Tevazomib

Tevazomib

bortezomib

Manufacturer:

SC Sindan

Distributor:

DKLL

Marketer:

Teva Pharma
Full Prescribing Info
Contents
Bortezomib.
Description
Each vial contains 3.5 mg Bortezomib as mannitol boronic ester.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mamalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-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 signalling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death.
Pharmacodynamics: Bortezomib is a selective, reversible proteasome inhibitors and experiments have demonstrated that bortezomib is a cytotoxic to a variety of cancer cell types. Bortezomib causes a reduction of tumour growth in vivo in many preclinical tumour models, including multiple myeloma.
Pharmacokinetics: Following intravenous bolus administration of 1.0 mg/m2 and 1.3 mg/m2 doses to 24 patients with multiple myeloma (n= 12 per each dose level), the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively. In subsequent doses administered twice weekly, mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours for the 1.0 mg/m2 dose and 76 to 108 hours for the 1.3 mg/m2 dose. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 L/h following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively.
In the PK/PD substudy in a Phase III trial, following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to multiple myeloma patients (n=14 for IV, n=17 for SC), the total systemic exposure after repeat dose administration (AUClast) was comparable for subcutaneous and intravenous administration. The Cmax after SC administration (20.4 ng/mL) was lower than IV (223 ng/mL).
Distribution: The mean distribution volume of bortezomib ranged from 489 to 1884 L/m2 following single- or repeat-dose intravenous administration of 1.0 mg/m2 or 1.3 mg/m2 to patients with multiple myeloma. This suggests that ortezomib distributes widely to peripheral tissues. In vitro bortezomib binding to human plasma protein averaged 83% over a concentration range of 10 to 1000 ng/mL.
Metabolism: Bortezomib is primarily metabolized via cytochrome P450-mediated deboronation to metabolites that subsequently are hydroxylated. In vitro studies indicate that CYP3A4 and 2C19 are quantitatively the major isoforms with CYP1A2, 2C9 and 2D6 having a minor contribution to the overall metabolism of bortezomib. Evaluated deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
Elimination: The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m2 dose and 76 to 108 hours after the 1.3 mg/m2 dose. The mean total body clearances were 102 and 112 L/h following the first dose for doses of 1 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, respectively.
Special Populations and Conditions: Gender and Race, Pediatrics, Geriatrics, and Renal Insufficiency: There are no data on effects of bortezomib on the pharmacokinetics in these special populations and conditions.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in 60 cancer patients at bortezomib doses ranging from 0.5 to 1.3 mg/m2. When compared to patients with normal hepatic function, mild hepatic impairment did not alter doseĀ­ normalized bortezomib AUC. However, the dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be monitored closely.
Indications/Uses
Tevazomib (bortezomib) for Injection is indicated as follows: As part of combination therapy for the treatment of patients with previously untreated multiple myeloma who are unsuitable for stem cell transplantation.
As part of a medically recognized combination therapy for induction treatment of patients with previously untreated multiple myeloma who are suitable for stem cell transplantation (studies were conducted with intravenous administration of bortezomib).
For the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for stem cell transplantation. Bortezomib administered subcutaneously was studied in this patient population where it was shown to be non-inferior to the intravenous administration (defined as retaining at least 60% of the intravenous administration effect).
For the treatment of patients with mantle cell lymphoma who have relapsed or were refractory to at least 1 prior therapy.
Geriatrics (>65 years of age): No overall differences in safety or effectiveness of bortezomib were observed between younger patients and patient's ≥ 65 years of age. Greater sensitivity of some older individuals cannot be ruled out.
Pediatrics and Adolescents (<18 years of age): The safety and effectiveness of bortezomib in children and adolescents have not been established.
Dosage/Direction for Use
Dosing Considerations: Tevazomib may be administered: Intravenously (at a concentration of 1 mg/mL) as a 3 to 5 second bolus injection or subcutaneously (at a concentration of 2.5 mg/mL).
Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
For subcutaneous administration, the reconstituted solution is injected into the thighs (right or left) or abdomen (right or left). Injection sites should be rotated for successive injections. New injections should be given at least 2.5 cm from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.
If local injection site reactions occur following Tevazomib administration subcutaneously, a less concentrated Tevazomib solution (1 mg/mL instead of a 2.5 mg/mL) may be administered subcutaneously. Alternatively, the intravenous route of administration should be considered.
In clinical trials, local skin irritation was reported in 5% of patients but extravasation of bortezomib was not associated with tissue damage. In a clinical trial of subcutaneous bortezomib, a local reaction was reported in 6% of patients as an adverse event, mostly redness.
Treatment must be administered under the supervision of a physician qualified and experienced in the use of antineoplastic agents.
Bortezomib has been studied in patients with impaired hepatic function. Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated as per the recommended bortezomib dose. Patients with moderate or severe hepatic impairment should be started on a reduced dose.
The safety and effectiveness of Tevazomib in children and adolescents have not been established.
Mode of Administration: Tevazomib is a cytotoxic agent. Caution should be used during handling and preparation. Proper aseptic technique should be used since no preservative is present. Use of gloves and other protective clothing to prevent skin contact is recommended.
Different volumes of normal (0.9%) saline injection USP are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for the subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
For each 3.5 mg single-use vial of bortezomib reconstitute with the following volume of normal (0.9%) saline injection USP based no the route of administration: See Table 1.

Click on icon to see table/diagram/image

After determining patient body surface area (BSA) in square metres, use the following equations to calculate the total volume (mL) of reconstituted Tevazomib to be administered: See Equation.

Click on icon to see table/diagram/image

The reconstituted product should be a clear and colourless 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: Tevazomib contains no antimicrobial preservative. When reconstituted as directed, Tevazomib may be stored at 25°C. Reconstituted Tevazomib should be administered within eight hours of preparation. The reconstituted material may be stored for up to eight hours in the original vial or in a syringe. The total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.
Overdosage
Accidental overdosage of at least twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. There is no known specific antidote for Tevazomib 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.
Contraindications
Tevazomib for Injection is contraindicated in patients with hypersensitivity to bortezomib, boron or any of the excipients.
Tevazomib is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib.
Special Precautions
General: Dose Preparation: The recommended starting dose of Tevazomib is 1.3 mg/m2. Tevazomib may be administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL. When administered intravenously, Tevazomib is administered as a 3 to 5 second bolus intravenous injection. Tevazomib is for intravenous or subcutaneous use only. Tevazomib should not be administered by any other route.
Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
Tumour Lysis Syndrome: Because Act Bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells, the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Cardiovascular: Tevazomib treatment is commonly associated with orthostatic/postural hypotension which is not an acute reaction and is observed throughout treatment. In the Phase II and III relapsed multiple myeloma studies, the incidence of hypotension (postural, orthostatic, and hypotension NOS) was 11% and 12%, respectively. In the Phase II study, there was no prior history of orthostatic hypotension in these patients but half had pre-existing hypertension, one-third had evidence of peripheral neuropathy, and orthostatic hypotension was associated with syncope in some patients. In another Phase II study, there was evidence of autonomic nervous system abnormalities following bortezomib therapy. The mechanism is unknown although it may be due to bortezomib-induced autonomic neuropathy. Most cases required pharmacological treatment, including hydration and/or adjustment of antihypertensive medications. Administration of mineralocorticoids and/or sympathomimetics was infrequently required. 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. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness or fainting spells.
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 disease should be closely monitored.
There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
Events of pericarditis (<1%) have been reported in clinical trials and during post-marketing use of bortezomib. New or worsening cases of pericarditis should be investigated promptly.
In the Phase III relapsed multiplle myeloma study of intravenous bortezomib versus dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the bortezomib and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar kn the bortezomib and dexamethasone groups, 5% and 4%, respectively.
Gastrointestinal: Gastrointestinal events, including nausea, diarrhea, constipation, and vomiting occur frequently during bortezomib treatment. Events usually occur earlier in treatment (cycles 1 and 2), and may persist for several cycles, sometimes requiring administration of antiemetics and antidiarrheals. Fluid and electrolyte replacement should be administered if the patient becomes dehydrated. Cases of ileus have been reported and patients who experience constipation should be closely monitored.
Hematologic: Although bortezomib treatment may be associated with hematological toxicities, significant myelosuppression is uncommon. The most common hematological toxicity is thrombocytopenia which is generally dose related, occurring during Days 1 to 11 of therapy, with a return to baseline in platelet count during the rest period (Days 12 to 21) in each treatment cycle. Onset is common Cycles 1 and 2 but can continue throughout therapy. On average, the pattern of platelet count decrease and recovery remained consistent over the 8-cycle study period and there was no evidence of cumulative thrombocytopenia. The mean platelet nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pre-treatment platelet count is shown in Table 1. In the Phase III relapsed multiple myeloma study, the incidence of significant bleeding events (≥ Grade 3) was similar on both the intravenous bortezomib (4%) and dexamethasone (5%) arms. Platelet count should be monitored prior to each dose of Tevazomib. Tevazomib therapy should be held when the platelet count is <25 x 109/L and re-initiated at a reduced dose. There have been reports of gastrointestinal and intracerebral hemorrhage in association with bortezomib induced thrombocytopenia. Platelet transfusions, red blood cell transfusions and administration of growth factors may be utilized in the management of haematological toxicities. (See Table 2.)

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Hepatic/Biliary: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with Tevazomib at reduced starting doses and closely monitored for toxicities.
Rare cases of acute liver failure have been reported in bortezomib-treated patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include asymptomatic 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.
Neurologic: Treatment with bortezomib is commonly associated with peripheral neuropathy that is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported, including those with fatal outcomes.
In clinical trials, of the patients who experience treatment-emergent neuropathy, 70% had previously been treated with neurotoxic agents and 80% had signs or symptoms of peripheral neuropathy at baseline. Worsening of existing neuropathy is dose related and cumulative. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy (hyperesthesia, hypoesthesia, paresthesia, neuropathic pain or weakness) may experience worsening during treatment with Tevazomib and it is recommended that all patients should be monitored for symptoms of neuropathy.
Complete resolution to baseline has been documented in 14% of patients with severe symptoms in the Phase II studies, with limited follow-up data available. In the Phase III relapsed multiple myeloma study, following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy, and the median time to improvement or resolution was 107 days.
In the Phase III relapsed multiple myeloma study comparing bortezomib administered intravenously vs subcutaneously; the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of subjects in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Therefore, patients with pre-existing peripheral neuropathy or at high risk of peripheral neuropathy may benefit from starting bortezomib subcutaneously.
Starting Tevazomib subcutaneously may be considered for patients with pre-existing or at risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated with Tevazomib only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy may require a change in the dose, schedule or cessation of Tevazomib therapy.
Autonomic neuropathy may contribute to some adverse reactions, such as postural hypotension, diarrhea, constipation with ileus and pyrexia. Severe autonomic neuropathy resulting in treatment interruption or discontinuation has been reported.
Posterior reversible encephalopathy syndrome: There have been rare reports of posterior reversible encephalopathy syndrome (PRES) (formerly RPLS) in patients receiving bortezomib. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue. The safety of reinitiating bortezomib therapy in patients previously experiencing PRES is not known.
Progressive Multifocal Leukoencephalopathy (PML): Cases of John Cunningham (JC) virus infection of unknown causality, resulting in PML and death, have been reported in patients treated with bortezomib. Very rare postmarketing cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with bortezomib in combination with, or following other therapies. Signs and symptom of PML include new onset or worsening neurological signs or symptoms suchs as confusion or problems thinking, loss of balance, blurred vision or loss of vision, decreased strength or weakness in an arm or leg or change in the way of walking or talking. If such signs or symptoms or observed, PML should be considered in the differential diagnosis, and further evaluation is recommended, including consideration of a neurologist consultation. Discontinue Tevazomib if PML is diagnosed.
Renal: Hypercalcaemia and renal failure are complications of multiple myeloma most often associated with high tumour burden. Supportive treatments for these complications include bisphosphonates (for hypercalcemia and myeloma bone disease), hydration and other measures depending on the patient's status and the type and severity of the complications.
Respiratory: There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as penumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving bortezomib. Some of these events have been fatal. A pre-treatment chest radiography should be done to determine if any additional diagnostic measures are necessary and to serve as a baseline for potential post-treatment pulmonary changes.
In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnea), a prompt diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio should be considered prior to continuing Tevazomib therapy.
In a clinical trial, two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion over 24 hours with daunorubicin and bortezomib for relapsed acute myelogenous leukemia died of ARDSc early in the course of therapy. Therefore, this specific regimen is not recommended.
Use in Children: Pediatrics (<18 years of age): The safety and effectiveness of bortezomib in children and adolescents have not been established.
Use In Pregnancy & Lactation
Use in Pregnancy: Women of child-bearing potential should avoid becoming pregnant while being treated with Tevazomib. Males and females of child-bearing capacity should use effective contraceptive measures during treatment and for 3 months following treatment.
Bortezomib was not teratogenic in rats and rabbits at the highest dose tested (0.45 and 0.55 mg/m2, respectively) but caused post-implantation loss in rabbits.
No placental transfer studies have been conducted with bortezomib. There are no adequate and well-controlled studies in pregnant women. If Tevazomib is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be aware of the potential hazard to the fetus.
Use in Lactation: It is not known whether bortezomib is excreted in milk. Because many drugs are excreted in milk and because of the potential for serious adverse reactions from bortezomib in nursing infants, women should be advised against breast-feeding while being treated with Tevazomib.
Adverse Reactions
Multiple Myeloma: Herpes Zoster Virus Reactivation: The administration of bortezomib has been associated with herpes zoster reactivation. In the randomized Phase III study in relapsed multiple myeloma, the incidence of herpes zoster occurring on treatment with bortezomib was 13% (42/331) versus 5% (15/332) in the high-dose dexamethasone group. In the randomized study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in subjects treated with intravenous bortezomib, melphalan and prednisone (VMP) than in the control group treated with melphalan and prednisone (14% vs 4%, respectively). In this study, antiviral prophylaxis was administered to 26% (90/340) of patients in the VMP treatment group. In this treatment group, herpes zoster virus reactivation was less common in subjects receiving prophylactic antiviral therapy (3% [3/90]) than in subjects who did not receive prophylactic antiviral therapy (17% [43/250]). In the post-market setting, cases of herpes meningoencephalitis and ophthalmic herpes have been reported.
Blood and lymphatic system disorders: Disseminated intravascular coagulation.
Cardiac disorders: Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, cardiac arrest, congestive heart failure, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, pulmonary edema, ventricular tachycardia.
One case of torsades de pointes (not described previously) has been reported in a patient receiving bortezomib; causality has not been established.
Ear and labyrinth disorders: Hearing impaired.
Eye disorders: Diplopia.
Gastrointestinal disorders: Ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, small intestinal obstruction, large intestinal perforation, stomatitis, melena, acute pancreatitis.
General disorders and administration site conditions: Injection site erythema.
Hepatobiliary: Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis and liver failure.
Immune system disorders: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, acute renal failure (proliferative glomerulonephropathy), diffuse polyarthritis and rash.
Infections and infestations: Aspergillosis, bacteremia, urinary tract infection, herpes viral infection, listeriosis, septic shock, toxoplasmosis, oral candidiasis.
Injury, poisoning and procedural complications: Skeletal fracture, subdural hematoma.
Metabolism and nutrition disorders: Hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hypernatremia, hyponatreamia, tumour lysis syndrome.
Nervous system: Ataxia, coma, dizziness, dysarthria, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, hemorrhagic stroke, motor dysfunction, spinal cord compression, paraplegia, transient ischemic attack.
Psychiatric: Agitation, confusion, mental status changes, psychotic disorder, suicidal ideation.
Renal and urinary: Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure - acute and chronic, glomerular nephritis proliferative.
Respiratory, thoracic and mediastinal: Acute respiratory distress syndrome, aspiration, pneumonia, atelectasis, chronic obstructive airways disease exacerbated, dysphagia, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, respiratory failure.
Skin and subcutaneous tissue disorders: Urticaria, face edema.
Vascular: Cerebrovascular accident, deep venous thrombosis, peripheral embolism, pulmonary embolism, pulmonary hypertension.
Abnormal Hematologic and Clinical Chemistry Findings: Hematological abnormalities are expected in patients with advanced multiple myeloma. With bortezomib, cyclical thrombocytopenia was seen, with a general progressive decrease in platelet count during the bortezomib dosing period (Days 1 to 11) and a return to baseline in platelet count during the rest period (Days 12 to 21) in each treatment cycle. A trend towards an increase in hemoglobin and absolute neutrophil count across treatment cycles was noted especially with an improvement in the underlying disease. A trend towards a decrease in the absolute lymphocyte count was noted across the 8 treatment cycles; however, no trend was noted by cycle. Effects on electrolytes and calcium (hyper- and hypokalemia, hyper- and hyponatremia, hyper- and hypocalcemia) and hyphosphatemia, hypochloremia and hypomagnesmia were noted.
Post-Market Adverse Drug Reactions: The following adverse events have been reported from post-marketing experience: Central neurotoxicity/psychiatric events including seizures, mental status changes, encephalopathy, acute psychosis, bilateral hearing loss, dysautonomia, posterior reversible encephalopathy syndrome.
Cardiovascular and pulmonary events including tachycardia, heart failure, cardiac tamponade, pericarditis, pulmonary hypertension, cardiac and cardiopulmonary arrest, complete heart block, pneumonitis, respiratory failure, pulmonary alveolar hemorrhage, pleural effusion, acute pulmonary edema, cardiogenic shock.
Serious bleeding events including subarachnoid hemorrhage, intracerebral hemorrhage, disseminated intravascular coagulation, ischemic stroke, ischemic colitis, spinal cord ischemia.
Hypersensitivity events including immune complex type diseases, angioedema, anaphylactic reaction.
Tumour lysis syndrome.
Amyloidosis.
Hepatic abnormalities including increased transaminases, alkaline phosphatase, gamma-glutamyl transferase, hepatocellular damage, hepatitis, pancreatitis.
Renal abnormalities including acute renal failure, nephrotic syndrome, renal tubular acidosis, renal necrosis, graft loss and renal graft loss.
Sepsis and septic shock.
Gastrointestinal events including ischemic colitis and paralytic ileus.
Hyper- and hypocalcemia, hyper- and hypokalemia, severe hyponatremia, inappropriate ADH secretion.
Acute diffuse infiltrative pulmonary disease.
Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Herpes meningoencephalitis and ophthalmic herpes.
Optic neuropathy and blindness.
Progressive multifocal leukoencephalopathy (John Cunningham [JC]) virus infection.
Drug Interactions
Drug-Drug Interactions: Bortezomib is a substrate for cytochrome P450 (CYP) 3A4, 2C19, 1A2, 2D6 and 2C9 in human liver microsomes and a weak inhibitor of CYP isozymes 1A2, 2C9, 2D6 and 3A4 (IC50 ≥ 30 μM or 11.5 μg/mL) and CYP2C19 (IC50 ≥ 18 μM or 6.9 μg/mL).
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of IV botezomib showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. The concomitant use of Tevazomib with strong CYP3A4 inducers is therefore not recommended, as efficacy may be reduced. Examples of CYP3A4 inducers are rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort. In the same drug-drug interaction study, the effect of dexamethasone, a weaker CYP3A4 inducer was assessed. There was no significant effect on bortezomib pharmacokinetics based on data from 7 patients.
In a small drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A inhibitor, the results were variable and the effects of ketoconazole are incompletely known. The study indicated that the bortezomib AUC mean increased by 35% (90% CI: 1.032-1.772 fold), in the presence of ketoconazole, based on data from 12 patients. Therefore, use Tevazomib with caution when co-administering with potent CYP3A4 inhibitors such as ketoconazole and ritonavir.
In a drug-drug interactions study assessing the effect of omeprazole, a potent inhibitor of CYP2C19, there was no significant effect on the pharmacokinetics of bortezomib, based on data from 17 patients.
A drug-drug interaction study assessing the effect of melphalan-prednisone on intravenously administered bortezomib showed a 17% increase in mean bortezomib AUC based on data from 21 patients.
During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving Tevazomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Drug-Lifestyle Interactions: Tevazomib may be associated with fatigue, dizziness, syncope, orthostatic/postural hypotension or blurred vision. Therefore, patients are advised to be cautious when operating machinery or when driving.
Caution For Usage
Special Handling Instructions: Tevazomib for Injection is a cytotoxic agent. Caution should be used during handling and preparation. Proper aseptic technique should be used since no preservative is present. Use of gloves and other protective clothing to prevent skin contact is recommended.
Storage
Store in original package to protect from light. Do not store above 30°C.
Discard unused portion.
The product may be stored for up to eight hours in a syringe; however, total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.
ATC Classification
L01XG01 - bortezomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.
Presentation/Packing
Powd for inj (vial, sterile white to off-white cake or powder) 3.5 mg x 10 mL x 1's.
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