused portion of dexrazoxane solutions

Selected incompatibility:

• Product labeling recommends not mixing or administering dexrazoxane with any other drugs

Recommendations for Drug Administration and Ancillary Care for Dexrazoxane

Utilized as an Antidote for Anthracycline^✫ Extravasations

General:

• Dexrazoxane dosage should be decreased by 50% in persons whose creatinine clearance is <40 mL/min (<0.66 mL/s)

• Dimethylsulfoxide (DMSO) should not be applied topically to treat anthracycline extravasations in patients who are receiving dexrazoxane

  • Anecdotal clinical reports and experimental evidence in mice indicate concomitant use of topical DMSO at the site of anthracycline extravasation decreases the efficacy of systemically administered dexrazoxane

• Dexrazoxane is a cytotoxic drug and may produce myelosuppression additive to what is expected from antineoplastic treatments

• Reversible increases in liver enzymes (serum AST, ALT, bilirubin) may follow dexrazoxane use

Dosage and administration:

• Cooling packs (if used) should be removed from an extravasation site at least 15 minutes before dexrazoxane administration to improve blood flow to the affected site

  • Vasoconstriction caused by local hypothermia may compromise dexrazoxane distribution to the affected area

• Dexrazoxane administration must begin within 6 hours after an extravasation event to be optimally effective

• Administer dexrazoxane via a large-caliber vein:

  Day 1  Dexrazoxane 1000 mg/m² (maximum recommended single dose = 2000 mg) in 1000 mL of 0.9% NS intraVENously over 1–2 hours, via an administration site not affected by the extravasation

  Day 2^† Dexrazoxane 1000 mg/m² (maximum recommended single dose = 2000 mg) in 1000 mL of 0.9% NS intraVENously over 1–2 hours via an administration site not affected by the extravasation

  Day 3^†  Dexrazoxane 500 mg/m² (maximum recommended single dose = 1000 mg) in 1000 mL of 0.9% NS intraVENously over 1–2 hours via an administration site not affected by the extravasation (total dosage/3-day course = 2500 mg/m²; maximum recommended dose/3-day course = 5000 mg)

Docetaxel

[One- vial formulation] TAXOTERE^® (docetaxel) injection concentrate, intravenous infusion (IV); product label January 2013. sanofi-aventis U.S. LLC, Bridgewater, NJ

[Two-vial formulation] TAXOTERE^® (docetaxel) injection concentrate, intravenous infusion (IV); product label January 2013. sanofi-aventis U.S. LLC, Bridgewater, NJ

Docetaxel injection, USP, for intravenous infusion only, product label May 2013. Manufactured by Zydus Hospira Oncology Private Ltd., Gujarat, India. Distributed by Hospira, Inc., Lake Forest, IL

Docetaxel injection for intravenous infusion only; product label June 2011. Manufactured for Sandoz, Princeton, NJ. Manufactured by EBEWE Pharma Ges.m.b.H. Nfg.KG, A-4866 Unterach, Austria

DOCEFREZ^™ (docetaxel) for injection, intravenous infusion; product label, May 2011. Manufactured by Sun Pharmaceutical Ind. Ltd., Halol-389 350, Gujarat, India. Distributed by Caraco Pharmaceutical Laboratories, Ltd., Detroit, MI

Product-Specific Identification, Storage, and Stability

General Guidance

• Do not use plasticized PVC equipment or devices that will come into contact with DOCEtaxel solutions during drug preparation or administration

  • Phthalate plasticizers (including DEHP; di-2-ethylhexyl phthalate) may be leached from PVC containers and administration sets

• Glass, polypropylene, and polyolefin devices and equipment, and containers and tubing with surfaces in contact with drug products composed of those materials are appropriate for use in manipulating, containing, and administering DOCEtaxel solutions and minimize patient exposure to phthalate plasticizers¹⁹

Product-Specific Preparation and Stability

Preparing the Following Products for Clinical Use:

Docetaxel Injection For Intravenous Infusion Only (Hospira, Inc.),

Docetaxel Injection For Intravenous Infusion Only (Sandoz, Inc.), and

One-vial formulation of TAXOTERE^® (sanofi-aventis U.S. LLC)

• Do not use the one-vial formulation of TAXOTERE^® with the two-vial formulation of TAXOTERE^® (Injection Concentrate and diluent)

• After removing TAXOTERE^® (one-vial formulation) from refrigeration, allow the vials to stand at room temperature for approximately 5 minutes before proceeding

Dilute the concentrated drug product:

1. Use only a 21-gauge needle to withdraw the drug product from a vial

   • Larger bore needles (eg, 18- and 19-gauge) may result in stopper coring and introduce particulate matter into the drug product

2. With a calibrated syringe, aseptically withdraw the an amount of concentrated DOCEtaxel solution required for a patient's dose and transfer it into an appropriate parenteral product bag or bottle containing a volume of either 0.9% NS or D5W sufficient to produce a final DOCEtaxel concentration within the range 0.3–0.74 mg/mL

   • CAUTION: Product concentrations vary among commercial DOCEtaxel injection products:

     • The generic products from Hospira, Inc. and Sandoz, Inc. contain DOCEtaxel at a concentration of 10 mg/mL

     • The concentration for the single-vial formulation of Taxotere^® (sanofi-aventis U.S. LLC) is 2 times greater, that is 20 mg/mL

   • Product concentrations must not exceed 0.74 mg DOCEtaxel per milliliter

3. Thoroughly mix the admixture by manual rotation and by gently inverting the product container

4. When prepared as described with the one-vial formulation of TAXOTERE^® and stored between 2°–25°C (35.6°–77°F), DOCEtaxel solutions are stable for 6 hours

   • Physical and chemical in-use stability of TAXOTERE^® (one-vial formulation) when prepared as recommended in non-PVC containers and stored at 2°–8°C has been demonstrated for up to 48 hours

     Caution: Product labeling for the one-vial formulation of TAXOTERE® (only) includes a warning about product stability after dilution:

     • TAXOTERE^® infusion solution produced with the one-vial formulation (a solution diluted for administration to patients) is supersaturated; therefore, over time, crystals may appear in solution

     • Solutions in which crystals or particulate matter appear should not be used but should be discarded

     • A similar warning does not appear in product labeling for other DOCEtaxel products identified in this section

Preparing the 2-vial formulation of TAXOTERE^® (sanofi-aventis U.S. LLC)

• Do not use the 2-vial formulation (injection concentrate and diluent) with the 1-vial formulation

Prepare an initial dilution:

1. After removing TAXOTERE^® and diluent vials from refrigeration, allow them to stand at room temperature for approximately 5 minutes before proceeding

2. Use only a 21-gauge needle to withdraw the drug product from a vial because larger-bore needles (eg, 18- and 19-gauge) may result in stopper coring and introduce particulate matter into the drug product

3. Aseptically withdraw the entire contents of an appropriate diluent vial (approximately 1.8 mL for Taxotere 20 mg and approximately 7.1 mL for Taxotere 80 mg) into a syringe by partially inverting the vial, and transfer the solution to the vial of TAXOTERE^® concentrate with which it was co-packaged to produce an initially diluted solution containing 10 mg DOCEtaxel/mL

   • CAUTION: Product concentrations vary among commercial docetaxel injection products:

     • After initial dilution, the concentration of the 2-vial formulation of TAXOTERE^® (sanofi-aventis U.S. LLC) is 10 mg/mL

     • In contrast, the concentration for the single-vial formulation of TAXOTERE^® is 2 times greater, that is, 20 mg/mL

4. Do not shake the vials. Mix the initially diluted solution by repeatedly inverting for at least 45 seconds the Taxotere concentrate vials into which the ethanol-in-water diluent was injected

5. The initially diluted TAXOTERE^® solution should be clear; however, there may be some foam on top of the solution caused by polysorbate 80. If foam is present, allow the vials to stand for a few minutes to allow any foam to dissipate. It is not necessary to wait for all foam to dissipate before continuing preparation

   • The initially diluted solution may be used immediately or stored under refrigeration or at room temperature for a maximum of 8 hours