Natco Bortezomib Bortenat 2mg

[Drug Name] Velcade (Bortezomib for Injection)

[Indications] 1. This product is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies and whose disease has progressed during their last therapy. 2. This product is indicated for the treatment of patients with relapsed or refractory mantle cell lymphoma who have received at least one prior therapy. Safety and efficacy data for this indication are derived from a single-arm Phase II clinical study conducted abroad in patients with mantle cell lymphoma that relapsed following prior therapy; clinical studies specifically targeting the Chinese population are currently lacking.

[Dosage and Administration] 1. Recommended Dose for Adult Monotherapy: The recommended dose of this product is a single injection of 1.3 mg/m², administered twice weekly for 2 consecutive weeks (i.e., on Days 1, 4, 8, and 11), followed by a 10-day rest period (i.e., from Day 12 to Day 21). A 3-week period constitutes one treatment cycle; there must be an interval of at least 72 hours between consecutive doses. For maintenance therapy extending beyond 8 cycles, the drug may be administered according to the standard regimen, or alternatively, according to a maintenance regimen of once-weekly administration for 4 consecutive weeks (on Days 1, 8, 15, and 22), followed by a 12-day rest period (from Day 22 to Day 25). 2. Dose Adjustment and Re-initiation of Therapy: In the event of Grade 3 non-hematologic toxicity or any Grade 4 hematologic toxicity (excluding neuropathy, which is discussed below), treatment with this product should be withheld. Once the toxic symptoms have resolved, treatment with this product may be resumed at a reduced dose (e.g., 1.3 mg/m² reduced to 1.0 mg/m²; 1.0 mg/m² reduced to 0.7 mg/m²). 3. If a patient develops neuralgia or peripheral sensory neuropathy associated with treatment with this product, treatment should be managed by adjusting the dose as recommended by the physician. If a patient has pre-existing severe neuropathy, this product should be administered only after a careful assessment of the risks and benefits. [NCI Common Toxicity Criteria] Administration Method: This product must be completely dissolved in 3.5 mL of normal saline and then administered via central venous catheter or peripheral intravenous injection over a period of 3 to 5 seconds, followed by a flush with 0.9% Sodium Chloride Injection.

[Composition] Active Ingredient: Bortezomib. Chemical Name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl)amino]propyl]amino]butyl]boronic acid.

[Description] This product is a white or off-white cake or powder.

[Adverse Reactions] The efficacy and safety of this product at the recommended dose of 1.2 mg/m² were evaluated in three clinical studies: 1. A randomized, dexamethasone-controlled Phase III trial (M34101-029), treating 669 patients with relapsed or refractory multiple myeloma following 1 to 3 lines of therapy; 2. A single-arm, open-label, multicenter Phase II trial, treating 202 patients who had received 2 lines of therapy and recently experienced disease progression (M24100-025); 3. A Phase II clinical trial evaluating the dose-response of this product, treating patients with relapsed multiple myeloma who had experienced disease progression or relapse, or who had previously received this product at a dose of 1.0 mg/m² or 1.3 mg/m² as first-line therapy (M34100-024).

[Contraindications] This product is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

[Precautions] 1. This product should be administered under the supervision of a physician experienced in the use of antineoplastic agents, and complete blood cell counts (CBC) should be monitored frequently during treatment. As this product is an antineoplastic agent, caution should be exercised during its preparation; gloves should be worn during handling to prevent skin contact. Overall, the safety profile of this product as monotherapy is similar to that observed with the combination regimen of melphalan and prednisone. 2. Peripheral Neuropathy. Treatment with this product may result in peripheral neuropathy, predominantly sensory in nature, although rare cases of sensorimotor neuropathy have also been reported. In patients with pre-existing symptoms (such as numbness, pain, or a burning sensation in the feet or hands) or signs of peripheral neuropathy, symptoms of neuropathy (including Grade ≥2) may worsen during treatment with this product. It is recommended to monitor such patients for symptoms of neuropathy, such as burning sensations, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. If patients develop new peripheral neuropathy or experience an exacerbation of symptoms, the dosage and treatment regimen for this product should be adjusted. In a Phase III trial involving single-agent therapy, following dose adjustments, 51% of patients with Grade ≥2 peripheral neuropathy reported improvement or resolution of their neuropathy. In a Phase II trial for multiple myeloma, 73% of patients who discontinued treatment due to Grade 2 neuropathy, or who experienced Grade ≥3 neuropathy, reported improvement or resolution of their neuropathy. The long-term outcomes of peripheral neuropathy have not been studied in patients with mantle cell lymphoma. 3. Hypotension. In Phase II and Phase III trials involving single-agent therapy for multiple myeloma, the incidence of hypotension (orthostatic or postural, as well as unspecified hypotension) ranged from 11% to 12%. This phenomenon was observed throughout the entire course of treatment. Caution is advised when administering this product to patients with a history of syncope, those taking medications known to cause hypotension, or those who are dehydrated. Orthostatic or postural hypotension may be managed by adjusting antihypertensive medications, providing fluid repletion, or administering mineralocorticoids and/or sympathomimetic agents. 4. Cardiac Disorders. Reports have been received regarding the occurrence or exacerbation of acute congestive heart failure, and/or a reduction in left ventricular ejection fraction; these reports include cases involving patients with no pre-existing risk factors or with very low risk factors for reduced left ventricular ejection fraction. Patients at risk for such events, or those with pre-existing cardiac disease, should be closely monitored. In a Phase III trial evaluating monotherapy for multiple myeloma, the incidence of cardiac disorders was 15% in the bortezomib group and 12% in the dexamethasone group. The incidence of heart failure (acute pulmonary edema, heart failure, congestive heart failure, cardiogenic shock, pulmonary edema) was similar in both groups, at 5% and 4%, respectively. Isolated cases of QT interval prolongation have been reported; however, a causal relationship has not been established. 5. Hepatic Adverse Events. There have been rare reports of acute hepatic failure in patients receiving multiple concomitant medications and in those with severe underlying medical conditions. Other hepatic adverse events include elevated liver enzymes, hyperbilirubinemia, and hepatitis. Upon discontinuation of the product, these changes may be reversible. Data regarding re-administration of the product to these patients are limited. 6. Pulmonary Disorders. There have been rare reports of acute diffuse infiltrative pulmonary disorders of unknown etiology—such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and Acute Respiratory Distress Syndrome (ARDS)—occurring in patients receiving this product. Some of these events have been fatal. The reporting rate for these events appears to be higher in Japan. Patients presenting with new or worsening pulmonary symptoms should undergo prompt diagnostic evaluation and receive appropriate medical management. In one clinical trial, two patients with relapsed acute myeloid leukemia died from ARDS shortly after initiating treatment with high-dose (2 g/m²) cytarabine via continuous infusion, in combination with daunorubicin and bortezomib. There have been reports of pulmonary hypertension associated with this product in patients without underlying left-sided heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a comprehensive diagnostic evaluation should be performed promptly. 7. Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Cases of RPLS have been reported in patients treated with this product. RPLS is a rare, reversible neurological disorder that may present with seizures, hypertension, headaches, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging—preferably Magnetic Resonance Imaging (MRI)—can be used to confirm the diagnosis; patients who develop RPLS should discontinue treatment with this product. The safety of re-initiating treatment with this product in patients with a history of RPLS has not been established. 8. Laboratory Monitoring. Complete blood counts should be closely monitored during treatment with this product. 9. Gastrointestinal Adverse Events. Treatment with this product may cause nausea, diarrhea, constipation, and vomiting; antiemetics and antidiarrheals may sometimes be required to manage these symptoms. If patients become dehydrated, fluids and electrolytes should be replenished. Since treatment with this product may induce vomiting and/or diarrhea, patients should be advised to take appropriate measures to prevent dehydration. Patients should be instructed to consult a physician if they experience vertigo, dizziness, or syncope. 10. Tumor Lysis Syndrome. As this product is a cytotoxic agent capable of rapidly destroying malignant cells, it may precipitate complications associated with Tumor Lysis Syndrome. Patients presenting with a high tumor burden prior to treatment are at risk of developing Tumor Lysis Syndrome. 11. Patients with Hepatic Impairment. This product is metabolized via hepatic enzymes; consequently, its clearance may be reduced in patients with hepatic impairment. Such patients should be closely monitored for signs of toxicity during treatment with this product. 12. Patients with Renal Impairment. Renal impairment does not affect the pharmacokinetics of this product. Therefore, no dosage adjustment is required for patients with renal insufficiency. Since dialysis reduces the concentration of this product, it should be administered after the completion of dialysis. For information regarding dosage adjustments for melphalan in patients with renal impairment, please refer to the manufacturer's prescribing information for melphalan. 13. Effects on Ability to Drive and Operate Machinery. This product may cause fatigue, dizziness, syncope, or blurred vision. Therefore, patients experiencing these symptoms are advised against driving or operating machinery. 14. Keep out of the reach of children. [Drug Interactions] 1. *In vitro* and *ex vivo* animal studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) enzyme isoforms 1A2, 2C9, 2C19, 2D6, and 3A4. Since the contribution of CYP2D6 to bortezomib metabolism is limited (7%), it is not expected that the CYP2D6 poor metabolizer phenotype would affect the overall distribution of bortezomib. 2. In a drug interaction study evaluating the effect of ketoconazole (a potent CYP3A4 inhibitor) on bortezomib, data from 12 patients showed that the mean AUC of bortezomib increased by 5%. Therefore, patients should be closely monitored when bortezomib is co-administered with CYP3A4 inhibitors (e.g., ketoconazole, ritonavir). In a drug interaction study evaluating the effect of omeprazole (a potent CYP2C19 inhibitor) on bortezomib, data from 17 patients showed no significant effect on the pharmacokinetics of bortezomib. In a drug interaction study evaluating the effect of combination therapy with melphalan and prednisone on bortezomib, data from 21 patients showed that the mean AUC of bortezomib increased by 17%. This result was considered to be of no clinical relevance. 3. In clinical trials, there have been reports of hypoglycemia and hyperglycemia in diabetic patients taking oral hypoglycemic agents. During treatment with this product, blood glucose levels in patients taking oral antidiabetic agents should be closely monitored, and adjustments to the dosages of antidiabetic agents should be considered. Patients should be advised to exercise caution when co-administering drugs known to cause peripheral neuropathy (e.g., amiodarone, antiviral agents, isoniazid, nitrofurantoin, or statins) or drugs known to cause a reduction in blood pressure.

[Pharmacological Actions] Pharmacology: 1. Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. 2. The ubiquitin-proteasome pathway plays a crucial role in regulating the intracellular concentrations of specific proteins, thereby maintaining the stability of the intracellular environment. 3. Proteolysis affects multiple levels of intracellular signaling cascades; such disruption of the normal intracellular environment can lead to cell death. However, inhibition of the 26S proteasome can prevent the proteolysis of specific proteins. 4. *In vitro* studies have demonstrated that Bortezomib exhibits cytotoxicity against various types of cancer cells. *In vivo* studies using preclinical tumor models have demonstrated that Bortezomib can delay tumor growth, including that of multiple myeloma.

[Storage] Store in a tightly sealed container.

Product Specifications

Product Name: Velcade (Bortezomib for Injection) 2 mg — Natco Bortezomib Bortenat 2 mg

Common Name: Bortezomib for Injection

Composition: The active ingredient of this product is Bortezomib. Excipients include: Mannitol and Nitrogen gas.

Dosage Form: This product is a white or off-white powder or solid cake.

Specification: 2 mg

Manufacturer: Natco Pharma Ltd

Indications: Multiple Myeloma

This product may be used in combination with Melphalan and Prednisone (MP regimen) for the treatment of patients with previously untreated multiple myeloma who are not candidates for high-dose chemotherapy and hematopoietic stem cell transplantation; or as a monotherapy for the treatment of patients with multiple myeloma who have relapsed after receiving at least one prior therapy.

Mantle Cell Lymphoma

This product may be used for the treatment of patients with relapsed or refractory mantle cell lymphoma who have received at least one prior therapy before receiving this product. Safety and efficacy data for this indication are derived from a single-arm, Phase II clinical study conducted abroad involving patients with mantle cell lymphoma who relapsed after prior therapy (see [Clinical Trials]); clinical study data specifically for the Chinese population are currently lacking.

Dosage and Administration:Recommended Adult Dosage: The recommended dose of this product is 1.3 mg/m² administered as a single injection twice weekly for 2 consecutive weeks (i.e., on Days 1, 4, 8, and 11), followed by a 10-day rest period (i.e., from Day 12 to Day 21). A treatment course consists of 3 weeks, with a minimum interval of 72 hours between two consecutive doses. In clinical studies, patients confirmed to have achieved a complete response received an additional 2 cycles of Velcade treatment. It is recommended that patients who achieve a response receive a total of 8 cycles of Velcade treatment. Dose Adjustment and Re-initiation of Treatment: Treatment with this product should be withheld in the event of Grade 3 non-hematologic toxicity or any Grade 4 hematologic toxicity (excluding neuropathy, which is discussed below). Once the toxic symptoms have resolved, treatment with this product may be resumed at a 25% reduced dose (e.g., 1.3 mg/m² reduced to 1.0 mg/m²; 1.0 mg/m² reduced to 0.7 mg/m²). If a patient develops neuralgia or peripheral sensory neuropathy associated with treatment with this product, treatment should be administered with dose adjustments as recommended in the table below. If a patient has pre-existing severe neuropathy, this product should be used only after a careful assessment of the risks and benefits. Method of Administration: This product must be completely dissolved in 3.5 mL of normal saline and administered via intravenous injection through a catheter over a period of 3 to 5 seconds, followed by a flush with 0.9% Sodium Chloride Injection.