Velcade Information
Velcade (Bortezomib) Dosage And Administration
Prior to initiating any cycle of therapy with Velcade (Bortezomib) in combination with melphalan and prednisone:
For dose modifications guidelines for peripheral neuropathy see .
Velcade (Bortezomib) therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below []. Once the symptoms of the toxicity have resolved, Velcade (Bortezomib) therapy may be reinitiated at a 25% reduced dose (1.3 mg/m/dose reduced to 1 mg/m/dose; 1 mg/m/dose reduced to 0.7 mg/m/dose).
For dose modifications guidelines for peripheral neuropathy see.
The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose.
Velcade (Bortezomib) is an antineoplastic. Procedures for proper handling and disposal should be considered. []
In clinical trials, local skin irritation was reported in 5% of patients, but extravasation of Velcade (Bortezomib) was not associated with tissue damage.
Proper aseptic technique should be used. Reconstitute with 3.5 mL of 0.9% Sodium Chloride resulting in a final concentration of 1 mg/mL of bortezomib. The reconstituted product should be a clear and colorless solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.
Stability
Velcade (Bortezomib) contains no antimicrobial preservative. Reconstituted Velcade (Bortezomib) should be administered within 8 hours of preparation. When reconstituted as directed, Velcade (Bortezomib) may be stored at 25°C (77°F). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.
Velcade (Bortezomib) Dosage Forms And Strengths
Each single-use vial of Velcade (Bortezomib) contains 3.5 mg of bortezomib as a sterile lyophilized powder.
Velcade (Bortezomib) Contraindications
Velcade (Bortezomib) is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
Velcade (Bortezomib) Warnings And Precautions
Velcade (Bortezomib) should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with Velcade (Bortezomib) .
There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving Velcade (Bortezomib) . Some of these events have been fatal.
In a clinical trial, the first two patients given high-dose cytarabine (2g/m per day) by continuous infusion with daunorubicin and Velcade (Bortezomib) for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
There have been reports of pulmonary hypertension associated with Velcade (Bortezomib) administration in the absence of left heart failure or significant pulmonary disease.
In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.
Velcade (Bortezomib) Adverse Reactions
The following adverse reactions are also discussed in other sections of the labeling:
Velcade (Bortezomib) Drug Interactions
Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2.
7.1 CYP3A4 inhibitors:
7.2 CYP2C19 inhibitors:
7.3 CYP3A4 inducers:
Efficacy may be reduced when Velcade (Bortezomib) is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving Velcade (Bortezomib) .
St. John's Wort () may decrease bortezomib exposure unpredictably and should be avoided.
7.4 Dexamethasone:
7.5 Melphalan-Prednisone:
Velcade (Bortezomib) Use In Specific Populations
Pregnancy Category D []
Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (0.075 mg/kg; 0.5 mg/m in the rat and 0.05 mg/kg; 0.6 mg/m in the rabbit) when administered during organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m based on body surface area.
Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05mg/kg (0.6 mg/m) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. The dose is approximately 0.5 times the clinical dose of 1.3 mg/m based on body surface area.
There are no adequate and well-controlled studies in pregnant women. If Velcade (Bortezomib) is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the Velcade (Bortezomib) arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥ 65 were longer on Velcade (Bortezomib) compared to dexamethasone [5.5 mo versus 4.3 mo, and 8.0 mo versus 4.9 mo, respectively]. On the Velcade (Bortezomib) arm, 40% (n=46) of evaluable patients aged ≥ 65 experienced response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and 4 events was 64%, 78% and 75% for Velcade (Bortezomib) patients ≤ 50, 51-64 and ≥ 65 years old, respectively. []
No overall differences in safety or effectiveness were observed between patients ≥ age 65 and younger patients receiving Velcade (Bortezomib) ; but greater sensitivity of some older individuals cannot be ruled out.
Velcade (Bortezomib) Overdosage
There is no known specific antidote for Velcade (Bortezomib) overdosage []. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension and thrombocytopenia. In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given.
Studies in monkeys and dogs showed that IV bortezomib doses as low as 2 times the recommended clinical dose on a mg/m basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at 1 hour post-administration, with progression to death in 12 to 14 hours following drug administration.
Velcade (Bortezomib) Description
Velcade (Bortezomib) for Injection is an antineoplastic agent available for intravenous injection (IV) use only. Each single use vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. Inactive ingredient: 35 mg mannitol, USP.
Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a mannitol boronic ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine.
The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid.
Bortezomib has the following chemical structure:
The molecular weight is 384.24. The molecular formula is CHBNOThe solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5.
Velcade (Bortezomib) Nonclinical Toxicology
Carcinogenicity studies have not been conducted with bortezomib.
Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.
Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses ≥ 0.3 mg/m (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m. Velcade (Bortezomib) could have a potential effect on either male or female fertility.
Cardiovascular Toxicity
2
Chronic Administration:
Velcade (Bortezomib) How Supplied/storage And Handling
Velcade (Bortezomib) for Injection is supplied as individually cartoned 10 mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder.
Velcade (Bortezomib) Patient Counseling Information
Physicians are advised to discuss the following with patients prior to treatment with Velcade (Bortezomib) :
Velcade (Bortezomib)
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