INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLOFTRINID

Composition:

Active substance: bortezomib;

1 vial contains 1 mg of bortezomib (in the form of mannitol boronic ester);

after reconstitution, 1 ml of solution for intravenous injection contains 1 mg of bortezomib;

Excipient: mannitol (E 421).

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: mass or powder of white or almost white color.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Proteasome inhibitors. Bortezomib.

ATC code: L01XG01.

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 regulatory 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 a large number of tested receptors and proteases and is more than 1500-fold more selective for the proteasome than for other enzymes. The kinetics of proteasome inhibition were determined in vitro; bortezomib dissociated from the proteasome with a half-life (t1/2) of 20 minutes, indicating 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 transcription factor NF-kB. Inhibition of the proteasome 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 multiple myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.

Studies 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 various 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 bone 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 above 50 mL/min, the mean maximum plasma concentration (Cmax) of the first dose of bortezomib was 57 ng/mL and 112 ng/mL, respectively. With subsequent administrations, the mean maximum plasma concentration of bortezomib ranged from 67 ng/mL to 106 ng/mL for the 1.0 mg/m² dose and from 89 ng/mL to 120 ng/mL for the 1.3 mg/m² dose.

After intravenous bolus or subcutaneous administration of 1.3 mg/m² 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. The maximum concentration (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, with a 90% confidence interval of 80.18–122.80%.

Distribution. The mean volume of distribution (Vd) of bortezomib ranges from 1659 to 3294 liters following single or multiple doses of 1.0 mg/m² or 1.3 mg/m² in patients with multiple myeloma, indicating extensive distribution into peripheral tissues. Plasma protein binding of bortezomib at concentrations of 0.01–1.0 µg/mL is 82.9%. The fraction of bortezomib bound to plasma proteins is independent of concentration.

Metabolism. In vitro studies using human liver microsomes and expressed cDNA indicate that bortezomib is primarily metabolized by cytochrome P450 enzymes, including CYP3A4, CYP2C19, and CYP1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated into other metabolites. Bortezomib deboronated metabolites are inactive as inhibitors of the 26S proteasome.

Elimination. The mean t1/2 of bortezomib after multiple administrations ranges from 40 to 193 hours. Bortezomib is cleared more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 L/h and 112 L/h after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 L/h to 32 L/h and from 18 L/h 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 61 patients, primarily with solid tumors and varying degrees of hepatic dysfunction; bortezomib doses ranged from 0.5 mg/m² 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 and severe hepatic impairment. Dose adjustment and careful monitoring are recommended for these patients.

Renal impairment. Pharmacokinetic studies were conducted in patients with varying degrees of renal function, categorized by creatinine clearance (CrCL) as follows: patients with normal renal function (CrCL ≥60 mL/min/1.73 m², n=12), mild renal impairment (CrCL = 40–59 mL/min/1.73 m², n=10), moderate renal impairment (CrCL = 20–39 mL/min/1.73 m², n=9), and severe renal impairment (CrCL <20 mL/min/1.73 m², n=3). Patients undergoing dialysis who received the drug dose after dialysis were also included in the study (n=8). Patients received intravenous bortezomib 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 evaluated in 104 pediatric patients (aged 2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia, who received bortezomib 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 t1/2 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 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, to boron, or to any excipient of the medicinal product. Acute diffuse infiltrative lung and pericardial diseases.

When bortezomib is used in combination with other medicinal products, refer to the instructions for medical use of these products for additional contraindications.

Special safety precautions.

General warnings. Gloftrenid – a cytotoxic agent; therefore, caution should be exercised during its reconstitution and administration. Gloves and protective clothing are recommended to prevent skin contact.

Appropriate aseptic techniques must be strictly followed when handling bortezomib, as the product contains no preservatives.

Fatal outcomes have been reported following accidental intrathecal administration of bortezomib. The medicinal product Gloftrenid must be administered only intravenously or subcutaneously.

DO NOT ADMINISTER GLOFTRENID INTRATHECALLY.

Proper disposal procedure. For single use only. Any unused medicinal product or waste material should 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, altered overall exposure to the drug is not expected in poor metabolizers of this enzyme.

Drug interaction studies evaluating the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of intravenous bortezomib 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 is recommended in patients receiving bortezomib concomitantly with potent CYP3A4 inhibitors (such as ketoconazole, ritonavir).

Studies evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of intravenous bortezomib showed no significant effect on bortezomib pharmacokinetics in 17 patients included in the study.

Studies involving 6 patients evaluating the effect of rifampicin, a potent CYP3A4 inducer, revealed an average reduction in intravenous bortezomib AUC 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 it may reduce the efficacy of bortezomib.

In the same study, dexamethasone, a weaker CYP3A4 inducer, did not significantly alter bortezomib pharmacokinetics based on data from 7 patients.

Drug interaction studies evaluating the effects of melphalan and prednisone on the pharmacokinetics of intravenous bortezomib in 21 patients demonstrated an average increase in bortezomib AUC by 17%. This increase in bortezomib AUC is not considered clinically significant.

During clinical trials, cases of hypo- and hyperglycemia were reported in diabetic patients receiving oral hypoglycemic agents. Patients receiving oral antidiabetic medications should monitor blood glucose levels closely and adjust antidiabetic drug doses accordingly during bortezomib treatment.

Special precautions for use.

If bortezomib is used in combination with other medicinal products, refer to the instructions for medical use of these medicinal products prior to initiating treatment. If thalidomide is used, special attention must be paid to pregnancy diagnosis and contraceptive measures.

Intrathecal administration. Fatal outcomes have been reported due to accidental intrathecal administration of bortezomib. Bortezomib must be administered only intravenously or subcutaneously. INTRATHECAL ADMINISTRATION OF BORTEZOMIB IS CONTRAINDICATED.

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 commonly observed during bortezomib treatment. 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 patients with mantle cell lymphoma, reversible thrombocytopenia was one of the most common hematological toxicities. 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 value in trials of bortezomib monotherapy in patients with multiple myeloma and 50% in trials of bortezomib in patients with mantle cell lymphoma. In patients with progressive myeloma, the severity of thrombocytopenia correlated with pre-treatment platelet count: 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 ≥ III thrombocytopenia occurred more frequently in the bortezomib group (VcR-CAP) than in patients receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall incidence of bleeding events of all grades, as well as bleeding events of at least grade III severity, 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 hemorrhage associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of bortezomib. Bortezomib therapy 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 bortezomib treatment should be carefully evaluated, especially in cases of moderate or severe thrombocytopenia and risk factors for bleeding.

Complete blood counts with differential and platelet counts should be frequently monitored during bortezomib therapy. Platelet transfusion should be considered if clinically indicated.

In patients with mantle cell lymphoma, reversible neutropenia between treatment cycles has been observed; cumulative neutropenia was not observed. White blood cell counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline before the start of the next cycle. In a clinical trial of bortezomib in patients with mantle cell lymphoma, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received granulocyte 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 should be taken. The use of granulocyte colony-stimulating factor should be considered for managing hematological toxicity. If initiation of a new treatment cycle is delayed multiple times, prophylactic use of granulocyte colony-stimulating factor should be considered.

Herpes zoster reactivation. Antiviral prophylaxis should be considered for patients receiving bortezomib. In phase III clinical trials involving patients with previously untreated multiple myeloma, the overall incidence 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 incidence 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 bortezomib, HBV testing 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 bortezomib. Antiviral prophylaxis should be considered.

Progressive multifocal leukoencephalopathy (PML). Very rare cases of John Cunningham (JC) virus infection leading to PML with fatal outcomes have been reported in patients treated with bortezomib. Patients diagnosed with PML had a history of or were concurrently receiving immunosuppressive therapy with bortezomib. Most PML cases were diagnosed within the first 12 months after initiating 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 should be taken. Bortezomib 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 fifth 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 incidence of grade II peripheral neuropathy was 24% in the subcutaneous group and 41% in the intravenous group. Grade III 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 a neurological examination; dose adjustment, change in administration schedule, 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 recommended for patients receiving bortezomib in combination with neurotoxic agents (e.g., thalidomide); dose reduction or discontinuation of bortezomib should be considered.

In addition to peripheral neuropathy, autonomic neuropathy may contribute to certain adverse reactions such as postural hypotension and acute constipation with intestinal obstruction. Information on autonomic neuropathy and its impact on these adverse reactions is limited.

Seizures. Rare cases of seizure development 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 to moderate in severity and occurs throughout treatment. Most patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension prior to treatment. Most patients required treatment for orthostatic hypotension, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly associated with bolus infusion of bortezomib; the mechanism of its development is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be induced by bortezomib or may be exacerbated by 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 cases 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 consult a physician if they experience dizziness, presyncope, or syncope.

Reversible posterior leukoencephalopathy syndrome (PRES). Cases of PRES have been reported in patients receiving bortezomib. PRES is a rare reversible neurological disorder characterized by seizures, hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Diagnosis is confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Bortezomib treatment should be discontinued if PRES occurs.

Heart failure. Cases of new-onset or worsening congestive heart failure and/or reduced left ventricular ejection fraction have been reported with bortezomib use. Fluid retention may lead to signs and symptoms of heart failure. Patients with risk factors or pre-existing heart disease should be under medical supervision.

ECG monitoring. Isolated cases of QT interval prolongation have been observed in clinical trials, although 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. A baseline chest X-ray is recommended before treatment initiation to assess baseline lung status and for comparison in case of potential treatment-related lung dysfunction.

In case of new or worsening pulmonary symptoms (e.g., cough, dyspnea), prompt diagnosis and appropriate therapeutic interventions should be initiated. The benefit-risk ratio of continuing bortezomib treatment should be carefully evaluated.

In clinical trials, two out of two patients receiving high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS at the beginning of treatment. Therefore, this specific regimen of concomitant high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.

Renal function disorders. Renal impairment is commonly observed in patients with multiple myeloma. Close 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; therefore, these patients should receive reduced doses and be closely monitored for signs of toxicity.

Hepatic reactions. Rare cases of acute liver failure have been reported in patients receiving bortezomib concomitantly with other drugs and in patients with serious comorbidities. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis that 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 at highest risk are those with high tumor burden prior to treatment initiation. Close monitoring of such patients and appropriate preventive measures are recommended.

Warnings regarding concomitant use of other medicinal products. Patients should be closely monitored when bortezomib is combined with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.

Prior to initiating treatment with Gloftrinid, hepatic function should be corrected in case of impairment, and caution should be exercised when treating patients receiving 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 if serious reactions occur.

Use during pregnancy or breastfeeding.

Contraception in women and men

Due to the genotoxic potential of bortezomib, women of reproductive potential must use effective contraception and avoid pregnancy during bortezomib treatment and for 8 months after treatment completion. Male patients must use effective contraception and should be advised not to father a child during bortezomib treatment and for 5 months after treatment completion.

Pregnancy

There are no clinical data on the use of bortezomib in pregnant women. The teratogenic potential of bortezomib has not been fully investigated.

In preclinical studies, bortezomib at the maximum tolerated doses did not affect embryonic development in rats and rabbits during organogenesis. Pre- and postnatal developmental studies in animals have not been conducted. Bortezomib is not recommended during pregnancy except when the patient's clinical condition necessitates bortezomib treatment. If bortezomib is used during pregnancy or if pregnancy occurs during bortezomib treatment, the patient should be informed of the potential risk to the fetus.

Thalidomide is a medicinal product with known human teratogenic effects, causing severe, life-threatening congenital malformations. Thalidomide is contraindicated in pregnant women and women of reproductive potential. Patients receiving bortezomib in combination with thalidomide must comply with pregnancy prevention requirements (for further information, see the thalidomide product information).

Breastfeeding period

It is unknown whether bortezomib is excreted in human milk, but to prevent the occurrence of severe adverse effects in the infant, breastfeeding is not recommended during bortezomib treatment.

Fertility

Studies on the effect of bortezomib on fertility have not been conducted.

Ability to affect reaction speed when driving or operating machinery.

Bortezomib has a moderate effect on reaction speed when driving or operating 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 (see section "Adverse reactions").

Method of Administration and Dosage

Treatment with bortezomib should be initiated under the supervision of a qualified physician experienced in treating cancer patients. However, treatment with bortezomib may also be administered under the supervision of a healthcare professional experienced in the use of antineoplastic agents. Preparation of the solution must be performed only by qualified medical personnel (see section "Special Precautions").

Instructions for Solution Preparation. Solution preparation must be performed only by qualified medical personnel.

For intravenous administration: Before use, the contents of the vial should be carefully reconstituted with 1.0 mL of 0.9% sodium chloride injection solution using a syringe of appropriate size, without removing the stopper from the vial. 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.

Relapsed Multiple Myeloma (patients who have received at least one prior therapy)

Monotherapy

The recommended dose of bortezomib for adults 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 is considered one treatment cycle. Upon achieving a complete clinical response, two additional treatment cycles are recommended. Patients with a partial response but not complete remission should continue bortezomib therapy, but for no more than 8 cycles. At least 72 hours must elapse between consecutive bortezomib doses.

In the event of any grade III non-hematological toxicity or grade IV hematological toxicity (excluding neuropathies), bortezomib treatment must be withheld. After resolution of toxicity symptoms, treatment may be resumed at a dose reduced by 25% (reduce 1.3 mg/m² to 1.0 mg/m²; reduce 1.0 mg/m² to 0.7 mg/m²). If toxicity symptoms do not resolve or recur during treatment with the reduced dose, discontinuation of bortezomib should be considered, unless the benefits of continued treatment outweigh the risks.

Neuropathic Pain and/or Peripheral Neuropathy

In case of development of neuropathic pain and/or peripheral neuropathy, the drug dose should be adjusted (see Table 1). Bortezomib should be administered to patients with a history of severe neuropathy only after careful benefit-risk assessment.

Table 1

Recommended* dose modifications for bortezomib-induced neuropathy

* 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, and using the telephone.

*** Self-care activities include bathing, dressing/undressing, eating, using the toilet, taking medications, and being out of bed.

Combination therapy with pegylated liposomal doxorubicin

The recommended dose of bortezomib in 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 is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.

Pegylated liposomal doxorubicin is administered at a dose of 30 mg/m² on Day 4 of the bortezomib treatment cycle via 1-hour intravenous infusion after bortezomib injection.

Up to 8 cycles of this combination therapy should be administered, provided the disease does not progress and the patient tolerates treatment well. Patients who achieve a complete response may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires administration of more than 8 cycles. Patients in whom paraprotein levels continue to decline after 8 cycles may also continue treatment as long as treatment remains well tolerated 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 is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.

Dexamethasone is administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the bortezomib 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 this medicinal product.

Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma

See dose modification recommendations for bortezomib monotherapy described above.

Previously untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation

Combination therapy with melphalan and prednisone

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, bortezomib is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29, and 32). In Cycles 5–9, bortezomib is administered once weekly (Days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of bortezomib.

Melphalan and prednisone are administered orally on Days 1, 2, 3, and 4 of the first week of each cycle.

Table 2

Recommended dosing regimen of bortezomib in combination with melphalan and prednisone

M − melphalan, P − prednisone.

Dosing adjustment and re-establishment recommendations for combination therapy with melphalan and prednisone

Prior to starting a new treatment cycle:

platelet count is ≥ 70×10⁹/L and absolute neutrophil count is ≥ 1.0×10⁹/L; non-hematological toxicity has returned to Grade 1 or baseline levels.

Table 3

Dose adjustment during subsequent cycles of bortezomib in combination with melphalan and prednisone therapy

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 must elapse between consecutive doses of bortezomib.

Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.

Administer 4 cycles of treatment 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 must elapse between consecutive doses of bortezomib.

Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib 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).

A total of 4 treatment cycles are recommended. Patients achieving at least a partial response to treatment are recommended to receive 2 additional cycles of therapy.

Table 4

Recommended dosing regimen of bortezomib in combination with dexamethasone and thalidomide for patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation

B = bortezomib, Dx = dexamethasone, T = thalidomide.

a – Increase the dose of thalidomide to 100 mg starting 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 modification guidelines for bortezomib when used as monotherapy.

If bortezomib is used in combination with other chemotherapeutic agents, refer to the respective product information for dose adjustments of 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 (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 bortezomib. A total of 6 treatment cycles are recommended. Patients who first demonstrate a response to treatment during the 6th cycle should receive 2 additional treatment cycles.

Medications administered via intravenous infusion on day 1 of each 3-week bortezomib treatment cycle: rituximab at a dose of 375 mg/m², cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m².

Prednisone is administered orally at a dose of 100 mg/m² on days 1, 2, 3, 4, and 5 of each bortezomib treatment cycle.

Dose modification recommendations for patients with untreated mantle cell lymphoma

Prior to initiating a new treatment cycle:

• Platelet count ≥ 100,000 cells/µL and absolute neutrophil count ≥ 1,500 cells/µL;
• Platelet count ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration;
• Hemoglobin level ≥ 8 g/dL;
• Non-hematological toxicity has resolved to grade 1 or baseline levels.

Treatment with bortezomib should be withheld in case of any bortezomib-related non-hematological toxicity ≥ grade III (except neuropathy) or hematological toxicity ≥ grade III. Refer to Table 5 for dose modification recommendations.

Granulocyte colony-stimulating factors (G-CSF) may be used to manage hematological toxicity. If initiation of a new treatment cycle has been delayed multiple times, consider prophylactic use of granulocyte colony-stimulating factor. Platelet transfusion should be considered as necessary for the management of thrombocytopenia.

Table 5

Dose adjustment during therapy for patients with untreated mantle cell lymphoma

If bortezomib is used in combination with other chemotherapeutic agents, refer to the prescribing information for those medicinal products regarding dose adjustment recommendations in the event of toxicity.

Special patient groups

Elderly patients

To date, 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 bortezomib in elderly patients with previously untreated multiple myeloma who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation. Therefore, no dose adjustment recommendations can be given for this patient group.

In a study of bortezomib use in patients with previously 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 bortezomib 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 tolerance.

Table 6

Recommendations for adjustment of initial bortezomib doses in patients with hepatic impairment

AST – aspartate aminotransferase; ULN – upper limit of normal.

*Based on the National Cancer Institute Organ Dysfunction Working Group classification of liver function impairment severity (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

Gloftrinid 1 mg, powder for solution for injection, is intended for intravenous use only.

Gloftrinid 3.5 mg, powder for solution for injection, is intended for intravenous or subcutaneous administration.

Gloftrinid must not be administered by any other route. Accidental intrathecal administration of the drug has resulted in fatal outcomes.

Intravenous injection

Gloftrinid 1 mg powder for solution for injection is intended for intravenous use only. The reconstituted solution should be administered as a 3- to 5-second intravenous bolus injection through a peripheral or central venous catheter immediately after preparation. After injection, the catheter must be flushed with 0.9% sodium chloride solution for injection. At least 72 hours must elapse between consecutive doses of Gloftrinid.

Children

The safety and efficacy of bortezomib in pediatric patients (under 18 years of age) have not been established. Current data are insufficient to provide dosage recommendations for pediatric use.

Overdose

Overdoses exceeding the recommended dose by more than two-fold have been associated with acute hypotension and thrombocytopenia resulting in death.

There is no known specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressors and/or inotropic agents) and body temperature is recommended.

Adverse Reactions

Severe adverse reactions reported during bortezomib treatment include rare cases of cardiac arrest, tumor lysis syndrome, pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders, and rarely, autonomic neuropathy. The most commonly observed adverse reactions during bortezomib therapy are nausea, diarrhea, constipation, vomiting, asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.

Multiple Myeloma

The adverse reactions listed in Table 7 are considered possibly related to bortezomib administration. 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 administered to 3974 patients for the treatment of multiple myeloma.

Adverse reactions are categorized by system organ class 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 (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity. Also included are adverse reactions not observed during clinical trials but reported in the post-marketing period.

Table 7

Adverse reactions in patients with multiple myeloma treated with bortezomib in clinical trials, and all adverse reactions reported in the post-marketing period regardless of indication.

* 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 of bortezomib in 240 patients with mantle cell lymphoma who received bortezomib 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-CAP), and in 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 of these events in both treatment groups suggests that these adverse reactions may not be 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 treatment in patients with multiple myeloma.

Adverse reactions occurring at a frequency ≥1% and with similar or higher frequency 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 listed 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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity.

Table 8

Adverse reactions in patients with mantle cell lymphoma who received BR-CAP in a clinical trial

*Grouping of more than one MedDRA term.

Description of selected adverse reactions

Herpes zoster reactivation

Multiple myeloma

Antiviral prophylaxis was administered in 26% of patients receiving bortezomib in combination with melphalan and prednisone. The incidence of herpes zoster in this group was 17% among patients who did not receive antiviral agents, compared to 3% among those who received antiviral agents.

Mantle cell lymphoma

Antiviral prophylaxis was administered in 57% of patients receiving bortezomib as part of combination therapy with the BcR-CAP regimen. Herpes zoster occurred 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 treatment with the 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 the BcR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B was similar in both treatment groups (0.8% in the BcR-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 (study IFM-2005-01) and with dexamethasone and thalidomide (study MMY-3010) (see Table 9).

Table 9

Incidence of peripheral neuropathy (PN) during induction therapy by toxicity grade and need for treatment interruption due to PN

VDDx = vincristine, doxorubicin, dexamethasone; BDx = bortezomib, dexamethasone; TDx = thalidomide, dexamethasone;

BTDx = bortezomib, thalidomide, dexamethasone.

Peripheral neuropathy includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.

Table 10

Frequency of peripheral neuropathy (PN) events in the bortezomib study in patients with mantle cell lymphoma, by toxicity grade and need for treatment interruption due to PN

BR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisolone; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; PN = peripheral neuropathy.

Peripheral neuropathy includes peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.

Elderly patients with mantle cell lymphoma

In the BR-CAP treatment group, 42.9% of patients were aged 65–74 years and 10.4% were aged ≥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 BR-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, patients receiving subcutaneous bortezomib had a 13% lower incidence of treatment-related adverse reactions of Grade III toxicity or higher, and a 5% lower rate of treatment interruption with bortezomib, compared to patients receiving intravenous bortezomib. The overall incidence of diarrhea, lower abdominal pain, abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathy was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of Grade III or higher peripheral neuropathy 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.

Serious reactions occurred in 2 patients (1%): 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 mortality rate 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 of bortezomib re-treatment involving 130 patients with relapsed multiple myeloma who had previously achieved at least a partial response to a bortezomib-containing regimen, adverse reactions of all grades occurring in at least 25% of patients included primarily 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.

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: http://aisf.dec.gov.ua/.

Shelf life.

Unopened vial

3 years.

Reconstituted solution

Chemical and physical in-use stability has been demonstrated for 8 hours at 25°C/60% humidity in the dark, both in the vial and in a polypropylene syringe.

From a microbiological standpoint, if the reconstitution/dilution method does not exclude the risk of microbial contamination, the medicinal product should be used immediately. If not used immediately, the storage time and conditions prior to use are the responsibility of the user.

Storage conditions.

The vial should be stored in the outer cardboard package to protect from light. This medicinal product does not require special temperature conditions for storage.

For information on storage conditions after dilution of the medicinal product, see section "Shelf life."

Keep out of the reach of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in section "Method of administration and dosage" ("Instructions for preparation of solution").

Packaging.

1 mg of powder for solution for injection in a glass vial with a rubber stopper and a flip-off cap.

Each cardboard box contains one single-use vial.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and location of operations.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.