Herzuma®

INSTRUCTIONS for medical use of the medicinal product Herzuma®

Composition:

Active substance: trastuzumab;

1 vial of lyophilisate contains: 150 mg trastuzumab;

Excipients: L-histidine hydrochloride, L-histidine, α,α-trehalose dihydrate, polysorbate 20.

Pharmaceutical form. Lyophilisate for concentrate for solution for infusion.

Main physicochemical properties: lyophilized powder from white to pale yellow in color. Reconstituted solution – clear or slightly opalescent liquid, colorless or light yellow.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Monoclonal antibodies and antibody-drug conjugates. HER2 (human epidermal growth factor receptor 2) inhibitors. Trastuzumab.

ATC code L01FD01.

Pharmacological properties.

Pharmacodynamics.

Trastuzumab is a recombinant humanized monoclonal antibody of the IgG1 class, produced in Chinese hamster ovary cells, containing murine hypervariable regions of the variable portion. The antibody specifically binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER2).

The proto-oncogene HER2 (also known as neu or c-erbB2) encodes a transmembrane receptor-like single-chain protein with a molecular weight of 185 kDa, structurally related to the epidermal growth factor receptor. HER2 overexpression is observed in 15–20% of cases of primary breast cancer. The overall frequency of HER2-positive metastatic gastric cancer observed during screening for study BO18255 was 15% based on positive IHC3+ or IHC2+/FISH+ test results, or 22.1% when using a broader definition according to which either IHC3+ or FISH+ results are sufficient to define HER2-positive status. Amplification of the HER2 gene leads to increased expression of the HER2 protein on the surface of these tumor cells, resulting in strong activation of the HER2 receptor.

Studies in patients with breast cancer have shown that patients whose tumors overexpress HER2 have shorter disease-free survival compared to patients without tumor overexpression of HER2.

Animal studies and in vitro experiments have demonstrated that trastuzumab inhibits the proliferation of human tumor cells overexpressing HER2. Trastuzumab mediates antibody-dependent cellular cytotoxicity. In vitro, trastuzumab-induced antibody-dependent cellular cytotoxicity is primarily directed against tumor cells overexpressing HER2.

Determination of HER2 overexpression or HER2 gene amplification in breast cancer

Trastuzumab should be used only for the treatment of patients with confirmed HER2 overexpression or HER2 gene amplification. HER2 overexpression must be diagnosed by evaluation of fixed tumor specimens using immunohistochemistry (IHC) (see section "Dosage and administration"). HER2 gene amplification is determined by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) on fixed tumor tissue sections. Indications for prescribing trastuzumab include strong HER2 overexpression with an IHC score of 3+ or a positive FISH or CISH result.

To achieve accurate test results, testing should be performed in specialized laboratories capable of ensuring the validity of the testing procedure.

The following system is recommended for assessment of HER2 overexpression by IHC:

Overall, the FISH test is considered positive if the ratio of the number of HER2 gene copies in the tumor cell to the number of copies of chromosome 17 is greater than or equal to 2, or if more than 4 copies of the HER2 gene are present in the tumor cell when chromosome 17 testing is not performed. Overall, the CISH test result is considered positive if more than 5 copies of the HER2 gene are present in the nucleus in more than 50% of tumor cells.

For complete information on performing the analysis and evaluating its results, refer to the instructions for use of the approved FISH and CISH methodologies.

Definition of HER2 overexpression or HER2 gene amplification in metastatic gastric cancer or gastroesophageal junction cancer.

Only reliable and validated methodologies should be used to determine HER2 overexpression or HER2 gene amplification. Immunohistochemistry (IHC) is recommended as the initial testing method. In cases requiring additional determination of HER2 gene amplification status, silver-enhanced in situ hybridization (SISH) or FISH technology should be used. To achieve accurate test results, testing should be performed in specialized laboratories capable of ensuring test procedure validation. For complete information on performing the analysis and evaluating its results, refer to the instructions for use of the approved FISH and CISH methodologies.

Patients included in the ToGA trial had an HER2-positive status defined as IHC 3+ or FISH-positive. Clinical trial results showed a positive treatment effect only in patients with the highest level of HER2 protein overexpression, defined as IHC 3+ or IHC 2+ with a positive FISH result.

In a comparative methodology study (study D008548), a high level of concordance (95%) was observed between SISH and FISH methods in determining HER2 gene amplification in patients with gastric cancer.

Trastuzumab should only be administered to patients with pronounced HER2 overexpression, i.e., IHC 3+ or IHC 2+ with a positive FISH or SISH result.

HER2 gene amplification must be determined by in situ hybridization methods, such as FISH or SISH, using fixed tumor tissue blocks.

Recommended scoring system for evaluating HER2 overexpression by IHC:

Overall, the results of FISH or SISH assays are considered positive if the ratio of the number of HER2 gene copies in tumor cells to the number of chromosome 17 copies is greater than or equal to 2.

HER2 expression is primarily observed in the intestinal histological subtype. In contrast to breast cancer, immunohistochemical staining methods are generally ineffective in gastric cancer.

HER2 may be detected as a free molecule in plasma (shedding). However, the level of HER2 expression in blood plasma does not correlate with the clinical course of the disease. There are no available data on the shedding process in gastric cancer.

Pharmacokinetics.

The pharmacokinetics of trastuzumab were evaluated through a population pharmacokinetic analysis of pooled data from 1582 patients with HER2-positive metastatic breast cancer, early-stage breast cancer, metastatic gastric cancer, or other tumor types, as well as healthy volunteers who received trastuzumab intravenously (across 18 Phase I, II, and III studies). The concentration-time profile of trastuzumab was characterized by a two-compartment model with parallel linear and nonlinear elimination from the central compartment. Due to the nonlinear elimination, total clearance increases as concentration decreases.

Linear clearance was 0.136 L/day in breast cancer patients. The maximum elimination rate (Vmax) for nonlinear elimination was 8.81 mg/day, and the Michaelis-Menten constant (Km) was 8.92 mg/L. The volume of the central compartment was 2.62 L in patients with breast cancer and 3.63 L in patients with metastatic gastric cancer.

Tables 1 and 2 present population-predicted pharmacokinetic (PK) exposure (with 5th to 95th percentiles) and PK parameter values at clinically relevant drug concentrations (C_max and C_min) in patients with breast cancer and metastatic gastric cancer receiving treatment according to approved regimens administered once weekly and once every three weeks.

Table 1

Population-predicted PK values in Cycle 1 (median with 5–95th percentiles) for intravenous treatment regimens in patients with breast cancer and metastatic gastric cancer

Table 2

Predicted population pharmacokinetic exposure values at steady state (with median 5–95 percentiles) for intravenous trastuzumab dosing regimens in patients with breast cancer, early-stage breast cancer, and metastatic gastric cancer

• Cmin,ss = Cmin at steady state

** Cmax,ss = Cmax at steady state

*** time to reach 90% of steady state

Predicted population pharmacokinetic parameters at steady state for intravenous trastuzumab regimens in patients with metastatic breast cancer, early-stage breast cancer, and metastatic gastric cancer

Elimination of trastuzumab

The elimination of trastuzumab from the body was evaluated after intravenous administration on a weekly schedule or once every 3 weeks using appropriate population pharmacokinetic models. Results of these studies demonstrate that in at least 95% of patients, serum concentrations of the drug were < 1 mcg/mL 7 months after the last dose (approximately 3% of the population-predicted C_min,ss, or approximately 97% elimination).

Circulating extracellular domain of the HER2 receptor

Covariate analysis of data obtained only in a subgroup of patients showed that individuals with higher levels of circulating extracellular domain of the HER2 receptor had a faster nonlinear clearance (lower than Km) (p < 0.001). A correlation was observed between the shed antigen and aspartate aminotransferase (AST) levels; part of the shed antigen's effect on clearance may be related to AST levels.

Baseline levels of circulating extracellular domain of the HER2 receptor observed in patients with metastatic gastric cancer were comparable to those in patients with metastatic breast cancer and early-stage breast cancer, and no significant effect on trastuzumab clearance was observed.

Clinical characteristics.

Indications.

Breast cancer

Before initiating treatment with the medicinal product Herzuma®, it is necessary to confirm the presence of HER2 overexpression in tumor tissue in patients – either by immunohistochemical analysis (staining should be scored as 3+) or by molecular biology methods (detection of HER2 gene amplification by fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]).

Metastatic breast cancer

Herzuma® is indicated for the treatment of metastatic breast cancer with HER2 tumor overexpression:

• as monotherapy in patients who have received one or more chemotherapy regimens for metastatic disease;
• in combination with paclitaxel or docetaxel in patients who have not received chemotherapy for metastatic disease;
• in combination with an aromatase inhibitor in postmenopausal women with hormone receptor-positive breast cancer who have not received chemotherapy for metastatic disease.

There are no available data on patients who have previously received adjuvant treatment for early-stage breast cancer with Herzuma®.

HER2-overexpressing breast cancer (early stages):

Herzuma® is indicated for the treatment of patients with HER2-positive early-stage breast cancer:

• following surgery, chemotherapy (neoadjuvant or adjuvant), and (if applicable) radiotherapy;
• following adjuvant chemotherapy with doxorubicin and cyclophosphamide in combination with paclitaxel or docetaxel;
• in combination with adjuvant chemotherapy with docetaxel and carboplatin;
• in combination with neoadjuvant chemotherapy, followed by continued use of Herzuma® as adjuvant therapy, for the treatment of locally advanced (including inflammatory) breast cancer or tumors with a diameter > 2 cm.

Metastatic gastric cancer or gastroesophageal junction cancer

Herzuma® in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who have not previously received chemotherapy for metastatic disease. Herzuma® should be administered only to patients with metastatic gastric cancer exhibiting HER2 tumor overexpression, defined as either IHC 2+ expression confirmed by positive FISH or silver in situ hybridization (SISH) testing, or IHC 3+ expression. Validated and accurate testing methods must be used.

Contraindications.

Herzuma® is contraindicated in patients with hypersensitivity to trastuzumab, proteins from Chinese hamster ovary (CHO) cells, or any other component of the medicinal product.

Concomitant use of Herzuma® and anthracyclines is not recommended in the treatment of metastatic breast cancer or in adjuvant therapy. In neoadjuvant treatment regimens, concomitant administration of Herzuma® and anthracyclines should be performed with caution and only in patients who have not previously received chemotherapy.

Herzuma® is contraindicated in patients with dyspnea at rest due to lung metastases or concomitant diseases.

Special safety precautions.

To improve traceability of biological medicinal products, the trade name Herzuma® should be clearly documented in the patient’s medical record. Substitution with another medicinal product requires the prescriber’s approval. The information in this instruction for medical use applies exclusively to Herzuma®.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic/pharmacodynamic interactions

Specific studies on interactions between Herzuma® and other medicinal products in humans have not been conducted. No clinically significant interactions with medicinal products used concomitantly in clinical practice have been observed.

In studies where Herzuma® was administered at therapeutic doses in combination with docetaxel, carboplatin, or anastrozole, no changes in the pharmacokinetics of these agents or trastuzumab were observed.

Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents

Pharmacokinetic data from clinical studies (BO15935 and M77004) involving female patients with HER2-positive metastatic breast cancer (hereinafter – MBC) demonstrated that the pharmacokinetics of paclitaxel and doxorubicin (and their main metabolites 6-a-hydroxyl-paclitaxel [POH], doxorubicinol, and DOL) were not altered in the presence of trastuzumab (at an initial loading dose of 8 mg/kg or 4 mg/kg intravenously, followed by 6 mg/kg every 3 weeks or 2 mg/kg weekly, respectively). However, trastuzumab may increase the overall exposure to one of the metabolites of doxorubicin (7-deoxy-13-dihydro-doxorubicinone, D7D). The biological activity of D7D and the clinical significance of its increased levels are unknown. No changes in trastuzumab concentrations were observed in the presence of paclitaxel and doxorubicin.

Data from the non-comparative study JP16003, evaluating the effect of trastuzumab (loading dose 4 mg/kg intravenously, followed by 2 mg/kg weekly intravenously) and docetaxel (60 mg/m² intravenously) in Japanese women with HER2-positive MBC, indicated that concomitant administration of trastuzumab did not affect the pharmacokinetics of a single dose of docetaxel. Study JP19959 was a substudy within study BO18255 (ToGA), conducted in male and female Japanese patients with advanced gastric cancer, to evaluate the pharmacokinetics of capecitabine and cisplatin when administered with or without trastuzumab. Results from this interaction substudy showed that exposure to biologically active metabolites (e.g., 5-FU) of capecitabine was not altered when capecitabine was administered concomitantly with cisplatin or with cisplatin and trastuzumab. However, higher concentrations and a prolonged elimination half-life of capecitabine were observed when administered in combination with trastuzumab. The pharmacokinetics of cisplatin were not altered by concomitant administration of capecitabine or capecitabine with trastuzumab.

Effect of other antineoplastic agents on the pharmacokinetics of trastuzumab

Comparison of modeling of trastuzumab serum concentrations after monotherapy with trastuzumab (loading dose 4 mg/kg followed by 2 mg/kg weekly intravenously) and serum concentrations observed in Japanese women with HER2-positive MBC (study JP16003) revealed no evidence of an effect of concomitant docetaxel administration on trastuzumab pharmacokinetics.

Comparison of pharmacokinetic results from two Phase II studies (BO15935 and M77044) and one Phase III study (H0648g), in which patients received trastuzumab and paclitaxel concomitantly, and two Phase II studies in which trastuzumab was administered as monotherapy (WO16229 and MO16982), in women with HER2-positive MBC, indicated that individual and mean serum concentrations of trastuzumab varied within and between studies, but there was no clear evidence of a significant effect of concomitant paclitaxel administration on trastuzumab pharmacokinetics.

No evidence of an effect of concomitant docetaxel on trastuzumab pharmacokinetics was found in a comparative analysis of plasma concentration modeling of trastuzumab after its administration (as monotherapy, weekly intravenous loading dose) and plasma trastuzumab concentrations in HER2-positive female patients with MBC from Japan (study JP16003). Pharmacokinetic results were compared in Phase 2 clinical trials involving HER2-positive female patients with MBC and in a Phase 3 clinical trial with concomitant administration of trastuzumab and paclitaxel. Mean trough concentrations of trastuzumab varied within and between trials, but the impact of concomitant paclitaxel administration on trastuzumab pharmacokinetics was not clearly defined. Concomitant administration of anastrozole with trastuzumab did not affect the pharmacokinetics of trastuzumab.

Special precautions for use

Sterile water for injection used to reconstitute the solution in single-use vials of 150 mg does not contain benzyl alcohol.

Infusion reactions

Serious infusion-related adverse reactions, including dyspnea, arterial hypotension, nausea, fever, bronchospasm, tachycardia, decreased oxygen saturation, urticaria, and rash, have been rarely observed in patients during administration of HerzuMA®. These events may represent infusion-related reactions (IRRs) and may have a delayed onset. Most of these events occurred during or within 2.5 hours after the start of the first infusion. In case of infusion-related reactions (IRRs), the infusion should be interrupted or the infusion rate reduced, and the patient's condition should be monitored until all observed symptoms resolve.

To reduce the risk of infusion reactions, premedication may be administered. Patients should be closely monitored and advised to immediately report any symptoms. If such reactions occur, the HerzuMA® infusion should be stopped and the patient observed until symptoms resolve. Symptomatic treatment may include analgesic/antipyretic agents such as meperidine or paracetamol, or antihistamines such as diphenhydramine. In most patients, symptoms resolved, and subsequent trastuzumab infusions were administered.

Severe reactions have been successfully managed with supportive therapy, such as oxygen, beta-blockers, and corticosteroids (see section "Adverse reactions"). Rarely, such reactions have been associated with potentially life-threatening clinical outcomes. The risk of fatal infusion reactions is increased in patients with baseline dyspnea due to lung metastases or concomitant diseases; therefore, HerzuMA® is contraindicated in such patients (see section "Contraindications").

There have also been reports of initial improvement followed by clinical deterioration and delayed reactions with rapid clinical worsening. Fatal cases have occurred within several hours to one week after infusion. In very rare cases, patients developed infusion-related symptoms and pulmonary symptoms more than 6 hours after the start of trastuzumab infusion. Patients should be informed about the possibility of such delayed onset of symptoms and advised to seek medical attention if such symptoms occur.

Cardiotoxicity

General considerations

Patients receiving trastuzumab therapy have an increased risk of developing congestive heart failure (NYHA functional classes II–IV) or asymptomatic left ventricular dysfunction. This has been observed during monotherapy with trastuzumab or combination therapy with taxanes following anthracycline-based therapy (doxorubicin or epirubicin). The severity of heart failure may range from mild to severe and may result in death (see section "Adverse reactions"). Caution should be exercised when treating patients with increased cardiac risk (e.g., patients with hypertension, ischemic heart disease, congestive heart failure, diastolic dysfunction, or elderly patients).

Concomitant use of trastuzumab and anthracyclines is not recommended in patients with metastatic breast cancer or in the adjuvant treatment setting. In the neoadjuvant setting, concomitant administration of trastuzumab and anthracyclines should be performed with caution and only in patients who have not previously received chemotherapy (see section "Contraindications"). The maximum cumulative dose in low-dose anthracycline regimens should not exceed 180 mg/m² (doxorubicin) or 360 mg/m² (epirubicin). If patients have received concurrent low-dose anthracyclines and trastuzumab in the neoadjuvant setting, additional cytotoxic therapy should not be administered in the postoperative period. Clinical experience with neoadjuvant/adjuvant regimens in patients aged 65 years and older is limited.

Most cardiac adverse effects manifested within the first 18 months, regardless of the treatment regimen. Overall, their incidence did not increase after 3 years. In most cases, left ventricular dysfunction improved after discontinuation of trastuzumab therapy and/or initiation of heart failure treatment.

Since the half-life of trastuzumab is approximately 28–38 days, it may circulate in the bloodstream for up to 27 weeks after treatment discontinuation.

The risk of cardiotoxicity is increased in patients receiving anthracyclines after stopping HerzuMA®. If possible, anthracycline-based therapy should be avoided for 7 months after discontinuation of HerzuMA®.

All patients should undergo a thorough cardiac evaluation prior to initiation of HerzuMA® therapy, especially those who previously received anthracyclines. This evaluation should include medical history, physical examination, ECG, echocardiography, and/or radionuclide ventriculography. Monitoring for early detection of cardiac dysfunction should be performed with baseline cardiac assessment, every 3 months during treatment, and every 6 months for 24 months after the last dose of HerzuMA®.

In patients receiving anthracycline-based chemotherapy, continued monitoring is recommended, repeated annually for 5 years after the last dose of HerzuMA® or longer if persistent reduction in left ventricular ejection fraction (LVEF) is observed.

If LVEF decreases by 10 or more percentage points from baseline or falls below 50%, trastuzumab therapy should be interrupted and LVEF reassessed approximately 3 weeks later. If LVEF does not improve or further declines, or if clinically significant heart failure develops, HerzuMA® should be discontinued unless the benefit outweighs the risk for the individual patient. In patients with asymptomatic cardiac dysfunction, monitoring should be performed more frequently (e.g., every 6–8 weeks). Persistent left ventricular dysfunction, even in the absence of clinical symptoms, should prompt consideration of discontinuing HerzuMA® unless clear clinical benefit is evident.

The safety of resuming or continuing HerzuMA® therapy in patients who have developed cardiotoxicity has not been prospectively studied. In case of symptomatic heart failure developing during HerzuMA® therapy, standard heart failure treatments should be initiated. The condition of most patients who developed heart failure or asymptomatic cardiac dysfunction in clinical trials improved with treatment using angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and beta-blockers.

Use in elderly patients and patients with cardiac dysfunction

Clinical data indicate that trastuzumab distribution is not influenced by age or serum creatinine levels. In clinical trials, elderly patients did not receive reduced doses of trastuzumab. Relevant pharmacokinetic studies in elderly patients and patients with renal or hepatic impairment did not demonstrate any impact on trastuzumab distribution.

Adjuvant and neoadjuvant therapy

Patients with a history of myocardial infarction, treatment-requiring angina, congestive heart failure (including NYHA functional classes II–IV), other cardiomyopathies, treatment-requiring arrhythmias, clinically significant valvular heart disease, poorly controlled arterial hypertension (patients with hypertension controlled by standard medical therapy were allowed in studies), or hemodynamically significant pericardial effusion were excluded from clinical trials of adjuvant breast cancer therapy with HerzuMA®.

In patients with early-stage breast cancer, the incidence of symptomatic and asymptomatic cardiac events was increased when HerzuMA® was administered after anthracycline-containing chemotherapy compared to regimens with docetaxel or carboplatin that did not include anthracyclines. The incidence of such events was higher with concurrent administration of HerzuMA® and taxanes than with sequential administration. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months.

Risk factors for cardiac events included older age (>50 years), low baseline LVEF, reduced LVEF (<55%), decreased LVEF before or after initiation of paclitaxel or HerzuMA®, and prior or concomitant use of antihypertensive medications. In patients who received HerzuMA® after completion of adjuvant chemotherapy, the risk of cardiac dysfunction was associated with higher cumulative anthracycline dose prior to HerzuMA® initiation and higher body mass index (BMI >25 kg/m²).

Pulmonary reactions

During post-marketing use of trastuzumab, severe pulmonary events have been rarely reported. These events have sometimes led to fatal outcomes. Cases of interstitial lung disease have been reported, including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema, and respiratory failure. Risk factors for interstitial lung disease include prior or concomitant use of other antineoplastic agents capable of inducing interstitial lung disease, such as taxanes, gemcitabine, vinorelbine, and radiation therapy. Patients with dyspnea at rest due to extensive malignant disease or concomitant conditions have an increased risk of pulmonary events and should not be treated with trastuzumab. These events may occur as part of an infusion-related reaction or with delayed onset. Patients with pneumonia, particularly those receiving concomitant taxane therapy, should be informed about this risk.

Use during pregnancy or breastfeeding

The medicinal product has an adverse pharmacological effect on pregnancy and/or the fetus and/or the newborn.

Reproductive toxicity studies were conducted in cynomolgus monkeys administered doses up to 25 times higher than the weekly maintenance dose of trastuzumab in humans (2 mg/kg IV) and showed no evidence of impaired fertility or fetal harm. Trastuzumab was shown to cross the placenta during both early (gestational age 20–50 days) and late (gestational age 120–150 days) fetal development. It is unknown whether trastuzumab affects fetal toxicity or fertility. Since animal reproductive studies do not always predict effects in humans, trastuzumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus.

In the post-marketing period, cases of fetal renal enlargement and/or impaired renal function associated with oligohydramnios have been reported in pregnant women receiving trastuzumab, some of which were accompanied by fetal pulmonary hypoplasia and resulted in fetal death. Women of childbearing potential should be advised to use effective contraception during trastuzumab therapy and for at least 7 months after the last dose. Women who become pregnant during trastuzumab treatment or within 7 months after the last dose should be informed of the potential risk to the fetus. Pregnant women receiving trastuzumab should be closely monitored by a multidisciplinary team of specialists.

Lactation studies in cynomolgus monkeys administered doses up to 25 times higher than the weekly maintenance dose of trastuzumab in humans (2 mg/kg IV) demonstrated that trastuzumab is excreted in milk. The presence of trastuzumab in infant serum was not associated with adverse effects on growth or development from birth to 1 month of age. It is unknown whether trastuzumab is excreted in human breast milk. Human IgG1 is excreted in human milk, but the potential for harm to the infant is unknown; therefore, women should avoid breastfeeding during trastuzumab therapy and for 7 months after the last dose.

Ability to affect driving and operating machinery

HerzuMA® has a minor influence on the ability to drive and operate machinery. Dizziness and somnolence may occur during treatment with HerzuMA® (see section "Adverse reactions"). Patients experiencing symptoms related to the use of the medicinal product (see section "Special precautions for use") should be advised not to drive or operate machinery until symptoms have completely resolved.

Administration and Dosage

It is important that treatment with HerzuMA® be initiated under the supervision of a qualified physician experienced in the treatment of oncology patients.

Prior to starting therapy, HER2 status must be determined (see section "Indications").

To avoid medication errors in the use of prescribed medicinal products, it is essential to check the labels on the vials to ensure that the product being prepared and administered is indeed HerzuMA® (trastuzumab), and not trastuzumab emtansine. HerzuMA® must be administered as an intravenous infusion. Intravenous bolus or rapid push administration of the drug is not permitted!

Below are the recommended initial and maintenance doses for both monotherapy and combination therapy regimens.

Metastatic Breast Cancer: Weekly Regimen

Monotherapy

Loading Dose

The recommended loading dose of HerzuMA® is 4 mg/kg body weight administered over 90 minutes as an intravenous infusion. During each trastuzumab infusion, patients must be closely monitored for the development of chills, fever, and other infusion-related reactions (see section "Adverse Reactions"). In case of infusion reactions, the infusion should be interrupted. After symptoms resolve, the infusion may be resumed.

Maintenance Doses

The recommended weekly maintenance dose of HerzuMA® is 2 mg/kg body weight, with a possible infusion duration of 30 minutes if the initial dose was well tolerated. During each trastuzumab infusion, patients must be closely monitored for the development of chills, fever, and other infusion-related reactions (see section "Adverse Reactions"). In case of infusion reactions, the infusion should be interrupted. After symptoms resolve, the infusion may be resumed.

Combination Therapy with Paclitaxel or Docetaxel

The doses of HerzuMA® in combination therapy do not differ from those used in monotherapy. Paclitaxel or docetaxel should be administered the day after the first dose of HerzuMA®. Subsequently, paclitaxel or docetaxel may be administered every 3 weeks immediately after administration of the maintenance doses of HerzuMA®, provided prior administrations were well tolerated.

For dosage recommendations for paclitaxel or docetaxel, refer to the respective product instructions.

Use in Combination with an Aromatase Inhibitor

The doses of HerzuMA® in combination therapy do not differ from those used in monotherapy. In the pivotal study, administration of HerzuMA® and anastrozole occurred on Day 1. No restrictions on the interval between administration of these agents were established. For information on anastrozole dosing, refer to the respective product instructions. If the patient was receiving tamoxifen, its use should be discontinued at least one day before starting combination therapy.

Metastatic Breast Cancer: Administration Once Every 3 Weeks

As an alternative to weekly administration, a 3-weekly regimen is also recommended, both as monotherapy and in combination with paclitaxel, docetaxel, or an aromatase inhibitor.

Loading dose of HerzuMA® is 8 mg/kg body weight, followed by a dose of 6 mg/kg body weight 3 weeks later. Subsequent maintenance doses of HerzuMA® at 6 mg/kg body weight are administered every 3 weeks. The drug is administered by infusion over approximately 90 minutes. If the initial dose is well tolerated, the maintenance dose infusion may be administered over 30 minutes.

Early-Stage Breast Cancer

The treatment regimens with HerzuMA® described below should be continued until disease recurrence or for a total of 52 weeks (1 year), whichever comes first.

Weekly Administration

With the weekly regimen, the loading dose is 4 mg/kg body weight, followed by weekly administration of 2 mg/kg body weight.

Administration Once Every 3 Weeks

With the 3-weekly regimen, the recommended loading dose of HerzuMA® is 8 mg/kg body weight. The recommended maintenance dose of HerzuMA® administered every 3 weeks is 6 mg/kg body weight, starting 3 weeks after the initial dose.

If monotherapy with HerzuMA® is continued after combination with chemotherapy, a dose of 6 mg/kg every 3 weeks should be administered.

For information on studies of HerzuMA® in combination with chemotherapy, see section "Pharmacological Properties".

Metastatic Gastric Cancer or Gastroesophageal Junction Cancer: 3-Weekly Regimen

Loading dose is 8 mg/kg body weight, followed by a dose of 6 mg/kg body weight 3 weeks later. Maintenance doses of HerzuMA® at 6 mg/kg body weight are repeated every 3 weeks. The drug is administered by infusion over approximately 90 minutes. If the initial dose is well tolerated, the maintenance dose infusion may be administered over 30 minutes.

Early-Stage or Metastatic Breast Cancer, Metastatic Gastric Cancer or Gastroesophageal Junction Cancer

Duration of Treatment

Patients with metastatic breast cancer or advanced gastric cancer and gastroesophageal junction cancer should be treated with HerzuMA® until disease progression. Patients with early-stage breast cancer should receive treatment for 1 year or until disease recurrence, whichever occurs first. Continuing treatment for early-stage breast cancer beyond 1 year is not recommended (see section "Pharmacological Properties").

Missed Doses

If a scheduled dose of HerzuMA® is missed by 1 week or less, the standard maintenance dose should be administered as soon as possible (weekly regimen: 2 mg/kg body weight; 3-weekly regimen: 6 mg/kg body weight), without waiting for the next scheduled cycle. Administration of maintenance doses of HerzuMA® (weekly regimen: 2 mg/kg body weight; 3-weekly regimen: 6 mg/kg body weight) should continue according to the original schedule.

If a patient misses a dose of HerzuMA® for more than 1 week, the loading dose should be re-administered over approximately 90 minutes (weekly regimen: 4 mg/kg body weight; 3-weekly regimen: 8 mg/kg body weight). Subsequent maintenance doses of HerzuMA® (weekly regimen: 2 mg/kg body weight; 3-weekly regimen: 6 mg/kg body weight) should be administered according to the original schedule.

Dose Reduction

Dose reduction was not performed in clinical studies. Treatment with HerzuMA® may be continued during reversible, chemotherapy-induced myelosuppression; however, patients should be closely monitored during this period to avoid complications of neutropenia. For information on dose reduction or extended intervals during chemotherapy, refer to the respective product instructions.

Special Patient Populations

Elderly Patients

According to available data, the bioavailability of HerzuMA® is not age-dependent (see section "Pharmacokinetics"). Dose reduction was not performed in elderly patients during clinical studies.

Pediatric Patients

The safety and efficacy of HerzuMA® in children and adolescents have not been studied.

Preparation and Storage of the Solution

Appropriate aseptic techniques should be followed during preparation. The contents of one 150 mg vial of HerzuMA® should be reconstituted (diluted) with 7.2 mL of sterile water for injection (not included). Do not use other solvents. This results in a single dose of 7.4 mL of solution with a trastuzumab concentration of 21 mg/mL and a pH of approximately 6.0.

To prevent precipitation and subsequent loss of dissolved HerzuMA®, shaking and excessive foaming should be avoided during reconstitution and preparation of the diluted infusion solution. Rapid injection from a syringe should also be avoided. A 4% volume overfill ensures that the labeled dose of 150 mg can be accurately withdrawn from each vial.

Preparation of 150 mg Concentrate in Vial

1. Using a sterile syringe, slowly add 7.2 mL of sterile water for injection to the vial containing the lyophilized powder for concentrate for infusion solution of HerzuMA®.
2. Gently swirl the vial in a rotational motion. DO NOT SHAKE.

Slight foaming during the process is normal. After reconstitution, allow the solution to stand for approximately 5 minutes. After reconstitution, no visible particles should be present in the vial.

The color of the prepared solution ranges from clear to pale yellow.

HerzuMA® 150 mg for Single Use

After reconstitution with sterile water for injection, the solution is physically and chemically stable for 48 hours at 2–8 °C (do not freeze). From a microbiological standpoint, the reconstituted solution of HerzuMA® should be used immediately unless it was prepared under controlled, validated aseptic conditions.

Further Dilution in Single-Dose Vials of HerzuMA®

Dilution of Reconstituted Solution

The volume of reconstituted solution required for a specific patient is calculated as follows:

• for administration of a loading dose of trastuzumab of 4 mg/kg body weight, or a maintenance dose of 2 mg/kg body weight:

body weight (kg) × required dose (4 mg/kg loading or 2 mg/kg maintenance dose)

Volume (mL) = -------------------------------------------------------------------------------------------------
21 (mg/mL) (this is the concentration of the reconstituted solution)

• for administration of a loading dose of trastuzumab of 8 mg/kg body weight, or subsequent doses of trastuzumab of 6 mg/kg body weight every 3 weeks:

body weight (kg) × required dose (8 mg/kg loading or 6 mg/kg maintenance dose)

Volume (mL) = -------------------------------------------------------------------------------------------------
21 (mg/mL) (this is the concentration of the reconstituted solution)

The required volume of reconstituted solution should be withdrawn from the 150 mg single-dose vial and added to an infusion bag containing 250 mL of 0.9% sodium chloride. Do not use 5% glucose solution (see section "Incompatibilities"). The infusion bag should be gently inverted to mix the solution without creating foam. Parenteral medicinal products should be visually inspected prior to administration to ensure absence of particles and discoloration.

The infusion solution should be used immediately after preparation.

Infusion Solution of HerzuMA®

If dilution was performed under aseptic conditions, the infusion solution of HerzuMA® in polyvinyl chloride, polyethylene, or polypropylene bags containing 0.9% sodium chloride is physically and chemically stable for 48 hours at temperatures not exceeding 30 °C. Since the product reconstituted with sterile water for injection does not contain preservatives, from a microbiological standpoint it should be used immediately unless it was prepared under controlled, validated aseptic conditions.

Storage Period for Reconstituted Solution and Infusion Solution

Any unused reconstituted solution or infusion solution prepared outside of controlled and validated aseptic conditions must be discarded. The prepared solution should be used immediately. Any unused portion should be discarded.

Pediatric Patients

The safety and efficacy of HerzuMA® in children and adolescents have not been studied.

Overdose

Cases of overdose were not reported in clinical studies. Individual cases of doses exceeding 10 mg/kg body weight have not been studied.

Adverse Reactions

The most serious and/or commonly observed adverse reactions during treatment with HerzuMA® are cardiotoxicity, infusion reactions, hematotoxicity (particularly neutropenia), infections, and pulmonary adverse reactions.

Heart failure of NYHA class II–IV is a common adverse event during trastuzumab therapy and, in some cases, may be fatal (see section "Special Warnings and Precautions").

Approximately 40% of patients receiving trastuzumab experience infusion reactions of any type. However, most infusion-related adverse effects are mild to moderate in severity (according to National Cancer Institute Common Toxicity Criteria, NCI-CTC) and occur primarily at the beginning of treatment, especially during the first three infusions, with decreasing frequency during subsequent infusions. Reactions include, among others, chills, fever, nausea, urticaria, rash, dyspnea, bronchospasm, tachycardia, and hypotension. Serious anaphylactic reactions requiring immediate intervention are very rare and usually occur during the first or second trastuzumab infusion (see section "Special Warnings and Precautions"). Leukopenia, febrile neutropenia, anemia, and thrombocytopenia are very commonly observed. Neutropenia is a common adverse effect. The frequency of hypoprothrombinemia is unknown. Serious pulmonary adverse reactions during trastuzumab therapy are rare but, in some cases, have been associated with fatal outcomes. These include lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema, and respiratory failure (see section "Special Warnings and Precautions").

List of Adverse Reactions

The following frequency categories are used according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology: 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), frequency not known (cannot be estimated from available data).

Infections and infestations: very common – nasopharyngitis (> 10%), infection; common – cystitis, herpes zoster, herpes infection, influenza, sinusitis, skin infections, rhinitis, upper respiratory tract infections, urinary tract infections, pharyngitis; frequency not known – cellulitis, sepsis, febrile neutropenia, septic shock, meningitis, bronchitis.

Neoplasms benign, malignant and unspecified (including cysts and polyps): frequency not known – progressive malignant neoplasm, progressive neoplasm.

Blood and lymphatic system disorders: very common – anemia (> 10%), thrombocytopenia (> 10%), febrile neutropenia (> 10%), leukopenia; common – neutropenia; frequency not known – hypoprothrombinemia, leukemia, immune thrombocytopenia.

Immune system disorders: common – hypersensitivity; frequency not known – anaphylactic reactions, anaphylactic shock.

Metabolism and nutrition disorders: very common – weight increased (> 10%), weight decreased (> 10%), decreased appetite (> 10%); common – anorexia; frequency not known – hyperkalemia, tumor lysis syndrome.

Psychiatric disorders: very common – insomnia (> 10%); common – anxiety, depression, disturbance in thinking; frequency not known – lethargy, paraneoplastic cerebellar degeneration.

Nervous system disorders: very common – tremor (> 10%), dizziness (11%), headache (21%), paresthesia (> 10%), hypoesthesia (> 10%), dysgeusia (> 10%); common – taste disturbance, hypertension, peripheral neuropathy, dizziness, somnolence; frequency not known – paralysis, ataxia, cerebral edema, lethargy, coma, cerebrovascular disorders.

Eye disorders: very common – lacrimation increased (> 10%), conjunctivitis (> 10%); common – dry eyes; frequency not known – optic disc edema, retinal hemorrhage, madarosis.

Ear and labyrinth disorders: uncommon – deafness; frequency not known – paralysis, ataxia, cerebral edema, lethargy, coma, cerebrovascular disorders.

Eye disorders: very common – increased lacrimation (> 10%), conjunctivitis (> 10%); common – dry eyes; frequency not known – optic nerve edema, retinal hemorrhage, loss of eyebrows and eyelashes.

Cardiac disorders: very common – atrial fibrillation (> 10%), irregular heartbeat (> 10%), decreased ejection fraction; common – congestive heart failure, supraventricular tachyarrhythmia, cardiomyopathy, palpitations; frequency not known – cardiogenic shock, pericardial effusion, pericarditis, bradycardia, gallop rhythm, tachycardia.

Vascular disorders: very common – lymphedema (> 10%), flushing (> 10%); common – arterial hypotension, arterial hypertension, vasodilation.

Respiratory, thoracic and mediastinal disorders: very common – wheezing (> 10%), dyspnea (14%), cough (> 10%), rhinorrhea (> 10%), epistaxis (> 10%), oropharyngeal pain (> 10%); common – bronchial asthma, lung disorders, pleural effusion, pneumonia; uncommon – pneumonitis, labored breathing; frequency not known (post-marketing reports) – interstitial lung disease, including pulmonary infiltrates, pulmonary fibrosis, respiratory failure, respiratory arrest, acute pulmonary edema, acute respiratory distress, pneumonia, bronchospasm, hypoxia, laryngeal edema, orthopnea, pneumonitis, exertional dyspnea, hiccup, acute respiratory distress syndrome, respiratory distress syndrome, decreased oxygen saturation, Cheyne-Stokes respiration.

Gastrointestinal disorders: very common – abdominal pain (16%), diarrhea (43%), lip swelling (> 10%), nausea (67%), vomiting (50%), dyspepsia (> 10%), stomatitis (> 10%), constipation (> 10%); common – dry mouth, hemorrhoids; uncommon – pancreatitis; frequency not known – gastritis.

Hepatobiliary disorders: common – hepatitis, hepatic tenderness on palpation, hepatocellular disorders; uncommon – jaundice; frequency not known – hepatic failure.

Skin and subcutaneous tissue disorders: very common – erythema (23%), rash (24%), facial swelling (> 10%), alopecia (> 10%), palmar-plantar erythrodysesthesia (> 10%), toxic nail effects (> 10%), nail disorders; common – acne, dry skin, subcutaneous hemorrhage, hyperhidrosis, maculopapular rash, pruritus, brittle nails (onychoclasis), dermatitis; uncommon – urticaria; frequency not known – angioneurotic edema, onychorexis, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders: very common – arthralgia (27%), muscle stiffness (> 10%), myalgia (27%); common – arthritis, back pain, bone pain, muscle spasms, neck pain, limb pain, musculoskeletal pain.

Renal and urinary disorders: common – renal disorders; frequency not known – membranous glomerulonephritis, glomerulonephropathy, renal failure, dysuria.

Reproductive system and breast disorders: common – breast inflammation/mastitis, breast pain.

Pregnancy, puerperium and perinatal conditions: frequency not known – renal hypoplasia, pulmonary hypoplasia.

General disorders and administration site conditions: very common – asthenia (45%), chest pain (11%), chills (15%), fatigue (35%), influenza-like symptoms (12%), infusion-related reactions (40%), pain (12%), pyrexia (12%), peripheral edema (> 10%), mucosal inflammation (> 10%); common – malaise, edema.

Immunogenicity

Anti-trastuzumab antibodies were detected in 8.1% of patients during neoadjuvant/adjuvant use (regardless of baseline anti-trastuzumab antibody levels). The clinical significance of these antibodies is unknown. However, there is no negative impact of anti-trastuzumab antibodies on the pharmacokinetics, efficacy (defined by pathological complete response), or safety (defined by frequency of infusion reactions) of trastuzumab.

Description of Selected Adverse Reactions of Trastuzumab

Cardiac Dysfunction

Congestive heart failure (CHF) (NYHA class II–IV) is a common adverse reaction associated with trastuzumab use and has led to fatal outcomes. Signs and symptoms of cardiac dysfunction such as dyspnea, orthopnea, increased cough, pulmonary edema, S3 gallop, or low left ventricular ejection fraction have been observed in patients receiving trastuzumab.

In three pivotal clinical trials using trastuzumab as adjuvant therapy in combination with chemotherapy, the incidence of cardiac dysfunction (symptomatic CHF) grade 3/4 according to NCI-CTC (National Cancer Institute Common Toxicity Criteria) was similar in patients receiving chemotherapy alone (i.e., not receiving trastuzumab) and in patients receiving trastuzumab after taxane therapy (0.3–0.4%). The incidence was highest in patients receiving trastuzumab concurrently with taxane (2.0%). Experience with concurrent use of trastuzumab and low-dose anthracycline in the neoadjuvant setting is limited.

When trastuzumab was administered after completion of adjuvant chemotherapy, heart failure of NYHA functional class II–IV was observed in 0.6% of patients in the 1-year treatment group after a median follow-up period of 12 months. After a median follow-up of 3.6 years, the incidence of severe CHF and left ventricular dysfunction following 1-year trastuzumab therapy remained low at 0.8% and 9.8%, respectively. In study BO16348, after a median follow-up of 8 years, the incidence of severe CHF (NYHA functional class III and IV) in the 1-year trastuzumab treatment group was 0.8%, and the incidence of symptomatic or asymptomatic left ventricular dysfunction was 4.6%.

Reversibility of severe CHF (defined as at least two consecutive LVEF measurements ≥ 50% after the event) was observed in 71.4% of patients treated with trastuzumab. Reversibility of symptomatic or asymptomatic ventricular dysfunction was observed in 79.5% of patients treated with trastuzumab. Approximately 17% of cardiac dysfunction events occurred after completion of trastuzumab therapy.

In pivotal metastatic trials of intravenous trastuzumab, the incidence of cardiac dysfunction ranged from 9% to 12% when used concurrently with paclitaxel, compared to 1–4% with paclitaxel monotherapy. With monotherapy, the incidence was 6–9%. The highest incidence of cardiac dysfunction was observed in patients receiving trastuzumab concurrently with anthracycline/cyclophosphamide (27%), significantly higher than with anthracycline/cyclophosphamide alone (7–10%). In a subsequent trial with prospective cardiac monitoring, the incidence of symptomatic CHF was 2.2% in patients receiving trastuzumab and docetaxel, compared to 0% in patients receiving docetaxel alone. In most patients (79%) who developed cardiac dysfunction in these three trials, improvement was observed after standard CHF treatment.

In the pivotal trial MO16432 (NOAH), trastuzumab was administered concurrently with neoadjuvant chemotherapy including three cycles of doxorubicin (cumulative dose 180 mg/m²), and the incidence of symptomatic cardiac dysfunction was 1.7% in the trastuzumab group. In another pivotal adjuvant trial (BO22227), trastuzumab was administered concurrently with neoadjuvant chemotherapy including four cycles of epirubicin (cumulative dose 300 mg/m²). The incidence of congestive heart failure was 0% in the trastuzumab group after a median follow-up of 40 months.

Infusion-Related Reactions (IRR) and Hypersensitivity

Symptoms of infusion-related reactions (IRR) and hypersensitivity observed in clinical trials of trastuzumab include, among others, chills, fever, dyspnea, arterial hypotension, wheezing, bronchospasm, tachycardia, low oxygen saturation, respiratory distress syndrome, rash, nausea, vomiting, and headache. IRR may be clinically difficult to distinguish from hypersensitivity reactions. The incidence of IRR of all grades varied across studies depending on the indication, data collection methodology, and whether trastuzumab was administered concurrently with chemotherapy or as monotherapy. Anaphylactic reactions were observed in isolated cases.

Hematotoxicity

Febrile neutropenia occurred very commonly. Common adverse reactions include, among others, anemia, leukopenia, thrombocytopenia, and neutropenia. The frequency of hypoprothrombinemia is unknown. The risk of neutropenia may be slightly increased when trastuzumab is used with docetaxel following anthracycline therapy.

Long-term Cardiac Follow-up in Early Breast Cancer

After a median follow-up of 8 years in study BO16348, the incidence of severe chronic heart failure (NYHA functional class III and IV) following 1 year of trastuzumab therapy (combined analysis of two trastuzumab treatment groups) was 0.8%, and the incidence of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%. Reversibility of severe chronic heart failure (defined as at least two consecutive LVEF measurements ≥ 50% after cardiac dysfunction) was observed in 71.4% of patients with chronic heart failure. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated in 79.5% of affected patients. Approximately 17% of heart failure events occurred after completion of trastuzumab therapy. In a pooled analysis of two studies (NSABP B-31 and NCCTG N9831) with a median follow-up of 8.1 years, the incidence of cardiac dysfunction defined by LVEF in the AC→PH group (doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab) remained unchanged compared to the analysis at a median follow-up of 2.0 years in the AC→PH group: a decline in LVEF of ≥ 10% to below 50% was observed in 18.5% of patients in the AC→PH group. Reversibility of left ventricular dysfunction was observed in 64.5% of AC→PH group patients who had symptomatic CHF and were asymptomatic at last follow-up, and in 90.3% of patients who experienced complete or partial recovery of LVEF.

Shelf Life

4 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage Conditions

Store at 2 to 8°C in a place inaccessible to children.

The shelf life of the reconstituted solution (diluent – sterile water for injection) is physically and chemically stable for 48 hours at a storage temperature of 2 to 8°C. Do not freeze. Any unused portion of the reconstituted solution must be discarded.

The shelf life of the reconstituted and diluted solution in polyvinyl chloride, polyethylene, or polypropylene bags containing 0.9% sodium chloride is physically and chemically stable for 48 hours at a temperature not exceeding 30°C. From a microbiological standpoint, the infusion solution of HerzuMA® should be used immediately unless prepared under controlled and validated aseptic conditions.

Incompatibilities

No incompatibility of HerzuMA® with polyvinyl chloride, polyethylene, or polypropylene infusion bags has been reported.

Glucose solution (5%) should not be used due to protein aggregation.

HerzuMA® must not be mixed with other medicinal products or reconstituted in them.

Packaging

150 mg of lyophilisate in a vial made of colorless glass, stoppered with a rubber stopper and sealed with a flip-off cap. 1 vial per carton.

Prescription Status

By prescription only.

Manufacturer

CELLTRION, Inc.

Manufacturer’s Location and Address of Business Activity

20, Academy-ro 51 beon-gil, Yeonsu-gu, Incheon, 22014, Republic of Korea.

Marketing Authorization Holder

Celltrion Healthcare Co., Ltd.

Location of Marketing Authorization Holder and/or its Representative

19 Academy-ro 51 beon-gil, Yeonsu-gu, Incheon, 22014, Republic of Korea.

Exclusive Distributor

Egis Pharmaceuticals Plc., Hungary.