Bortecade

Bortecade (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.
Bortecade (bortezomib) for injection is an antineoplastic agent available for intravenous injection (IV) use only.
Each single dose vial contains 3.5 mg of bortezomib as a sterile lyophilized powder.
Excipients/Inactive Ingredients: 35 mg mannitol EP.

Pharmacology: Pharmacodynamics: Mechanism of Action: Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis which can affect multiple signaling cascades within cell. This disruption of normal homeostatic mechanism can lead to cell death.
Pharmacokinetics: Hepatic Impairment: No pharmacokinetic studies were conducted with bortezomib in patients with hepatic impairment (see Precautions).
Renal Impairment: No pharmacokinetic studies were conducted with bortezomib in patients with renal impairment. Clinical studies included patients with creatinine clearance values ranging from 13.8 to 220 mL/min (see Precautions).
Pediatric: There are no pharmacokinetic data in pediatric patients.
Drug Interactions: No formal drug interaction studies have been conducted with bortezomib.
Bortezomib is a substrate of cytochrome P450 3A4, 2C19, and 1A2 (see Precautions). Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC50 values of >30 μM (>11.5 μg/mL). Bortezomib may inhibit 2C19 activity (ICSD=18 μM, 6.9 μg/mL) and increase exposure to drugs that are substrates for this enzyme. Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes. Patients who are concomitantly receiving Bortecade and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

Bortecade (bortezomib) for Injection is indicated for the treatment of multiple myeloma patients who have received at least 1 prior therapy and have demonstrated disease progression on the last therapy. Bortecade (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

Recommended Dosage: The recommended dose of Bortecade is 1.3 mg/m²/dose administered as a 3 to 5 second bolus intravenous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21). This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortecade. It is recommended that patients with a confirmed complete response receive 2 additional cycles of Bortecade beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of Bortecade therapy.
Dose Modification and Reinitiation of Therapy: Bortecade therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed as follows (see Precautions).
Once the symptoms of the toxicity have resolved, Bortecade therapy may be reinitiated at a 25% reduced dose (1.3 mg/m²/dose reduced to 1.0 mg/m²/dose; 1.0 mg/m²/dose reduced to 0.7 mg/m²/dose). The following table contains the recommended dose modification for the management of patients who experience Bortecade-related neuropathic pain and/or peripheral sensory neuropathy (Table 1). Patients with pre-existing severe neuropathy should be treated with Bortecade only after careful risk/benefit assessment. (See Table 1.)


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Administration: Bortecade is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with 0.9% sodium chloride solution for injection. The safety and effectiveness of Bortezomib in children has not been established.

Overdosage more than twice the recommended dose in patients has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. There is no known specific antidote for Bortezomib overdosage. In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature, (see Precautions and Dosage & Administration).

Bortezomib is contraindicated in patients with hypersensitivity to bortezomib, boron or mannitol.

Bortezomib should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
Peripheral Neuropathy: Bortezomib treatment causes peripheral neuropathy that is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with Bortezomib, Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a change in the dose and schedule of Bortezomib (see Dosage & Administration).
Hypotension: Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, or administration of mineralocorticoids and/or sympathomimetics (see Adverse Reactions).
Cardiac Disorders: Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with few or no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart diseases should be closely monitored.
Hepatic Events: Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of Bortezomib. There is limited re-challenge information in these patients.
Pulmonary Disorders: There have been rare 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 Bortezomib. Some of these events have been fatal. A higher proportion of these events have been reported in Japan. In the event of new or worsening pulmonary symptoms, a prompt diagnostic evaluation should be performed and patients treated appropriately.
Laboratory Tests: Complete blood counts (CBC) should be frequently monitored throughout treatment with Bortezomib.
Thrombocytopenia: Bortezomib is associated with thrombocytopenia (see Adverse Reactions). Platelets were lowest at Day 11 of each cycle of Bortezomib treatment and typically recovered to baseline by the next cycle. The cyclical pattern of platelet count decrease and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia. Platelet counts should be monitored prior to each dose of Bortezomib. Bortezomib therapy should be held when the platelet count is <25,000/uL and reinitiated at reduced dose, (see Dosage & Administration and Adverse Reactions). There have been reports of gastrointestinal and intracerebral hemorrhage in association with Bortezomib. Transfusion may be considered.
Gastrointestinal Adverse Events: Bortezomib treatment can cause nausea, diarrhea, constipation, and vomiting (see Adverse Reactions) sometimes requiring use of anti-emetics and antidiarrheal medications. Fluid and electrolyte replacement should be administered to prevent dehydration. Since patients receiving Bortezomib therapy may experience vomiting and/or diarrhea, patients should be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, lightheadedness or fainting spells.
Tumor Lysis Syndrome: Because Bortezomib is a cytotoxic agent and can rapidly kill malignant cells the complications of tumor lysis syndrome may occur. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Patients with Hepatic Impairment: Bortezomib is metabolized by liver enzymes and bortezomib's clearance may decrease in patients with hepatic impairment. These patients should be closely monitored for toxicities when treated with Bortezomib.
Patients with Renal Impairment: No clinical information is available on the use of Bortezomib in patients with creatinine clearance values less than 13 mL/min and patients on hemodialysis. These patients should be closely monitored for toxicities when treated with Bortezomib.
Effects on Ability to Drive and Use Machines: Bortezomib may cause tiredness, dizziness, fainting, or blurred vision. Patients should be advised not to drive or operate machinery if they experience these symptoms.

Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib. No placental transfer studies have been conducted with bortezomib. There are no adequate and well-controlled studies in pregnant women. If 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. Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breastfeeding during treatment with Bortezomib.
Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Bortezomib, women should be advised against breastfeeding while being treated with Bortezomib.

(See Table 2.)


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Patients with mantle cell lymphoma: The safety profile of Bortezomib in these patients with mantle cell lymphoma was similar to that observed in patients with multiple myeloma. Notable differences between the two patient populations were that thrombocytopenia, neutropenia, anemia, nausea, vomiting and pyrexia were reported more often in the patients with multiple myeloma than in those with mantle cell lymphoma; whereas peripheral neuropathy, rash and pruritus were higher among patients with mantle cell lymphoma compared to patients with multiple myeloma.

Bortezomib is a substrate for cytochrome P450 3A4, 2C19, and 1A2. Patients who are concomitantly receiving Bortezomib and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy (see Pharmacology: Pharmacokinetics under Actions).
Patients on oral antidiabetic agents receiving Bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Patients should be cautioned about the use of concomitant medications that may be associated with peripheral neuropathy (such as amiodarone, anti-virals, isoniazid, nitrofurantoin, or statins), or with a decrease in blood pressure.
Drug Laboratory Test Interaction: None known.

Instructions for use, handling; and disposal: Administration Precautions: Bortecade is an antineoplastic. Caution should be used during handling and preparation. Proper aseptic technique should be used. Use of gloves and other protective clothing to prevent skin contact is recommended. Extravasation of Bortecade was not associated with tissue damage.
Reconstitution/Preparation for Intravenous Administration: Prior to use, the contents of each vial must be reconstituted with 3.5 ml of normal (0.9%) saline, sodium chloride injection. 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.
Procedure for Proper Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.

Bortecade contains no antimicrobial preservative. When reconstituted as directed, Bortecade may be stored at 25°C. Reconstituted Bortecade should be administered within 8 hours of preparation. The reconstituted material may be stored for up to 8 hours in the original vial or in a syringe. The total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.
Unopened vials may be stored at controlled room temperature 25°C; excursions permitted from 15 to 30°C. Retain in original package to protect from light.
Shelf life: 36 months.
Unopened vials of Bortecade are stable until the date indicated on the package when stored in the original package protected from light.

Targeted Cancer Therapy

L01XG01 - bortezomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.

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