Mozerotrox
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Mозетрокс (MOZETROX)
Composition:
Active substance: bortezomib;
1 vial contains bortezomib 1.0 mg or 3.5 mg;
Excipient: mannitol (E 421).
Pharmaceutical form. Lyophilisate for solution for injection.
Main physicochemical properties: lyophilized powder or mass of white to almost white color.
Pharmacotherapeutic group. Antineoplastic agents. ATC code L01X X32.
Pharmacological Properties.
Pharmacodynamics.
Mechanism of action. Bortezomib is a proteasome inhibitor that inhibits the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex involved in the degradation of key proteins. This pathway plays a central role in regulating the turnover of specific proteins, thereby maintaining cellular homeostasis. Inhibition of the 26S proteasome leads to suppression of proteolysis and triggers a cascade of reactions resulting in apoptosis.
Bortezomib is highly selective for the proteasome. At a concentration of 10 µM, bortezomib does not inhibit any of the numerous tested receptors and proteases and is more than 1500 times more selective for the proteasome than for other enzymes. The kinetics of proteasome inhibition were calculated in vitro; bortezomib dissociated from the proteasome with a t½ of 20 minutes, thus demonstrating that proteasome inhibition by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple pathways, including but not limited to, altering regulatory proteins controlling the cell cycle and activation of the nuclear factor NF-kB. Proteasome inhibition leads to cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is essential for many aspects of tumor development, including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
Experiments have shown that bortezomib is cytotoxic to many types of cancer cells and that cancer cells are more susceptible to bortezomib-induced apoptosis than normal cells. In vivo, bortezomib causes a reduction in the growth of many experimental human tumors, including multiple myeloma.
Data from in vitro, ex-vivo, and animal model studies indicate that bortezomib enhances osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma who also had advanced-stage osteolytic disease and were treated with bortezomib.
Pharmacokinetics.
Absorption. After intravenous bolus administration of doses of 1.0 mg/m² and 1.3 mg/m² to 11 patients with multiple myeloma and creatinine clearance exceeding 50 mL/min, the mean maximum plasma concentration after the first dose of bortezomib was 57 and 112 ng/mL, respectively. With subsequent doses, the mean maximum plasma concentration of bortezomib ranged from 67 to 106 ng/mL for the 1.0 mg/m² dose and from 89 to 120 ng/mL for the 1.3 mg/m² dose.
After intravenous bolus or subcutaneous administration of a 1.3 mg/m² dose to patients with multiple myeloma (n=14 in the intravenous group and n=17 in the subcutaneous group), the total systemic exposure after repeated dosing (AUClast) was equivalent between subcutaneous and intravenous administration. Cmax after subcutaneous administration (20.4 ng/mL) was lower than after intravenous administration (223 ng/mL). The geometric mean ratio of AUClast was 0.99, and the 90% confidence interval was 80.18–122.80%.
Distribution. The mean volume of distribution (Vd) of bortezomib ranges from 1659 to 3294 liters after single or multiple doses of 1.0 mg/m² or 1.3 mg/m² in patients with multiple myeloma. This indicates extensive distribution of bortezomib into peripheral tissues. At bortezomib concentrations of 0.01–1.0 µg/mL, plasma protein binding is 83%. The fraction of bortezomib bound to plasma proteins was independent of concentration.
Metabolism. In vitro, bortezomib metabolism is primarily mediated by cytochrome P450 enzymes, including 3A4, 2C19, and 1A2. The main metabolic pathway is deboronation, leading to two metabolites, which are subsequently hydroxylated into other metabolites. Deboronated bortezomib metabolites are inactive as inhibitors of the 26S proteasome.
Elimination. The mean elimination half-life (T½) of bortezomib after multiple administrations ranges from 40 to 193 hours. Bortezomib is eliminated more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 and 112 L/h after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h and 18 to 32 L/h after subsequent doses of 1.0 mg/m² and 1.3 mg/m², respectively.
Special patient populations.
Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle involving 60 patients primarily with solid tumors and varying degrees of hepatic dysfunction; bortezomib doses ranged from 0.5 to 1.3 mg/m².
Mild hepatic impairment did not alter bortezomib AUC compared to normal hepatic function. Mean bortezomib AUC values increased by approximately 60% in patients with moderate to severe hepatic impairment. Dose adjustment and careful monitoring during treatment are recommended for these patients.
Renal impairment. Pharmacokinetic studies were conducted in patients with varying degrees of renal function, categorized by creatinine clearance (CrCL) into the following groups: normal (CrCL ≥ 60 mL/min/1.73m², n=12), mild impairment (CrCL = 40–59 mL/min/1.73m², n=10), moderate impairment (CrCL = 20–39 mL/min/1.73m², n=9), and severe impairment (CrCL < 20 mL/min/1.73m², n=3). Patients undergoing dialysis who received the dose after dialysis were also included in the study (n=8). Patients received intravenous bortezomib at doses of 0.7–1.3 mg/m² twice weekly. Bortezomib exposure (dose-normalized AUC and Cmax) was comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were determined in 104 pediatric patients (ages 2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia receiving bortezomib at a dose of 1.3 mg/m² twice weekly via intravenous bolus injection. According to population pharmacokinetic analysis, bortezomib clearance increases with increasing body surface area. The geometric mean (%CV) for clearance was 7.79 (25%) L/h/m², the volume of distribution at steady state was 834 (39%) L/m², and the elimination half-life was 100 (44%) hours. After adjusting for body surface area, other demographic factors such as age, body weight, and sex had no clinically significant effect on bortezomib clearance. Bortezomib clearance values in children, adjusted for body surface area, were comparable to those in adults.
Clinical Characteristics.
Indications.
Treatment of multiple myeloma, in combination with melphalan and prednisone, in previously untreated patients who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation (first-line therapy).
Treatment of progressive multiple myeloma as monotherapy, or in combination with pegylated liposomal doxorubicin or dexamethasone, in patients who have received at least one prior line of therapy and who have undergone hematopoietic stem cell transplantation or are not candidates for transplantation (second-line therapy).
Treatment of multiple myeloma, in combination with dexamethasone or dexamethasone and thalidomide, in previously untreated patients who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation (induction therapy).
Treatment of mantle cell lymphoma, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, in previously untreated patients who are not candidates for hematopoietic stem cell transplantation.
Contraindications.
Hypersensitivity to bortezomib, boron, or to any of the excipients of the medicinal product.
Acute diffuse infiltrative lung and pericardial diseases.
When using Mocetrex in combination with other medicinal products, refer to the instructions for medical use of these products for additional contraindications.
Special precautions.
General warnings. Mocetrex is a cytotoxic agent. Therefore, caution should be exercised during its reconstitution and administration. The use of gloves and protective clothing is recommended to prevent skin contact.
Appropriate aseptic techniques must be strictly followed when handling Mocetrex, as the product contains no preservatives.
Fatal outcomes have been reported due to accidental intrathecal administration of bortezomib. Bortezomib 1 mg must be administered intravenously only; 3.5 mg may be administered intravenously or subcutaneously. BORTEZOMIB MUST NOT BE ADMINISTERED INTRATHECALLY.
Instructions for solution preparation. Reconstitution must be performed only by qualified healthcare personnel.
For intravenous administration, prior to use, the contents of the vial should be dissolved in 1 mL (for the 1 mg dose) or in 3.5 mL (for the 3.5 mg dose) of 0.9% sodium chloride injection solution. The lyophilized powder dissolves in less than 2 minutes. After reconstitution, 1 mL of solution contains 1 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. The prepared solution should be inspected visually for particulate matter and discoloration prior to administration. If particles are present or discoloration occurs, the solution must not be used.
For subcutaneous administration, prior to use, the contents of each vial (3.5 mg) should be dissolved in 1.4 mL of 0.9% sodium chloride injection solution. Dissolution occurs in less than 2 minutes. After reconstitution, 1 mL of solution contains 2.5 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. The prepared solution should be inspected visually for particulate matter and discoloration prior to administration. If particles are present or discoloration occurs, the solution must not be used.
Proper disposal procedure. For single use only. Any unused medicinal product or waste material must be disposed of in accordance with local requirements.
Interaction with other medicinal products and other forms of interaction.
In vitro studies have demonstrated that bortezomib is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4. Since CYP2D6 plays a minor role in bortezomib metabolism, changes in overall drug distribution are not expected in poor metabolizers of this enzyme.
Drug interaction studies evaluating the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated an average increase in bortezomib AUC by 35% (90% CI [1.032 to 1.772]) based on data from 12 patients. Therefore, careful monitoring of patients receiving bortezomib concomitantly with potent CYP3A4 inhibitors (such as ketoconazole, ritonavir) is recommended.
A study evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) in 17 patients did not show a significant effect on bortezomib pharmacokinetics.
In a study involving 6 patients, the effect of rifampicin, a potent CYP3A4 inducer, was associated with an average reduction in bortezomib AUC (after intravenous administration) by 45%. Therefore, concomitant use of bortezomib with potent CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort extract) is not recommended, as the efficacy of bortezomib may be reduced.
In the same study, dexamethasone, a weak CYP3A4 inducer, did not significantly alter the pharmacokinetics of bortezomib based on data from 7 patients.
A drug interaction study evaluating the effect of melphalan and prednisone on the pharmacokinetics of bortezomib (after intravenous administration) in 21 patients demonstrated an average increase in bortezomib AUC by 17%, which is not clinically significant.
During clinical trials, cases of hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral antidiabetic agents. Patients receiving oral antidiabetic medications should have their blood glucose levels monitored and their antidiabetic drug doses adjusted during treatment with Mocetrex.
Special precautions for use.
If Mozytrox is used in combination with other medicinal products, the instructions for medical use of these medicinal products should be consulted prior to initiating treatment. When thalidomide is used, particular attention should be paid to pregnancy diagnosis and contraceptive methods.
Intrathecal administration. Fatal cases due to accidental intrathecal administration of bortezomib have been reported. Bortezomib 1 mg should be administered intravenously only; 3.5 mg — for intravenous or subcutaneous administration. BORTEZOMIB MUST NOT BE ADMINISTERED INTRATHECALLY.
Gastrointestinal complications. Bortezomib treatment may very commonly cause gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported as uncommon in frequency) have been reported; therefore, patients with constipation should be under medical supervision.
Hematological complications. Hematological toxicity (thrombocytopenia, neutropenia, and anemia) is very common during bortezomib therapy. In clinical trials evaluating bortezomib in patients with relapsed multiple myeloma and bortezomib in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen) in previously untreated mantle cell lymphoma patients, one of the most common hematological toxicities was reversible thrombocytopenia. Platelet counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. Cumulative thrombocytopenia was not observed. On average, the lowest measured platelet count was approximately 40% of the baseline level in trials of bortezomib monotherapy in multiple myeloma patients and 50% in trials of bortezomib in mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia was related to pre-treatment platelet counts: in 90% of 21 patients with baseline platelet counts < 75,000/µL, platelet counts were ≤ 25,000/µL during the study, including 14% with counts < 10,000/µL, whereas in patients with baseline platelet counts > 75,000/µL, only 14% of 309 patients had platelet counts ≤ 25,000/µL.
In patients with mantle cell lymphoma, grade ≥3 thrombocytopenia was more frequent in the group receiving bortezomib (VcR-CAP regimen) compared to those receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall frequency of bleeding events of all grades, as well as bleeding events of at least grade 3, was similar in both groups. In the VcR-CAP treatment group, 22.5% of patients required platelet transfusion compared to 2.9% in the R-CHOP group.
Cases of gastrointestinal and intracranial hemorrhages associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of bortezomib. Treatment with Mozytrox should be withheld if platelet counts decrease to < 25,000/µL during monotherapy or to ≤ 30,000/µL when used in combination with melphalan and prednisone. The benefit-risk ratio of Mozytrox treatment should be evaluated, especially in cases of moderate or severe thrombocytopenia and risk factors for bleeding.
Complete blood counts with differential leukocyte count and platelet count should be frequently performed during Mozytrox therapy. Platelet transfusion should be considered if clinically justified.
Reversible neutropenia between treatment cycles has been observed in patients with mantle cell lymphoma; cumulative neutropenia was not observed. White blood cell counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. In a clinical trial of bortezomib in mantle cell lymphoma patients, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received colony-stimulating factor. Since patients with neutropenia are at increased risk of developing infections, they should be monitored for signs of infection and appropriate therapeutic measures taken. The use of granulocyte colony-stimulating factor should be considered for managing hematological toxicity. If initiation of a new treatment cycle is delayed several times, prophylactic use of granulocyte colony-stimulating factor should be considered.
Herpes zoster reactivation. Antiviral prophylaxis should be considered for patients treated with Mozytrox. In phase III trials in previously untreated multiple myeloma patients, the overall frequency of Herpes zoster reactivation (shingles) was higher in the group receiving bortezomib + melphalan + prednisone (14%) compared to the group receiving melphalan + prednisone (4%).
Among patients with mantle cell lymphoma, the frequency of shingles was 6.7% in the VcR-CAP treatment group and 1.2% in the R-CHOP treatment group.
Hepatitis B virus (HBV) reactivation and infection.
Prior to initiating treatment with rituximab in combination with Mozytrox, HBV screening should be performed in patients with risk factors. HBV carriers and patients with a history of hepatitis B should be closely monitored for clinical signs and laboratory parameters during and after combination therapy with rituximab and Mozytrox. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of John Cunningham (JC) virus infection leading to PML with fatal outcome have been reported in patients treated with bortezomib. Patients diagnosed with PML had a history of or were receiving concomitant immunosuppressive therapy with bortezomib. Most PML cases were diagnosed within the first 12 months after initiation of bortezomib treatment. Patients should be regularly monitored for new or worsening neurological symptoms that may indicate PML, which should be considered in the differential diagnosis of central nervous system (CNS) disorders. If PML is suspected, patients should be referred to a physician experienced in managing PML, and appropriate diagnostic measures taken. Mozytrox treatment should be discontinued if PML is confirmed.
Peripheral neuropathy. Bortezomib treatment is very commonly associated with peripheral neuropathy, predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy typically peaks during the 5th bortezomib treatment cycle.
Careful monitoring of patients for neuropathic symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness is recommended.
In a phase III trial comparing intravenous and subcutaneous administration of bortezomib, the frequency of grade 2 peripheral neuropathy was 24% in the subcutaneous group and 41% in the intravenous group. Grade 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous group and 16% in the intravenous group.
If peripheral neuropathy develops or worsens, patients should undergo neurological examination; dose adjustment, schedule modification, or switching to subcutaneous administration may be necessary. Neuropathy should be managed with supportive measures.
Regular monitoring for treatment-induced neuropathy symptoms and neurological examination are required in patients receiving Mozytrox in combination with medicinal products associated with neuropathy (e.g., thalidomide); dose reduction or discontinuation of treatment should be considered as necessary.
In addition to peripheral neuropathy, autonomic neuropathy may contribute to certain adverse reactions such as orthostatic hypotension and acute constipation with intestinal obstruction. Information on autonomic neuropathy and its impact on these adverse reactions is limited.
Seizures. Rare cases of seizures have been reported in patients with a history of seizures or epilepsy. Special caution is required when treating patients with any risk factors for seizures.
Hypotension. Bortezomib therapy is often associated with postural/orthostatic hypotension. In most cases, it is mild or moderate in severity and occurs throughout treatment. Patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension prior to bortezomib treatment. Most patients required treatment for orthostatic hypotension, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly linked to bolus infusion of bortezomib; the mechanism of its development is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be associated with bortezomib use or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution is advised when treating patients with a history of syncope, those taking antihypertensive medications, and those with dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, hydration, glucocorticoids and/or sympathomimetics are recommended; antihypertensive medication doses may need to be reduced if necessary. Patients should be instructed to seek medical attention if they experience dizziness, pre-syncope, or syncope.
Posterior reversible encephalopathy syndrome (PRES). Cases of PRES have been reported in patients treated with bortezomib. PRES is a rare reversible neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Brain imaging, preferably magnetic resonance imaging (MRI), is required to confirm the diagnosis. Bortezomib treatment should be discontinued if PRES occurs.
Heart failure. Cases of development or worsening of pre-existing congestive heart failure and/or reduced left ventricular ejection fraction have been reported with bortezomib use. Fluid retention may contribute to the development of signs and symptoms of heart failure. Patients with risk factors or pre-existing heart disease should be monitored.
ECG monitoring. Isolated cases of QT interval prolongation have been observed in clinical trials; the cause has not been established.
Lung function disorders. Rare cases of acute diffuse infiltrative lung disorders of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been observed in patients receiving bortezomib. Some of these cases were fatal. Chest X-ray before treatment initiation is recommended to establish baseline lung status for comparison in case of potential treatment-induced lung function impairment.
In case of new or worsening pulmonary symptoms (e.g., cough, dyspnea), prompt diagnosis and appropriate therapeutic measures should be taken. The benefit-risk ratio of continuing Mozytrox treatment should be carefully considered.
In clinical trials, two out of two patients receiving high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion in combination with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS early in the treatment course. Therefore, this specific regimen combining high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.
Renal function disorders. Renal impairment is common in patients with multiple myeloma. Careful monitoring of such patients is recommended.
Hepatic function disorders. Bortezomib is metabolized by hepatic enzymes. In patients with moderate to severe hepatic impairment, bortezomib concentrations may increase; these patients should be treated with reduced doses and closely monitored for signs of toxicity.
Hepatic reactions. Rare cases of acute liver failure have been reported in patients treated with bortezomib in combination with other agents and in patients with serious comorbid conditions. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis, which resolved after bortezomib discontinuation, have also been reported.
Tumor lysis syndrome. Since bortezomib is a cytotoxic agent capable of rapidly killing tumor plasma cells, complications associated with tumor lysis syndrome may occur. Patients with high tumor burden prior to treatment initiation are primarily at risk. Careful monitoring of such patients and appropriate preventive measures are recommended.
Precautions regarding concomitant use of other medicinal products. Patients should be closely monitored by a physician when bortezomib is combined with strong CYP3A4 inhibitors. Caution is advised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Hepatic function should be corrected if impaired prior to initiating treatment, and caution should be exercised when prescribing the drug to patients taking oral hypoglycemic agents.
Potentially immune complex-mediated reactions. Immune complex-mediated reactions such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued in case of serious reactions.
Use during pregnancy or breastfeeding.
Contraception in women and men
Men and women of reproductive potential must use effective contraception during treatment and for 3 months after treatment completion.
Pregnancy
There are no clinical data on the use of Mozytrox in pregnant women. The teratogenic properties of bortezomib have not been fully investigated.
In preclinical studies, bortezomib at the maximum tolerated doses had no effect on embryonal development in rats and rabbits during organogenesis. Pre- and postnatal development studies in animals have not been conducted. Mozytrox is not recommended during pregnancy except in cases where the woman's clinical condition requires treatment with Mozytrox. If Mozytrox is used during pregnancy or if pregnancy occurs during treatment with Mozytrox, the patient should be informed of the potential harm to the fetus.
Thalidomide is a medicinal product with known teratogenic effects in humans, causing severe, life-threatening congenital malformations. Thalidomide is contraindicated during pregnancy and in women of reproductive potential. Patients receiving Mozytrox in combination with thalidomide must comply with pregnancy prevention requirements. For additional information, refer to the thalidomide product information.
Breastfeeding
It is unknown whether Mozytrox passes into breast milk, but to prevent the development of severe adverse effects in the infant, breastfeeding is not recommended during treatment with Mozytrox.
Fertility
Studies on the effect of Mozytrox on fertility have not been conducted.
Ability to affect reaction speed when driving or operating machinery.
Bortezomib has a moderate effect on the ability to drive or operate machinery. Bortezomib use is very commonly associated with fatigue, frequently with dizziness, orthostatic/postural hypotension, or visual disturbances, and uncommonly with syncope. Therefore, patients should be cautious when driving or operating machinery and should avoid such activities if these symptoms occur.
Method of Administration and Dosage
Treatment should be initiated under the supervision of a qualified physician experienced in the treatment of patients with oncological diseases, although Mocetox may be administered by a healthcare professional experienced in the use of antineoplastic agents. Preparation of the solution must be performed by qualified medical personnel only.
Relapsed Multiple Myeloma (patients who have received at least one prior line of therapy)
Monotherapy
The recommended dose of bortezomib for adults is 1.3 mg/m² of body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This 3-week period constitutes one treatment cycle. After achieving a complete clinical response, two additional treatment cycles are recommended. Patients achieving a partial response but not a complete remission should continue therapy with Mocetox for up to a maximum of 8 cycles. At least 72 hours must elapse between consecutive doses of Mocetox.
Dosage Adjustment and Reinitiation Recommendations for Mocetox as Monotherapy
If any non-hematologic toxicity of Grade III or hematologic toxicity of Grade IV occurs, except for neuropathies, treatment with Mocetox must be interrupted. After resolution of toxic symptoms, treatment may be resumed at a dose reduced by 25% (reduce dose from 1.3 mg/m² to 1.0 mg/m²; reduce dose from 1.0 mg/m² to 0.7 mg/m²). If toxic symptoms do not resolve or recur during treatment with the reduced dose, discontinuation of Mocetox should be considered, unless the benefits of continued treatment outweigh the risks.
Neuropathic Pain and/or Peripheral Neuropathy
The dose of the drug should be adjusted in the event of neuropathic pain and/or peripheral neuropathy (see Table 1). Mocetox should be administered to patients with a history of severe neuropathy only after careful benefit-risk assessment.
Table 1
Recommended* dose modification for Mocetox-induced neuropathy
| Severity of neuropathy |
Dose and administration frequency adjustment |
| Grade I (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional loss |
Dose and administration schedule do not require adjustment |
| Grade I with pain or Grade II (moderate symptoms; limitation of instrumental activities of daily living)** |
Reduce dose to 1 mg/m² or change Mozetrex dosing regimen to 1.3 mg/m² once weekly |
| Grade II with pain or Grade III (severe symptoms; limitation of self-care activities)*** |
Withhold Mozetrex treatment until resolution of toxicity symptoms. Then resume treatment at a reduced dose of 0.7 mg/m² once weekly. |
| Grade IV (life-threatening consequences; requiring urgent intervention) and/or severe autonomic neuropathy |
Discontinue Mozetrex treatment |
* Based on dose modifications observed in Phase II and III multiple myeloma studies and in the post-marketing period.
** Instrumental activities of daily living include cooking, shopping, using the telephone, etc.
*** Basic self-care activities include bathing, dressing/undressing, eating, using the toilet, taking medications, being out of bed, etc.
Combination therapy with pegylated liposomal doxorubicin.
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered intravenously or subcutaneously 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 constitutes one treatment cycle. At least 72 hours must elapse between consecutive doses of Mozerex.
Pegylated liposomal doxorubicin should be administered at a dose of 30 mg/m² on Day 4 of the Mozerex treatment cycle via a 1-hour intravenous infusion after Mozerex injection.
Up to 8 cycles of this combination therapy should be administered, provided the disease does not progress and patients tolerate treatment well. Patients who achieve complete remission may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires more than 8 treatment cycles. Patients whose paraprotein levels continue to decline after 8 cycles may also continue treatment as long as treatment remains tolerable and a response is observed.
Combination therapy with dexamethasone.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously 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 constitutes one treatment cycle. At least 72 hours must elapse between consecutive doses of Mozerex.
Dexamethasone should be administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the Mozerex treatment cycle.
Patients who show a response to treatment or stable disease after four cycles may continue treatment with this combination for up to four additional cycles. For further information on dexamethasone, refer to the prescribing information for that medicinal product.
Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma.
See dose modification recommendations for Mozerex monotherapy provided above.
Untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation
Combination therapy with melphalan and prednisone.
Mozerex (bortezomib) should be administered intravenously or subcutaneously in combination with oral melphalan and oral prednisone over nine 6-week treatment cycles (see Table 2). In cycles 1–4, Mozerex is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5–9, Mozerex is administered once weekly (Days 1, 8, 22, and 29). At least 72 hours must elapse between consecutive doses of Mozerex.
Melphalan and prednisone should be administered orally on Days 1, 2, 3, and 4 of the first week of each cycle.
Recommended dosing regimen of Mozerex in combination with melphalan and prednisone
Table 2
| Mozerotex 2 times a week (cycles 1-4) |
|||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
|||||||||||||
| Mozerotex (1.3 mg/m²) |
1 |
-- |
-- |
4 day |
8 day |
11 day |
Break |
22 day |
25 day |
29 day |
32 day |
Break |
|||||||
| M (9 mg/m²) P (60 mg/m²) |
1 day |
2 day |
3 day |
4 day |
-- |
-- |
Break |
-- |
-- |
-- |
-- |
Break |
|||||||
| Mozerotex 1 time a week (cycles 5-9) |
|||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
|||||||||||||
| Mozerotex (1.3 mg/m²) |
1 day |
-- |
-- |
-- |
8 day |
Break |
22 day |
29 day |
Break |
||||||||||
| M (9 mg/m²) P (60 mg/m²) |
1 day |
2 day |
3 day |
4 day |
-- |
Break |
-- |
-- |
Break |
||||||||||
M − melphalan, P − prednisone.
Dosing adjustment and re-initiation recommendations for combination therapy with melphalan and prednisone.
Prior to starting a new treatment cycle:
- platelet count must be ≥ 70×10⁹/L and absolute neutrophil count must be ≥ 1.0×10⁹/L,
- non-hematological toxicity has returned to Grade 1 or baseline levels.
Dose adjustment during subsequent cycles of Mozerix treatment in combination with melphalan and prednisone
Table 3
| Toxicity |
Dose adjustment or discontinuation of treatment |
| Hematological toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
|
Delay administration of Mosunetuzumab dose |
|
The Mosunetuzumab dose should be reduced by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2) |
| Non-hematological toxicity ≥ Grade III |
Mosunetuzumab treatment should be withheld until symptoms improve to baseline or Grade I severity. Mosunetuzumab may then be restarted at a reduced dose by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2). In case of Mosunetuzumab-dependent neuropathic pain and/or peripheral neuropathy, hold and/or adjust the Mosunetuzumab dose as specified in Table 1. |
For additional information on melphalan and prednisone, see the package leaflets for these medicinal products.
Untreated multiple myeloma in patients eligible for hematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasone.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Mometrex.
Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of each Mometrex treatment cycle.
Administer 4 treatment cycles with this combination.
Combination therapy with dexamethasone and thalidomide.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 17-day rest period (days 12–28). This 4-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Mometrex.
Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of each Mometrex treatment cycle.
Thalidomide should be administered orally at a dose of 50 mg daily on days 1–14 of the cycle; if tolerated, the dose should be increased to 100 mg daily on days 15–28. The dose may be further increased to 200 mg daily starting from the second cycle (see Table 4).
Administer 4 treatment cycles. Patients achieving at least a partial response to therapy should receive 2 additional treatment cycles.
Recommended dosing regimen of Mometrex in combination with dexamethasone and thalidomide for patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation
Table 4
| Mozerotix +Dx |
Cycles 1–4 |
||||||
| Week |
1 |
2 |
3 |
||||
| Mozerotix (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
||||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
||||
| Mozerotix + Dx + T |
Cycle 1 |
||||||
| Week |
1 |
2 |
3 |
4 |
|||
| Mozerotix (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
Break |
|||
| T (50 mg) |
Daily |
Daily |
- |
- |
|||
| T (100 mg)ᵃ |
- |
- |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
| Cycles 2–4ᵇ |
|||||||
| Mozerotix (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
Break |
|||
| T (200 mg)ᵃ |
Daily |
Daily |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
Dx – dexamethasone; T – thalidomide.
a Increase thalidomide dose to 100 mg from week 3 of cycle 1 if the 50-mg dose is tolerated, and to 200 mg if the 100-mg dose is tolerated.
b Patients who achieve a partial response after 4 treatment cycles may receive up to 6 treatment cycles.
Dosing recommendations for patients eligible for transplantation.
For dose adjustments in case of neuropathy, refer to the dose adjustment recommendations for Mozytrox used as monotherapy.
If Mozytrox is used in combination with other chemotherapeutic agents, refer to the respective product information for dose adjustment recommendations for these agents in case of toxicity.
Untreated mantle cell lymphoma
Combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen)
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously 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 constitutes one treatment cycle. At least 72 hours should elapse between consecutive administrations of Mozytrox. Administer 6 treatment cycles. Patients who first demonstrate response during cycle 6 should be given 2 additional cycles of therapy.
Drugs administered by intravenous infusion on day 1 of each 3-week Mozytrox treatment cycle: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m².
Prednisone should be administered orally at a dose of 100 mg/m² on days 1, 2, 3, 4, and 5 of each Mozytrox treatment cycle.
Dose adjustment recommendations for patients with untreated mantle cell lymphoma
Prior to initiation of a new treatment cycle:
- Platelet count must be ≥ 100,000 cells/µL and absolute neutrophil count must be ≥ 1,500 cells/µL;
- Platelet count must be ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration;
- Hemoglobin level ≥ 8 g/dL;
- Non-hematological toxicity must have resolved to grade 1 or baseline levels.
Treatment with Mozytrox should be withheld in case of any non-hematological toxicity ≥ grade III severity (except neuropathy) related to Mozytrox administration, or in case of hematological toxicity ≥ grade III severity. Refer to Table 5 for dose adjustment recommendations.
Granulocyte colony-stimulating factors may be used to manage hematological toxicity. If initiation of a new treatment cycle is delayed multiple times, consider prophylactic use of granulocyte colony-stimulating factor. Platelet transfusion should be considered for management of thrombocytopenia.
Dose adjustment during therapy for patients with untreated mantle cell lymphoma
Table 5
| Toxicity |
Dose modification or treatment interruption |
| Haematological toxicity |
|
˂ 10000 cells/μL. |
Treatment with Mozetrox should be withheld for up to 2 weeks until the absolute neutrophil count recovers to ≥ 750 cells/μL and platelet count to ≥ 25000 cells/μL.
|
|
Delay the Mozetrox dose administration. |
| Non-haematological toxicity ≥ Grade III related to Mozetrox administration. |
Treatment with Mozetrox should be withheld until symptoms improve to Grade II or better. Mozetrox may then be reinitiated at a dose reduced by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). For Mozetrox-dependent neuropathic pain and/or peripheral neuropathy, dose hold and/or modification should be performed as specified in Table 1. |
If Mozerotux is used in combination with other chemotherapeutic agents, refer to the package inserts of those medicinal products for information on dose adjustments in the event of toxicity.
Special patient groups
Elderly patients
Currently, there are no data indicating the need for dose adjustment in patients aged 65 years and older.
There are no studies evaluating the use of Mozerotux in elderly patients with untreated multiple myeloma who are candidates for high-dose chemotherapy followed by hematopoietic stem cell transplantation. Therefore, no recommendations on dose adjustment can be provided for this patient group.
In a study of Mozerotux in patients with untreated mantle cell lymphoma, 42.9% of patients were aged 65–74 years and 10.4% were aged ≥75 years. Patients aged 75 years and older tolerated treatment less well in both treatment arms (VcR-CAP and R-CHOP regimens).
Patients with hepatic impairment
Dose adjustment is not required for patients with mild hepatic impairment. For patients with moderate to severe hepatic impairment, treatment with Mozerotux should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, with subsequent gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on patient tolerability.
Recommendations for adjustment of initial doses of Mozerotux in patients with hepatic impairment
Table 6
| Severity of hepatic impairment* |
Bilirubin level |
AST levels |
Initial dose adjustment |
| Mild |
≤ 1.0 x ULN |
> ULN |
Not required |
| > 1.0x - 1.5x ULN |
Any |
Not required |
|
| Moderate |
> 1.5x - 3x ULN |
Any |
Reduce Mozetorox dose to |
| Severe |
> 3x ULN |
Any |
AST – aspartate aminotransferase; ULN – upper limit of normal.
* Based on the National Cancer Institute Organ Dysfunction Working Group classification of severity of liver function impairment (mild, moderate, and severe).
Patients with renal impairment.
Mild to moderate renal impairment (creatinine clearance > 20 mL/min/1.73 m²) does not affect the pharmacokinetics of bortezomib; therefore, dose adjustment is not required in this patient group. It is unknown whether severe renal impairment (creatinine clearance < 20 mL/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration.
1 mg of lyophilisate for solution for injection is intended for intravenous administration.
3.5 mg of lyophilisate for solution for injection is intended for intravenous or subcutaneous administration.
Accidental intrathecal administration of the drug has resulted in fatal outcomes.
Intravenous administration
The reconstituted solution should be administered immediately after preparation as a 3–5 second intravenous bolus injection through a peripheral or central venous catheter. After injection, the catheter must be flushed with 0.9% sodium chloride injection solution. At least 72 hours should elapse between consecutive doses of bortezomib.
Subcutaneous injections
The reconstituted bortezomib solution (3.5 mg) should be administered subcutaneously into the thigh (left or right) or abdomen (left or right quadrant). The solution should be injected subcutaneously at an angle of 45–90°. Injection sites should be rotated with subsequent injections.
In case of local reactions at the subcutaneous injection site, it is recommended to administer a less concentrated bortezomib solution subcutaneously (reconstitute bortezomib 3.5 mg to a concentration of 1 mg/mL instead of 2.5 mg/mL) or switch to intravenous administration.
Children.
The safety and efficacy of Mozetrex in pediatric patients (under 18 years of age) have not been established. Available data are insufficient to establish dosing recommendations for pediatric patients.
Overdose.
In patients, overdose exceeding the recommended dose by more than two-fold has been associated with acute reduction in blood pressure and thrombocytopenia resulting in fatal outcome.
There is no known specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressor and/or inotropic agents) and body temperature is recommended.
Adverse reactions.
Among severe adverse reactions during treatment with Mozerotux, there were infrequent reports of cardiac arrest, tumor lysis syndrome, pulmonary hypertension, reversible posterior encephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders, and rarely, autonomic neuropathy. The most common adverse reactions during treatment with Mozerotux are nausea, diarrhea, constipation, vomiting, asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Multiple myeloma.
The adverse reactions listed in Table 7 are considered possibly related to the use of bortezomib. These adverse reactions are based on pooled data from 5476 patients, of whom 3996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was used to treat multiple myeloma in 3974 patients.
Adverse reactions are grouped by organ systems and frequency of occurrence. Frequency is defined as: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and not known (cannot be estimated from available data). Within each group, adverse reactions are listed in decreasing order of severity. Also included are adverse reactions not observed during clinical trials but reported in the post-marketing period.
Table 7
| Organ systems |
Frequency |
Adverse reaction |
| Infections and infestations |
Common |
Herpes zoster (including disseminated and with ocular complications), pneumonia*, herpes simplex*, fungal infection* |
| Uncommon |
Infections*, bacterial infections*, viral infections*, sepsis (including septic shock)*, bronchopneumonia, herpesvirus infection*, herpetic meningoencephalitis#, bacteremia (including staphylococcal), hordeolum, influenza, cellulitis, device-related infections, skin infections*, ear infections*, staphylococcal infection, dental infection* |
|
| Rare |
Meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, post-viral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant neoplasm, plasma cell leukemia, renal cell carcinoma, tumor growth, mycosis fungoides, benign neoplasm* |
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, neutropenia*, anemia* |
| Common |
Leukopenia*, lymphopenia* |
|
| Uncommon |
Pancytopenia*, febrile neutropenia, coagulopathy*, leukocytosis*, lymphadenopathy, hemolytic anemia# |
|
| Rare |
Disseminated intravascular coagulation syndrome, thrombocytosis*, hyperviscosity syndrome, thrombocytopathy, thrombocytopenic purpura, other blood and hematopoietic organ disorders, hemorrhagic diathesis, lymphocytic infiltration |
|
| Immune system disorders |
Uncommon |
Angioedema#, hypersensitivity* |
| Rare |
Anaphylactic shock, amyloidosis, type III immune complex-mediated reactions |
|
| Endocrine disorders |
Uncommon |
Cushing's syndrome*, hyperthyroidism*, syndrome of inappropriate antidiuretic hormone secretion |
| Rare |
Hypothyroidism |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Dehydration, hypokalemia*, hyponatremia*, blood glucose disturbances*, hypocalcemia*, enzyme level disturbances* |
|
| Uncommon |
Tumor lysis syndrome, patient condition aggravatedª*, hypomagnesemia*, hypophosphatemia*, hyperkalemia*, hypercalcemia*, hypernatremia*, uric acid level disturbances*, diabetes mellitus*, fluid retention |
|
| Rare |
Hypermagnesemia*, acidosis, electrolyte imbalance*, hypervolemia, hypochloremia*, hypovolemia, hyperchloremia*, hyperphosphatemia*, metabolic disorders, vitamin B complex deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance |
|
| Psychiatric disorders |
Common |
Mood disorders*, anxiety*, sleep disorders* |
| Uncommon |
Psychiatric disorder*, hallucinations*, psychotic disorder*, confusion*, agitation |
|
| Rare |
Suicidal ideation*, adjustment disorder, delirium, decreased libido |
|
| Nervous system disorders |
Very common |
Neuropathies*, peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache* |
|
| Uncommon |
Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance disorders*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex abnormalities*, parosmia |
|
| Rare |
Intracranial hemorrhage*, intracerebral hemorrhage (including subarachnoid)*, brain edema, transient ischemic attack, coma, autonomic nervous system disorders, autonomic neuropathy, cranial nerve paralysis*, paralysis*, paresis*, presyncope, brainstem syndrome, cerebrovascular disorder, nerve root disorders, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunctions, other nervous system disorders, radiculitis, hypersalivation, hypotonia |
|
| Eye disorders |
Common |
Eye swelling*, visual disturbance*, conjunctivitis* |
| Uncommon |
Eye hemorrhage*, eyelid infections*, eye inflammation*, diplopia, dry eyes*, eye irritation*, eye pain, increased lacrimation, eye discharge |
|
| Rare |
Corneal damage*, exophthalmos, retinitis, scotoma, other eye (and eyelid) disorders, acquired dacryoadenitis, photophobia, photopsia, optic nerve neuropathy#, various degrees of visual impairment (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing impairment (up to deafness), ear discomfort* |
|
| Rare |
Ear hemorrhage, vestibular neuronitis, other ear disorders |
|
| Cardiac disorders |
Uncommon |
Cardiac tamponade#, cardiopulmonary shock*, atrial fibrillation (including atrial), heart failure (including left and right ventricular)*, arrhythmia*, tachycardia*, palpitations, angina pectoris, pericarditis (including pericardial effusion), cardiomyopathy*, ventricular dysfunction*, bradycardia |
| Rare |
Atrial flutter, myocardial infarction*, atrioventricular block*, cardiovascular disorders (including cardiogenic shock), flutter-fibrillation, unstable angina, heart valve disorders*, coronary artery insufficiency, sinus node arrest |
|
| Vascular disorders |
Common |
Hypotension*, orthostatic hypotension, hypertension* |
| Uncommon |
Cerebrovascular disorder#, deep vein thrombosis*, hemorrhage*, thrombophlebitis (including superficial), vascular collapse (including hypovolemic shock), phlebitis, flushing*, hematoma (including paranephric)*, peripheral circulation disorders*, vasculitis, hyperemia (including ocular)* |
|
| Rare |
Peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vasodilation, vascular discoloration, venous insufficiency |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, epistaxis, lower/upper respiratory tract infections*, cough* |
| Uncommon |
Pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage#, bronchospasm, chronic obstructive pulmonary disease*, hypoxemia*, airway patency deterioration*, hypoxia, pleurisy*, hiccups, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Lung failure, acute respiratory distress syndrome, apnea, pneumothorax, lung collapse, pulmonary hypertension, hemoptysis, pulmonary hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial disorders*, hypocapnia*, interstitial lung disease, lung infiltration, throat tightness, dry throat, increased upper respiratory tract secretion, throat irritation, upper respiratory tract cough syndrome |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, dyspepsia, stomatitis*, abdominal distension, oropharyngeal pain*, abdominal pain (including gastrointestinal and splenic region)*, oral cavity disorders*, flatulence |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting blood, lip swelling*, gastrointestinal obstruction (including small intestine obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, gingival bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, gastrointestinal tract inflammation*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, gastrointestinal motility disorders*, salivary gland disorders* |
|
| Rare |
Acute pancreatitis, peritonitis*, tongue swelling*, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma*, gastrointestinal ulcers and perforations*, gingival hyperplasia, megacolon, rectal discharge, oral-pharyngeal blistering*, lip pain, periodontitis, anal fissure, altered defecation rhythm, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Liver enzyme level abnormalities* |
| Uncommon |
Hepatotoxicity (including liver disorders), hepatitis*, cholestasis |
|
| Rare |
Liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, hepatic hemorrhage, cholelithiasis |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash*, pruritus*, erythema, dry skin |
| Uncommon |
Erythema multiforme, urticaria, acute febrile neutrophilic dermatosis, toxic skin eruptions, toxic epidermal necrolysis#, Stevens-Johnson syndrome#, dermatitis*, hair disorders*, petechiae, ecchymosis, skin irritation, purpura, skin induration*, psoriasis, hyperhidrosis, night sweats, pressure ulcers#, acne*, bullae*, skin pigmentation disorders* |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, hand-foot erythrodysesthesia syndrome, subcutaneous hemorrhage, livedo reticularis, skin induration, papules, photosensitivity reactions, seborrhea, cold sweat, other skin disorders, erythrosis, skin ulcers, nail disorders |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Musculoskeletal pain* |
| Common |
Muscle spasms*, limb pain, muscle weakness |
|
| Uncommon |
Muscle twitching, joint swelling, arthritis*, joint stiffness, myopathies*, heaviness sensation |
|
| Rare |
Rhabdomyolysis, temporomandibular joint dysfunction, fistula, joint effusion, jaw pain, bone disorders, infections and inflammation of musculoskeletal system and connective tissue*, synovial cyst |
|
| Renal and urinary disorders |
Common |
Renal failure* |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infections*, signs and symptoms of urinary tract disorders*, hematuria*, urinary retention, micturition disorders*, proteinuria, azotemia, oliguria*, polyuria |
|
| Rare |
Bladder irritation |
|
| Reproductive system and breast disorders |
Uncommon |
Vaginal bleeding, genital pain*, erectile dysfunction |
| Rare |
Testicular disorders*, prostatitis, breast disorders in women, epididymal tenderness, epididymitis, pelvic pain, vulvar ulcers |
|
| Congenital, familial and genetic disorders |
Rare |
Aplasia, gastrointestinal tract malformations, ichthyosis |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, pain*, fever* |
|
| Uncommon |
General physical health deterioration*, facial swelling*, injection site reactions*, mucosal disorders*, chest pain, gait disturbance, feeling of cold, extravasation*, catheter-related complications*, thirst sensation*, chest discomfort, sensation of body temperature change*, pain related to injection* |
|
| Rare |
Fatal outcome (including sudden), multiple organ failure, bleeding at administration site*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, tenderness, ulceration, irritation, non-cardiac substernal pain, catheter insertion site pain, foreign body sensation |
|
| Investigations |
Common |
Weight decreased |
| Uncommon |
Hyperbilirubinemia*, deviation of protein levels from normal*, weight increased, blood test abnormalities*, increased C-reactive protein level |
|
| Rare |
Blood gas abnormalities*, ECG abnormalities (including QT interval prolongation)*, international normalized ratio deviation*, increased gastric acidity, increased platelet aggregation, increased troponin I level, virus identification in serological tests*, urine test abnormalities* |
|
| Procedural complications |
Uncommon |
Fall, confusion |
| Rare |
Transfusion reactions, fractures*, tremor*, facial injury, joint injury*, burns, skin laceration, procedural pain, radiation injuries* |
|
| Surgical and medical procedures |
Rare |
Macrophage activation |
* Grouping of more than one MedDRA term.
From post-marketing sources.
ª Patient deterioration – a general term defined as weight loss of more than 5%, decreased appetite, poor nutrition, and lack of physical activity, often associated with dehydration, depression, immune dysfunction, and low cholesterol levels. Patient deterioration is not a distinct disease or syndrome; rather, it represents nonspecific manifestations of an underlying physical, mental, or psychosocial condition.
Mantle cell lymphoma.
The safety profile in 240 patients with mantle cell lymphoma who received bortezomib at a dose of 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), and 242 patients who received rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), was generally similar to the safety profile observed in patients with multiple myeloma; the main differences are described below. Additional adverse reactions observed with bortezomib in combination therapy (VcR-CAP) were hepatitis B virus infection (< 1%) and myocardial ischemia (1.3%). The similar incidence rates in both treatment groups suggest that these adverse reactions are not solely related to bortezomib. Treatment with bortezomib in patients with mantle cell lymphoma was associated with ≥ 5% higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to patients with multiple myeloma.
Adverse reactions occurring at a frequency of ≥ 1%, with similar or higher incidence in the VcR-CAP treatment group, which were possibly or probably related to the medicinal products included in the VcR-CAP combination regimen, are listed in Table 8. Also included are adverse reactions observed in the VcR-CAP treatment group that, according to investigator assessment, were possibly or probably related to bortezomib, based on experience from studies in patients with multiple myeloma.
Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies are defined as: very common (>1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity.
Table 8
| System Organ Classes |
Frequency |
Adverse Reaction |
| Infections and infestations |
Very common |
Pneumonia* |
| Common |
Sepsis (including septic shock)*, herpes zoster (including disseminated and with ocular complications), herpesvirus infection*, bacterial infections*, upper/lower respiratory tract infections*, fungal infection*, herpes simplex* |
|
| Uncommon |
Hepatitis B, infections*, bronchopneumonia |
|
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, febrile neutropenia, neutropenia*, leukopenia*, anemia*, lymphopenia* |
| Uncommon |
Pancytopenia* |
|
| Immune system disorders |
Common |
Hypersensitivity* |
| Uncommon |
Anaphylactic reaction |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Hypokalemia*, blood glucose abnormalities*, hyponatremia*, diabetes mellitus*, fluid retention |
|
| Uncommon |
Tumor lysis syndrome |
|
| Psychiatric disorders |
Common |
Sleep disorders* |
| Nervous system disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Neuropathies*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, sensory-motor peripheral neuropathy, dizziness*, dysgeusia*, autonomic neuropathy |
|
| Uncommon |
Autonomic nervous system disorders |
|
| Eye disorders |
Common |
Visual disturbances* |
| Ear and labyrinth disorders |
Common |
Dysacusis (including tinnitus)* |
| Uncommon |
Vertigo*, hearing impairment (up to deafness) |
|
| Cardiac disorders |
Common |
Cardiac fibrillation (including atrial), arrhythmia*, heart failure (including left and right ventricular)*, myocardial ischemia, ventricular dysfunction* |
| Uncommon |
Cardiovascular disorders (including cardiogenic shock) |
|
| Vascular disorders |
Common |
Hypertension*, hypotension*, orthostatic hypotension |
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, cough*, hiccups |
| Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute) |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, gastrointestinal inflammation*, abdominal pain (including gastrointestinal and splenic area pain)*, oral cavity disorders* |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)* |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including hepatic disorders) |
| Uncommon |
Hepatic failure |
|
| Skin and subcutaneous tissue disorders |
Very common |
Hair disorders* |
| Common |
Pruritus*, dermatitis*, rash* |
|
| Musculoskeletal and connective tissue disorders |
Common |
Muscle spasms*, musculoskeletal pain*, limb pain |
| Renal and urinary disorders |
Common |
Urinary tract infections* |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, injection site reactions*, fever* |
|
| Investigations |
Common |
Hyperbilirubinemia*, protein level abnormalities*, weight decreased, weight increased |
* Grouping of more than one MedDRA term.
Description of selected adverse reactions.
Herpes zoster virus reactivation
Multiple myeloma.
Antiviral prophylaxis was administered in 26% of patients receiving bortezomib in combination with melphalan and prednisone. Herpes zoster was observed in 17% of patients who did not receive antiviral agents, compared to 3% of patients who received antiviral agents.
Mantle cell lymphoma.
Antiviral prophylaxis was administered in 57% of patients receiving bortezomib as part of combination therapy with VcR-CAP regimen. Herpes zoster was observed in 10.7% of patients who did not receive antiviral agents, compared to 3.6% of patients who received antiviral agents.
Hepatitis B virus (HBV) reactivation and infection
Mantle cell lymphoma.
Cases of hepatitis B infection with fatal outcome were reported in 0.8% of patients (n=2) in the group receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and in 0.4% of patients (n=1) receiving bortezomib as part of combination therapy with VcR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B cases was similar in both treatment groups (0.8% in the VcR-CAP group versus 1.2% in the R-CHOP group).
Peripheral neuropathy during combination therapy
Multiple myeloma.
Peripheral neuropathy was observed in studies where bortezomib was used as induction therapy in combination with dexamethasone (IFM-2005-01 study) and with dexamethasone-thalidomide (MMY-3010 study) (see Table 9).
Incidence of peripheral neuropathy (PN) during induction therapy by toxicity grade and need for treatment interruption due to PN
Table 9
| Peripheral neuropathy indicators |
IFM-2005-01 |
MMY-3010 |
||
| VDDx (N=239) |
VcDx (N=239) |
TDx (N=126) |
VcTDx (N=130) |
|
| Incidence of PN (%) |
||||
| All grades PN |
3 |
15 |
12 |
45 |
| ≥ Grade II PN |
1 |
10 |
2 |
31 |
| ≥ Grade III PN |
˂1 |
5 |
0 |
5 |
| Discontinuation due to PN (%) |
˂1 |
2 |
1 |
5 |
VDDx – vincristine, doxorubicin, dexamethasone; VcDx – bortezomib, dexamethasone; TDx – thalidomide, dexamethasone; VcTDx – bortezomib, thalidomide, dexamethasone.
Peripheral neuropathy includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
Mantle cell lymphoma.
The frequency of peripheral neuropathy events observed during the study of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is presented in Table 10.
The frequency of peripheral neuropathy (PN) in the study of bortezomib in patients with mantle cell lymphoma, by severity of toxicity and need for treatment interruption due to PN.
Table 10
| Peripheral neuropathy parameters |
VcR-CAP (N=240) |
R-CHOP (N=242) |
| Incidence of PN (%) |
||
| All grades of PN |
30 |
29 |
| ≥ Grade II PN |
18 |
9 |
| ≥ Grade III PN |
8 |
4 |
| Discontinuation of treatment due to PN (%) |
2 |
<1 |
VcR-CAP – bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP – rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
Peripheral neuropathy includes: peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
Elderly patients with mantle cell lymphoma
In the VcR-CAP treatment group, 42.9% of patients were aged 65–74 years and 10.4% were ≥75 years. Although patients aged 75 years and older tolerated both treatment regimens less well, the rate of serious adverse reactions was 68% in the VcR-CAP group compared to 48% in the R-CHOP group.
Known differences in the safety profile of bortezomib when administered intravenously versus subcutaneously
In a Phase III study, in patients who received subcutaneous bortezomib, the incidence of treatment-emergent adverse reactions of Grade III toxicity or higher was 13% lower compared to patients who received intravenous bortezomib, and the rate of bortezomib treatment discontinuation was also 5% lower. The overall incidence of diarrhea, lower abdominal pain, abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathies was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of peripheral neuropathies of Grade III or higher was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower.
Injection site reactions occurred in 6% of patients, predominantly erythema. Symptoms resolved on average within 6 days, and dose modification was required in 2 patients. Two patients (1%) experienced serious reactions: 1 case of pruritus and 1 case of erythema.
The rate of fatal events during treatment was 5% in the subcutaneous group and 7% in the intravenous group. The rate of mortality due to disease progression was 18% in the subcutaneous group and 9% in the intravenous group.
Re-treatment of patients with relapsed multiple myeloma
In a study evaluating bortezomib as re-treatment involving 130 patients with relapsed multiple myeloma who had previously shown at least a partial response to bortezomib-containing therapy, adverse reactions of all grades occurring in at least 25% of patients predominantly included thrombocytopenia (55%), neuropathy (40%), anemia (37%), diarrhea (35%), and constipation (28%). Peripheral neuropathy of all grades and peripheral neuropathy ≥ Grade III were observed in 40% and 8.5% of patients, respectively.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging in a place protected from light at a temperature not exceeding 25 °C. Keep out of reach of children.
The reconstituted solution maintains physicochemical stability for 8 hours at 25 °C when stored in the original vial and/or syringe. From a microbiological standpoint, the product should be used immediately unless reconstitution was performed under aseptic conditions. If not used immediately, the responsibility for storage duration and conditions lies with the user.
Incompatibilities. Data not available.
Packaging.
1 vial of lyophilisate in a cardboard box.
Prescription status.
By prescription only.
Manufacturer.
RELIANCE LIFE SCIENCES PRIVATE LIMITED
RELIANCE LIFE SCIENCES PRIVATE LIMITED
Manufacturer's address and place of business.
PLANT 6, R-282, TTC AREA MIDC, DHIRUBHAI AMBANI LIFE SCIENCES CENTRE, THANE BELAPUR ROAD, NAVI MUMBAI, MAHARASHTRA 400701, INDIA
PLANT 6, R-282, TTC AREA OF MIDC, DHIRUBHAI AMBANI LIFE SCIENCES CENTRE, THANE BELAPUR ROAD, NAVI MUMBAI, MAHARASHTRA 400701, INDIA
Marketing authorization holder.
M.BIOTECH LimiteD
M.BIOTECH LimiteD
Address of the marketing authorization holder.
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom