Zercepak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZERCEPAC (ZERCEPAC)

Composition:

Active substance: trastuzumab;

1 vial contains 150 mg of trastuzumab;

1 ml of prepared (reconstituted) solution contains 21 mg of trastuzumab;

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

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: lyophilized powder, white to pale yellow in color.

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

ATC code L01F D01.

Pharmacological Properties

Pharmacodynamics

Trastuzumab is a recombinant humanized monoclonal antibody of the IgG1 class directed against the human epidermal growth factor receptor type 2 (HER2). The antibody specifically binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER2). HER2 protein overexpression occurs in 20–30% of all cases of primary breast cancer. Studies assessing HER2 positivity in gastric cancer (GC) using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) have shown a wide variability in HER2 positivity, ranging from 6.8% to 34.0% for IHC and from 7.1% to 42.6% for FISH. Research indicates that patients with breast cancer whose tumors overexpress HER2 have shorter disease-free survival compared to patients whose tumors do not overexpress HER2. The extracellular domain of the receptor (ECD, p105) can be shed into the bloodstream and detected in serum samples.

Mechanism of Action

Trastuzumab binds with high affinity and specificity to subdomain IV of the juxtamembrane region of the extracellular domain of HER2. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 signaling and prevents proteolytic cleavage of its extracellular domain—a mechanism of HER2 activation. As a result, trastuzumab has been shown to inhibit proliferation of human tumor cells that overexpress HER2, both in vitro and in animal models. Furthermore, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro studies have demonstrated that trastuzumab-mediated ADCC preferentially targets cancer cells overexpressing HER2 compared to cancer cells that do not overexpress HER2.

Detection of HER2 Gene Overexpression or Amplification

Detection of HER2 Gene Overexpression or Amplification in Breast Cancer

Zercepac should be administered only to patients whose tumors have been confirmed to exhibit HER2 gene overexpression or amplification by an accurate and validated assay. HER2 overexpression should be determined using immunohistochemical evaluation of fixed tumor tissue blocks (see section "Instructions for Use and Dosage"). HER2 gene amplification should be determined using fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) of fixed tumor tissue blocks. Patients are eligible for treatment with Zercepac if they show strong HER2 overexpression, defined as an IHC score of 3+ or a positive FISH or CISH result.

To ensure accurate and reproducible test results, testing should be performed in a specialized laboratory capable of validating the testing procedures.

The recommended scoring system for IHC staining patterns is presented in Table 1.

Table 1: Recommended scoring system for IHC staining patterns in breast cancer

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 control is not applied. 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 interpreting its results, refer to the instructions for use of the approved FISH and CISH methodologies. Official recommendations on HER2 testing may also be applied.

Any other method that may be used to assess HER2 protein or gene expression must be performed only in laboratories that provide validated testing methods according to the most current technologies. Such methods must be sufficiently accurate and reliable to demonstrate HER2 overexpression and must be capable of distinguishing moderate (congruent with 2+) from strong (congruent with 3+) HER2 overexpression.

Determination of HER2 overexpression or HER2 gene amplification in gastric cancer

To determine HER2 overexpression or HER2 gene amplification, only validated and reliable methodologies should be used. Immunohistochemistry (IHC) is recommended as the initial testing method, and in cases where HER2 gene amplification status also needs to be determined, either silver-enhanced in situ hybridization (SISH) or FISH should additionally be applied. However, SISH is recommended for concurrent assessment of histology and morphology. To ensure validation of testing methods and obtain accurate, reproducible results, HER2 testing should be performed in a laboratory with trained personnel. Full instructions on conducting and interpreting results are provided in the package insert accompanying the HER2 testing methods used.

If further determination of HER2 gene amplification status is required, silver-enhanced in situ hybridization (SISH) or FISH technology should be used. To achieve accurate test results, testing should be conducted in specialized laboratories capable of providing validation of the testing procedure. For complete information on performing the analysis and evaluating its results, refer to the instructions for use of the approved FISH and CISH methodologies.

In the ToGA trial (BO18255), patients included were those with 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.

HER2 overexpression should be determined by immunohistochemistry (IHC) assessment of fixed tumor blocks; HER2 gene amplification should be determined by hybridization-based assessment of fixed tumor blocks, such as FISH or SISH.

The recommended scoring system for HER2 overexpression by IHC is shown in Table 2.

Table 2: Recommended scoring system for HER2 overexpression by IHC

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

Pharmacokinetics

The pharmacokinetics of trastuzumab were evaluated through a population pharmacokinetic analysis of pooled data from 1582 patients with HER2-positive metastatic breast cancer (MBC), early breast cancer (EBC), metastatic gastric cancer (MGC), or other tumor types, as well as healthy volunteers who received intravenous trastuzumab (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.

T1/2 decreases as concentration declines within the dosing interval (see Table 6). Patients with MBC and EBC had similar pharmacokinetic parameters (e.g., clearance (CL), central compartment volume (Vc)) and predicted population steady-state exposures (Cmin, Cmax, and AUC). Linear clearance was 0.136 L/day in MBC, 0.112 L/day in EBC, and 0.176 L/day in MGC. Nonlinear elimination parameters were 8.81 mg/day for maximum elimination rate (Vmax) and 8.92 µg/mL for the Michaelis–Menten constant (Km) in MBC, EBC, and MGC. The central compartment volume was 2.62 L in patients with MBC and EBC and 3.63 L in patients with MGC. In the final population pharmacokinetic model, in addition to primary tumor type, patient body weight, serum aspartate aminotransferase level, and serum albumin level were identified as statistically significant covariates influencing trastuzumab exposure. However, the magnitude of the effect of these covariates on trastuzumab exposure suggests that they are unlikely to have a clinically significant impact on trastuzumab concentrations.

Population-predicted trastuzumab exposure values (with medians from the 5th to 95th percentiles) and pharmacokinetic parameter values at clinically relevant concentrations (Cmax and Cmin) in patients with MBC, EBC, and MGC receiving treatment according to approved dosing regimens administered weekly or once every three weeks are presented in Table 4 (Cycle 1), Table 5 (steady state), and Table 6 (pharmacokinetic parameters).

Table 4: Population-predicted pharmacokinetic values in Cycle 1 (with medians from the 5th to 95th percentiles) for intravenous treatment regimens in patients with MBC, EBC, and MGC

Table 5: Population-predicted pharmacokinetic exposure values at steady state (with medians from 5th to 95th percentiles) for intravenous trastuzumab regimens in patients with MBC, GEC, and MSL

• Cmin,ss = Cmin at steady state

• Cmax,ss = Cmax at steady state

• Time to reach 90% of steady state

Table 6: Population-predicted pharmacokinetic parameters at steady state following intravenous administration regimens of trastuzumab in patients with MBC, MGC, and MSH

Elimination of trastuzumab

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

Circulating extracellular domain of the HER2 receptor

Covariate analysis of data obtained 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 Km) (p < 0.001). A correlation was observed between 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 breast cancer, and no significant effect on trastuzumab clearance was observed.

Clinical Characteristics

Indications

Breast Cancer

The medicinal product Zercepac should only be administered to patients with metastatic or early breast cancer whose tumors exhibit HER2 protein overexpression or HER2 gene amplification, as determined by an accurate and validated test method (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use").

Metastatic Breast Cancer

Zercepac is indicated for the treatment of adult patients with HER2-positive metastatic breast cancer (MBC):

• as monotherapy in patients who have received at least two chemotherapy regimens for metastatic disease. Prior chemotherapy should include at least an anthracycline and a taxane, unless such treatment is contraindicated in these patients. In hormone receptor-positive patients, prior hormonal therapy should also have failed, unless such treatment is contraindicated;
• in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic disease and for whom an anthracycline is not appropriate;
• in combination with docetaxel for the treatment of patients who have not received chemotherapy for metastatic disease;
• in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone receptor-positive MBC who have not previously been treated with trastuzumab.

Early Breast Cancer

Zercepac is indicated for the treatment of adult patients with early breast cancer (EBC):

• following surgery, chemotherapy (neoadjuvant or adjuvant), and radiotherapy (if applicable) (see section "Pharmacodynamics");
• following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel;
• in combination with adjuvant chemotherapy containing docetaxel and carboplatin;
• in combination with neoadjuvant chemotherapy followed by adjuvant therapy with Zercepac in patients with locally advanced (including inflammatory) disease or tumors > 2 cm in diameter (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use").

Metastatic Gastric Cancer

Zercepac 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 received prior chemotherapy for metastatic disease. Zercepac should only be administered to patients with metastatic gastric cancer whose tumors show HER2 protein overexpression, defined as an IHC result of 2+ confirmed by silver in situ hybridization (SISH) or fluorescence in situ hybridization (FISH), or an IHC result of 3+. Accurate and validated testing methods should be used (see sections "Pharmacodynamics" and "Dosage and Administration").

Contraindications

Hypersensitivity to trastuzumab, proteins of Chinese hamster ovary cells, or any of the excipients of the medicinal product.

Severe dyspnea at rest due to complications of widespread malignancy or requiring supplemental oxygen therapy.

Interaction with Other Medicinal Products and Other Forms of Interaction

Specific interaction studies with other medicinal products in humans have not been conducted. No clinically significant interactions have been observed with medicinal products co-administered with Zercepac in clinical practice.

Effect of Trastuzumab on the Pharmacokinetics of Other Antineoplastic Agents

Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC showed that the exposure to paclitaxel and doxorubicin (and their major metabolites, 6-α-hydroxypaclitaxel (RON) and doxorubicinol (DOL)) was not altered in the presence of trastuzumab (administered intravenously as an 8 mg/kg or 4 mg/kg loading dose followed by 6 mg/kg every 3 weeks or 2 mg/kg weekly, respectively).

However, trastuzumab may increase the overall exposure to one metabolite of doxorubicin (7-deoxy-13-dihydro-doxorubicinol (D7D)). The biological activity of D7D and the clinical significance of its increased levels are not known.

Data from study JP16003, a non-comparative study of trastuzumab (loading dose 4 mg/kg IV infusion followed by weekly 2 mg/kg IV infusion) and docetaxel (60 mg/m² IV infusion) in Japanese women with HER2-positive MBC, showed that concomitant administration of trastuzumab did not affect the single-dose pharmacokinetics of docetaxel. Study JP19959 was an ancillary study to BO18255 (ToGA), conducted in Japanese male and female patients with advanced gastric cancer (AGC), to evaluate the pharmacokinetics of capecitabine and cisplatin when administered with or without trastuzumab. Results from this ancillary study showed that exposure to the bioactive metabolite (e.g., 5-fluorouracil) of capecitabine was not altered when co-administered with cisplatin, or when co-administered with capecitabine alone, or with capecitabine and trastuzumab. However, capecitabine itself showed higher concentrations and a longer elimination half-life when administered in combination with trastuzumab. These data also indicate that the pharmacokinetics of cisplatin are not affected by concomitant administration of capecitabine or capecitabine and trastuzumab.

Pharmacokinetic data from study H4613g/GO01305 in patients with metastatic or locally advanced unresectable HER2-positive cancer indicate that trastuzumab does not affect the PK of carboplatin.

Effect of Antineoplastic Agents on the Pharmacokinetics of Trastuzumab

Comparison of serum trastuzumab concentration modeling after trastuzumab monotherapy (loading dose 4 mg/kg followed by 2 mg/kg IV weekly) and serum concentrations observed in Japanese women with HER2-positive MBC (study JP16003) showed no evidence of an effect of concomitant docetaxel 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 concurrently, and from two Phase II studies in which trastuzumab was administered as monotherapy (WO16229 and MO16982), in women with HER2-positive MBC, indicates that individual and mean serum trastuzumab concentrations varied within and across studies, but there was no clear effect of concomitant paclitaxel on trastuzumab pharmacokinetics. Comparison of trastuzumab pharmacokinetic data from study M77044 in female patients with HER2-positive MBC treated with trastuzumab, paclitaxel, and doxorubicin, and data from trastuzumab monotherapy (H0649g) or trastuzumab in combination with an anthracycline and cyclophosphamide or paclitaxel (study H0648g) showed that doxorubicin or paclitaxel does not affect trastuzumab pharmacokinetics.

Pharmacokinetic data from study H4613g/GO01305 showed that carboplatin does not affect the pharmacokinetics of trastuzumab.

Concomitant administration of anastrozole with trastuzumab did not affect the pharmacokinetics of trastuzumab.

Special precautions for use

In order to improve traceability of biological medicinal products, the trade name and batch number of the medicinal product Zercepac should be clearly recorded in the patient's medical record. HER2 testing must be performed in a specialized laboratory that ensures proper validation of the testing procedure (see section "Pharmacodynamics"). Currently, there are no clinical data on re-treatment of patients previously treated with Zercepac as adjuvant therapy.

Cardiac dysfunction

During treatment with Zercepac, there is an increased risk of developing NYHA Class II–IV chronic heart failure or asymptomatic cardiac dysfunction. These events have been observed during treatment with Zercepac as monotherapy or in combination with paclitaxel or docetaxel, particularly following anthracycline chemotherapy (doxorubicin or epirubicin). Heart failure may be moderate to severe in severity and may lead to death (see section "Adverse reactions"). Caution should be exercised when treating patients with increased risk of cardiovascular complications (e.g., patients with hypertension, documented ischemic heart disease, congestive heart failure, left ventricular ejection fraction (LVEF) < 55%, or elderly patients).

All patients should undergo a thorough cardiac evaluation prior to initiation of treatment with Zercepac, especially those previously treated with anthracyclines and cyclophosphamide. This evaluation should include medical history, physical examination, ECG, echocardiography and/or radionuclide ventriculography (MUGA) or magnetic resonance imaging. Monitoring for early detection of patients developing cardiac dysfunction should be performed via cardiac assessment at baseline, every 3 months during treatment, and every 6 months after completion of treatment for up to 24 months from the last dose of Zercepac. A careful benefit-risk assessment is required before initiating Zercepac treatment.

Population pharmacokinetic modeling analysis indicates that trastuzumab may remain in the circulation for up to 7 months after discontinuation of Zercepac treatment (see section "Pharmacokinetics"). Patients receiving anthracyclines after stopping Zercepac are likely to have an increased risk of cardiac dysfunction. If possible, anthracycline-based therapy should be avoided for 7 months after discontinuation of Zercepac. If anthracyclines are administered, the patient's cardiovascular parameters should be closely monitored.

Formal cardiac evaluation should be performed in patients with pre-existing cardiovascular conditions identified during baseline screening. Cardiac function should be monitored in all patients during treatment (e.g., every 12 weeks). Monitoring may help identify patients developing cardiac dysfunction. More frequent monitoring (e.g., every 6–8 weeks) may be beneficial for patients developing asymptomatic cardiac dysfunction. If left ventricular function continues to decline but remains asymptomatic, the physician should consider discontinuing therapy if no clinical benefit from Zercepac treatment is observed.

The safety of continuing or resuming Zercepac in patients with cardiac dysfunction has not been prospectively studied. If LVEF decreases by ≥ 10 percentage points from baseline to a level below 55%, treatment should be suspended and LVEF reassessed approximately 3 weeks later. If LVEF does not improve or further declines, or if symptomatic chronic heart failure (CHF) develops, discontinuation of Zercepac should be seriously considered, except when benefit to the individual patient outweighs the risk. All such patients should be referred for cardiology evaluation and monitored closely.

If symptomatic heart failure develops during treatment with Zercepac, it should be managed with standard medications for CHF. In most patients who developed CHF or asymptomatic cardiac dysfunction in the pivotal clinical trials, improvement occurred with standard CHF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. Most patients with cardiac symptoms who continued to derive clinical benefit from trastuzumab therapy were able to continue treatment without additional clinical cardiac events.

Metastatic breast cancer

Concomitant administration of Zercepac and anthracyclines is not recommended for the treatment of metastatic breast cancer. Patients with MBC previously treated with anthracyclines are also at risk of cardiac dysfunction when treated with Zercepac, although this risk is lower than with concomitant administration of Zercepac and anthracyclines.

Early breast cancer

For patients with EBC, cardiac assessment should be repeated every 3 months during treatment and every 6 months after treatment discontinuation for up to 24 months from the last dose of Zercepac, as at baseline. Patients receiving anthracycline-containing chemotherapy should undergo further monitoring annually for 5 years after the last dose of Zercepac or longer if persistent LVEF decline is observed.

Patients with a history of myocardial infarction (MI), untreated angina, current or prior CHF (NYHA Class II–IV), LVEF < 55%, other cardiomyopathy, treated cardiac arrhythmia, clinically significant valvular heart disease, poorly controlled hypertension (hypertension controlled by standard treatment regimens is considered acceptable), or hemodynamically significant pericardial effusion were excluded from adjuvant and neoadjuvant pivotal trials with trastuzumab; therefore, treatment is not recommended for such patients.

Adjuvant therapy

Zercepac should not be used concomitantly with anthracyclines as adjuvant therapy.

In patients with EBC, an increased incidence of symptomatic and asymptomatic cardiac events has been observed when trastuzumab was administered following anthracycline-containing chemotherapy compared to a non-anthracycline regimen of docetaxel and carboplatin. Cardiac events were more pronounced when trastuzumab was administered concomitantly with taxanes than when administered sequentially after taxanes. Regardless of the regimen, most symptomatic cardiac events occurred within the first 18 months. In one of three pivotal trials with a median follow-up of 5.5 years (BCIRG006), patients receiving trastuzumab concomitantly with a taxane after anthracycline therapy experienced a persistent increase in cumulative incidence of symptomatic cardiac events or LVEF abnormalities up to 2.37%, compared to approximately 1% in the two control arms (anthracycline plus cyclophosphamide followed by taxane, and taxane, carboplatin, and trastuzumab).

Risk factors for cardiac events identified in four large adjuvant trials included older age (> 50 years), low LVEF (< 55%) relative to baseline before or after initiation of paclitaxel, a decline in LVEF by 10–15 percentage points, and prior or concomitant use of antihypertensive medications. In patients receiving trastuzumab after completion of adjuvant chemotherapy, the risk of cardiac dysfunction was associated with higher cumulative anthracycline dose received before starting trastuzumab and body mass index (BMI) > 25 kg/m².

Neoadjuvant therapy

For patients with EBC eligible for neoadjuvant therapy, Zercepac may be administered concomitantly with anthracyclines only if they have not previously received chemotherapy, and only with low-dose anthracyclines, i.e., with maximum cumulative doses of doxorubicin 180 mg/m² or epirubicin 360 mg/m².

Patients who received a full course of low-dose anthracyclines concomitantly with Zercepac during neoadjuvant therapy should not receive additional cytotoxic chemotherapy after surgery. In other situations, the decision on additional cytotoxic chemotherapy should be made based on individual patient characteristics.

Experience with concomitant use of trastuzumab and low-dose anthracyclines is currently limited to two studies (MO16432 and BO22227).

In the pivotal study MO16432, trastuzumab was administered concomitantly with neoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m²). The incidence of symptomatic cardiac dysfunction was 1.7% in the trastuzumab group.

In the pivotal study BO22227, trastuzumab was administered concomitantly with neoadjuvant chemotherapy containing four cycles of epirubicin (cumulative dose 300 mg/m²); with a median follow-up of over 70 months, the incidence of congestive heart failure was 0.3% in the intravenous trastuzumab group.

Clinical experience with use in patients aged 65 years and older is limited.

Infusion reactions and hypersensitivity

Serious infusion-related adverse reactions have been reported, including dyspnea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachycardia, hypoxia, anaphylaxis, respiratory distress, urticaria, and angioedema (see section "Adverse reactions"). Premedication may be used to reduce the risk of infusion reactions. Most of these events occurred during or within 2.5 hours of the start of the first infusion. If infusion-related reactions (IRR) occur, the infusion should be interrupted or the infusion rate reduced, and the patient's condition should be monitored until all observed symptoms resolve (see section "Dosage and administration"). Analgesic/antipyretic agents such as meperidine or paracetamol, or antihistamines such as diphenhydramine, may be used to manage these symptoms. In most patients, symptoms resolved and subsequent trastuzumab infusions were administered. Serious reactions were successfully managed with supportive therapy such as oxygen, beta-agonists, and corticosteroids (see section "Adverse reactions"). Rarely, these reactions were 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 comorbid conditions; therefore, Zercepac 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 occurred within several hours to one week after infusion. In very rare cases, patients experienced infusion-related symptoms and pulmonary symptoms more than 6 hours after the start of trastuzumab infusion. Patients should be informed of the possibility of such delayed onset of symptoms and advised to seek medical attention if such symptoms occur.

Pulmonary reactions

Severe pulmonary adverse reactions have been observed during post-marketing use of trastuzumab (see section "Adverse reactions"). These events have occasionally been fatal. Cases of interstitial lung disease have also been reported, including pulmonary 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. These events may occur as part of an infusion-related reaction or a delayed-onset reaction. Patients with baseline dyspnea due to lung metastases or comorbid conditions are at risk of pulmonary reactions and should not receive Zercepac. Caution should be exercised regarding pneumonitis, particularly in patients receiving concomitant taxane therapy.

Use during pregnancy or breastfeeding

Pregnancy

Women of reproductive potential should use effective contraception during treatment with Zercepac and for 7 months after the last dose of the drug (see section "Pharmacokinetics").

Reproductive toxicity studies in Cynomolgus monkeys receiving doses 25 times higher than the weekly maintenance dose for humans (2 mg/kg trastuzumab for intravenous administration) showed no evidence of impaired fertility or fetal harm. Placental transfer of trastuzumab was observed during both early (20–50 days of gestation) and late (120–150 days of gestation) stages of fetal development. It is unknown whether trastuzumab may affect reproductive capacity. Since animal reproductive studies do not always predict human response, trastuzumab should be avoided during pregnancy unless the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Post-marketing use of Zercepac has reported cases of fetal renal development abnormalities (e.g., renal hypoplasia) and/or impaired renal function, associated with oligohydramnios and sometimes linked to lethal fetal pulmonary hypoplasia when the drug was administered during pregnancy.

Women who become pregnant should be informed of the potential risk to the fetus. If a pregnant woman receives Zercepac or if a patient becomes pregnant during treatment with Zercepac or within 7 months after the last dose, intensive multidisciplinary medical monitoring is indicated.

Breastfeeding

In a study in lactating cynomolgus monkeys receiving Zercepac from day 120 to 150 of pregnancy at doses up to 25 times the weekly human maintenance dose (2 mg/kg body weight), trastuzumab was shown to be excreted into milk. The effects of in utero exposure to trastuzumab and the presence of trastuzumab in infant monkey serum were not associated with any adverse effects on growth or development from birth to 1 month of age. It is unknown whether trastuzumab is excreted in human breast milk. Since human IgG1 is excreted into breast milk and the potential harm to the infant is unknown, women should not breastfeed during treatment with Zercepac and for 7 months after the last dose.

Fertility

There is no information available on the effect of trastuzumab on fertility.

Effects on ability to drive and use machines

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

Administration and Dosage

Testing for HER2 tumor expression before starting treatment is mandatory (see sections "Indications" and "Pharmacodynamics"). Treatment with the medicinal product Zercepac must be initiated under the supervision of a physician experienced in the treatment of oncology patients.

The medicinal product Zercepac should be administered intravenously as an infusion only. Subcutaneous administration is prohibited!

To avoid medication errors, it is important to check the labels on the vials to ensure that Zercepac (trastuzumab) is being prepared and administered, and not trastuzumab-containing medicinal products (trastuzumab emtansine or trastuzumab deruxtecan).

Metastatic Breast Cancer

Administration once every 3 weeks

Recommended loading dose: 8 mg/kg body weight. Recommended maintenance dose: 6 mg/kg body weight every 3 weeks, initiated 3 weeks after the loading dose.

Weekly administration

Recommended loading dose: 4 mg/kg body weight. Recommended maintenance dose: 2 mg/kg body weight weekly, initiated 1 week after the loading dose.

Combination therapy with paclitaxel or docetaxel

In the pivotal study (H0648g, M77001), paclitaxel or docetaxel were administered the day after the first dose of trastuzumab (see the instructions for medical use of paclitaxel or docetaxel) and immediately after subsequent doses of trastuzumab if previous doses were well tolerated.

Combination with an aromatase inhibitor

In the pivotal study (BO16216), trastuzumab and anastrozole were administered from day 1. No restrictions on intervals between administration of these agents were established (for dosing, see the instructions for medical use of anastrozole or other aromatase inhibitors).

Early Breast Cancer

Weekly or once every 3 weeks administration

For the 3-weekly regimen, the recommended loading dose of Zercepac is 8 mg/kg body weight. The recommended maintenance dose of Zercepac administered every 3 weeks is 6 mg/kg body weight, initiated 3 weeks after the initial dose.

For the weekly regimen (loading dose of 4 mg/kg body weight followed by weekly doses of 2 mg/kg body weight) administered concurrently with paclitaxel after chemotherapy with doxorubicin and cyclophosphamide, follow the instructions for the respective medicinal products regarding dosing of combination chemotherapy.

Metastatic Gastric Cancer

Administration once every 3 weeks

The loading dose is 8 mg/kg body weight. The recommended maintenance dose administered 3 weeks after the loading dose is 6 mg/kg body weight.

Breast Cancer and Gastric Cancer

Duration of treatment

Patients with MBC or MGC should be treated with Zercepac until disease progression. Patients with EBC should receive treatment for 1 year or until disease recurrence, whichever occurs first. Treatment of early breast cancer should not be continued beyond 1 year.

Dose Reduction

Dose reductions were not performed during clinical trials. Treatment with Zercepac may continue 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 instructions.

If the left ventricular ejection fraction (LVEF) decreases by ≥ 10 percentage points from baseline to a level below 50%, treatment should be suspended and LVEF reassessed approximately 3 weeks later. If LVEF does not improve or further declines, or if symptomatic congestive heart failure (CHF) develops, discontinuation of Zercepac treatment should be seriously considered, except in cases where benefit to the individual patient outweighs the risk. All such patients should be referred for cardiology evaluation and monitored.

Missed Doses

If the missed administration of Zercepac is within 1 week or less (weekly regimen: 2 mg/kg body weight; 3-weekly regimen: 6 mg/kg body weight), the standard maintenance dose should be administered as soon as possible, without waiting for the next scheduled cycle. Subsequent maintenance doses should be administered 7 or 21 days later, depending on the weekly or 3-weekly regimen, respectively.

If a patient misses an administration of Zercepac for a period exceeding 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 (weekly regimen: 2 mg/kg body weight; 3-weekly regimen: 6 mg/kg body weight) should be administered 7 or 21 days later, depending on the weekly or 3-weekly regimen, respectively.

Special Patient Groups

Specific pharmacokinetic studies in elderly patients or patients with renal or hepatic impairment have not been conducted. Population pharmacokinetic analysis did not show that patient age or presence of renal impairment affects trastuzumab exposure.

Pediatric Patients

The safety and efficacy of Zercepac in children have not been studied.

Administration Method

Zercepac is intended for intravenous use only. The loading dose should be administered as a 90-minute intravenous infusion. Do not administer as an intravenous bolus or rapid push. The intravenous infusion of Zercepac should be administered by a healthcare professional trained to manage anaphylaxis, and emergency resuscitation equipment must be readily available. Patients should be monitored for at least 6 hours after the start of the first infusion and for at least 2 hours after the start of subsequent infusions for symptoms such as fever and chills or other infusion-related reactions (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). Interrupting or slowing the infusion rate may help manage such symptoms. The infusion may be resumed once symptoms subside.

If the initial loading dose is well tolerated, subsequent doses may be administered as a 30-minute infusion.

Preparation and Storage of Solution

Zercepac is supplied in sterile, preservative-free, non-pyrogenic, single-use vials.

Since the medicinal product does not contain antimicrobial preservatives or bacteriostatic agents, appropriate aseptic techniques must be followed during reconstitution and dilution. Sterility of prepared solutions must be ensured.

Aseptic Preparation, Handling, and Storage

Infusion preparation must be performed:

• by trained personnel according to good practice guidelines, especially regarding aseptic preparation of parenteral products;
• using a laminar flow hood or biological safety cabinet, and following standard precautions for safe handling of intravenous medicinal products.

The prepared solution must be stored under appropriate aseptic conditions.

Aseptic Reconstitution Instructions

1. Using a sterile syringe, slowly inject the appropriate volume (as specified below) of sterile water for injection (not supplied) into the vial of Zercepac, directing the stream onto the lyophilized powder. Avoid using other solvents for reconstitution.
2. Gently swirl the vial to facilitate reconstitution. DO NOT SHAKE!

To prevent formation of any precipitate and subsequent reduction in the amount of dissolved Zercepac, shaking and excessive foaming during reconstitution of Zercepac and preparation of the diluted infusion solution should be avoided. Rapid injection from a syringe should also be avoided.

Instructions for preparing 150 mg concentrate in a vial

Using a sterile syringe, slowly inject 7.2 mL of sterile water for injection into the vial of Zercepac powder to prepare a concentrate for infusion solution. Gently swirl the vial from side to side. Do not shake!

A small amount of foam may form during reconstitution. To minimize this, allow the solution to stand for approximately 5 minutes. The reconstituted concentrate should be clear and colorless or pale yellow. The solution should be essentially free of visible particles.

150 mg of Zercepac is reconstituted with 7.2 mL of sterile water for injection, resulting in 7.5 mL of solution for single use containing approximately 21 mg/mL of trastuzumab at a pH of approximately 6.0. A 5% overfill ensures that a 150 mg dose can be withdrawn from each vial.

The reconstituted solution must not be frozen.

Aseptic Dilution Instructions for 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 6 mg/kg body weight once 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 vial using a sterile needle and syringe and added to an infusion bag containing 250 mL of 0.9% sodium chloride. Do not use glucose-containing solutions (see section "Incompatibilities"). The infusion bag should be gently inverted to mix the solution without creating foam. Care must be taken to ensure sterility during preparation of the concentrate and the ready-to-use infusion solution. Parenteral medicinal products should be visually inspected before administration to confirm the absence of particles and discoloration.

The infusion solution should be used immediately after preparation. If diluted under aseptic conditions, the solution may be stored refrigerated at 2–8 °C for up to 24 hours.

Stability of Reconstituted Solution and Infusion Solution

Storage conditions and stability of the reconstituted solution are described in the section "Shelf Life". Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Children

The safety and efficacy of Zercepac in children have not been studied.

Overdose

No cases of overdose were reported in clinical trials. Single doses exceeding 10 mg/kg body weight have not been studied; however, a maintenance dose of 10 mg/kg three times weekly after an 8 mg/kg loading dose was studied in clinical trials in patients with metastatic gastric cancer. Doses up to this level were well tolerated.

Adverse Reactions

The most serious and/or commonly observed adverse reactions during treatment with the medicinal product Zercepac are cardiac dysfunction, infusion reactions, haematotoxicity (particularly neutropenia), infections, and pulmonary adverse reactions.

The following MedDRA terminology categories are used to describe the frequency of adverse reactions: 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), frequency not known (frequency cannot be estimated from available data).

Listed below are adverse effects and adverse reactions observed in pivotal clinical studies (N = 8386) and during post-marketing surveillance following intravenous administration of trastuzumab alone or in combination with chemotherapy.

All adverse reactions are listed at the highest percentage of occurrence observed in pivotal clinical studies. Additionally, adverse reactions reported during post-marketing surveillance are included.

Infections and parasitic diseases: very common – infections, nasopharyngitis; common – cystitis, influenza, pharyngitis, skin infections, sinusitis, upper respiratory tract infections, urinary tract infections, neutropenic sepsis, rhinitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency not known – progression of malignant neoplasm, progression of neoplasm.

Blood and lymphatic system disorders: very common – neutropenia, anaemia, febrile neutropenia, thrombocytopenia, leucopenia; frequency not known – hypoprothrombinaemia, immune thrombocytopenia.

Immune system disorders: common – hypersensitivity; rare – anaphylactic reactions+, anaphylactic shock+.

Metabolism and nutrition disorders: very common – weight decreased/weight loss, anorexia; frequency not known – tumour lysis syndrome, hyperkalaemia.

Psychiatric disorders: very common – insomnia; common – anxiety, depression.

Nervous system disorders: very common – tremor¹, dizziness, headache, paraesthesia, dysgeusia; common – peripheral neuropathy, hypertension, somnolence.

Eye disorders: very common – conjunctivitis, lacrimation increased; common – dry eye; frequency not known – optic disc oedema, retinal haemorrhage.

Ear and labyrinth disorders: uncommon – deafness.

Cardiac disorders: very common – increased blood pressure¹, decreased blood pressure¹, decreased ejection fraction*, atrial flutter¹, irregular heartbeat²; common – supraventricular tachyarrhythmia+¹, congestive heart failure+, cardiomyopathy, palpitations¹; uncommon – pericardial effusion; frequency not known – cardiogenic shock, gallop rhythm.

Vascular disorders: very common – flushing; common – hypotension, vasodilatation+¹.

Respiratory, thoracic and mediastinal disorders: very common – dyspnoea+, cough, epistaxis, rhinorrhoea; common – pneumonia+, asthma, lung disorders, pleural effusion+; uncommon – wheezing, pneumonia; frequency not known – pulmonary fibrosis*, respiratory distress+, respiratory failure+, lung infiltration+, acute pulmonary oedema+, acute respiratory distress syndrome+, bronchospasm+, hypoxia+, oxygen saturation decreased+, laryngeal oedema, orthopnoea, pulmonary oedema, interstitial lung disease.

Gastrointestinal disorders: very common – diarrhoea, vomiting, nausea, lip swelling, abdominal pain, dyspepsia, constipation, stomatitis; common – haemorrhoids, dry mouth.

Hepatobiliary disorders: common – hepatocellular disorders, hepatitis, liver tenderness on palpation; rare – jaundice.

Skin and subcutaneous tissue disorders: very common – erythema, rash, facial swelling¹, alopecia, nail disorders, hand-foot syndrome; common – acne, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, pruritus, onycholysis, dermatitis; uncommon – urticaria; frequency not known – angioneurotic oedema.

Musculoskeletal and connective tissue disorders: very common – arthralgia, muscle rigidity¹, myalgia; common – arthritis, back pain, bone pain, muscle spasms, neck pain, limb pain.

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

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

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

General disorders and administration site conditions: very common – asthenia, chest pain, chills, weakness, influenza-like symptoms, infusion reactions, pain, pyrexia, mucosal inflammation, peripheral oedema; common – malaise, oedema.

Injury, poisoning and procedural complications: common – contusion.

• The adverse reactions indicated were reported as fatal.

¹ The adverse reactions indicated were most frequently reported in association with infusion reactions. Exact percentages for these reactions are unknown.

* Observed during combination therapy following anthracyclines and in combination with taxanes.

Description of selected adverse effects

Cardiac dysfunction

Congestive heart failure (NYHA classes II–IV) is a common adverse reaction associated with trastuzumab use and has been associated with fatal outcomes (see section "Special warnings and precautions for use"). Signs and symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or decreased left ventricular ejection fraction have been observed in patients receiving trastuzumab therapy (see section "Special warnings and precautions for use").

In three pivotal adjuvant trastuzumab clinical trials combined with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (including symptomatic congestive heart failure) was similar in patients receiving chemotherapy alone (i.e., not receiving trastuzumab) and in patients receiving trastuzumab sequentially after taxane (0.3–0.4%). The highest incidence was observed in patients receiving trastuzumab concomitantly with taxane (2.0%). Experience with concurrent use of trastuzumab and low-dose anthracyclines in neoadjuvant therapy is limited (see section "Special warnings and precautions for use").

When trastuzumab was administered after completion of adjuvant chemotherapy, NYHA class III–IV heart failure was observed in 0.6% of patients in the one-year group after a median follow-up of 12 months. In study BO16348, after a median follow-up of 8 years, the incidence of severe CHF (NYHA classes III and IV) in the 1-year trastuzumab treatment group was 0.8%, and the incidence of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.

Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥ 50% after the event) was evident in 71.4% of patients receiving trastuzumab. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated in 79.5% of patients. Approximately 17% of cardiac dysfunction events occurred after completion of trastuzumab therapy.

In pivotal metastatic studies of intravenous trastuzumab, the incidence of cardiac dysfunction ranged from 9% to 12% when combined with paclitaxel compared to 1–4% with paclitaxel alone. For monotherapy, this rate was 6–9%. The highest rate 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 study 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.

The majority (79%) of patients who developed cardiac dysfunction in these studies experienced improvement after receiving standard CHF treatment.

Infusion reactions, allergic reactions and hypersensitivity

It is estimated that approximately 40% of patients receiving trastuzumab therapy experience some type of infusion-related reaction. However, most infusion-related reactions are mild or moderate in severity (NCI-CTC scale) and typically occur early in treatment, i.e., during the first, second, or third infusions, and decrease in frequency with subsequent infusions. Reactions include chills, fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, respiratory distress, rash, nausea, vomiting, and headache (see section "Special warnings and precautions for use"). The frequency of infusion-related reactions of all grades varied across studies depending on indications, data collection methodology, and whether trastuzumab was administered concurrently with chemotherapy or as monotherapy.

Severe anaphylactic reactions requiring immediate additional intervention usually occurred during the first or second trastuzumab infusion (see section "Special warnings and precautions for use") and were associated with fatal outcomes.

Anaphylactoid reactions have been observed in isolated cases.

Haematotoxicity

Febrile neutropenia, leucopenia, anaemia, thrombocytopenia, and neutropenia occurred very commonly. The frequency of hypoprothrombinaemia is unknown. The risk of neutropenia may be slightly increased when trastuzumab is used with docetaxel following anthracycline therapy.

Lung disorders

Severe pulmonary adverse reactions occurred in association with trastuzumab use and were associated with fatal outcomes. These include, in particular, lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema, and respiratory failure (see section "Special warnings and precautions for use").

Detailed information on risk minimization measures is provided in section "Special warnings and precautions for use".

Immunogenicity

In the neoadjuvant/adjuvant HER2-positive breast cancer study (BO22227), antibodies to trastuzumab (treatment-induced antibodies and antibodies occurring at higher titres due to treatment) were detected in 10.1% (30/296) of patients, with a median observation period of over 70 months. Neutralizing antibodies were detected in post-baseline samples from 2 out of 30 patients receiving trastuzumab. The clinical significance of these antibodies is unknown. However, there was no negative impact of these anti-trastuzumab antibodies on the pharmacokinetics, efficacy (defined as pathological complete response [pCR]), or safety (defined by the frequency of infusion reactions) of trastuzumab.

There are no available data on the immunogenicity of trastuzumab in gastric cancer.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life

4 years.

After aseptic reconstitution with sterile water for injection, chemical and physical stability of the reconstituted solution has been demonstrated for 48 hours at 2–8 °C.

After aseptic dilution in polyethylene or polypropylene bags containing 0.9% (9 mg/mL) sodium chloride injection solution, chemical and physical stability has been demonstrated for up to 84 days at 2–8 °C, 7 days at 23–27 °C, and 24 hours at 30 °C.

From a microbiological standpoint, the reconstituted solution and infusion solution should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user and should generally not exceed 24 hours at 2–8 °C, except when reconstitution was performed under controlled and validated aseptic conditions.

Storage conditions

Store in a refrigerator at 2–8 °C. Keep out of the reach of children.

Incompatibilities

The medicinal product Zercepac must not be mixed or diluted with other medicinal products except as specified in the section "Dosage and administration".

Zercepac is incompatible with glucose solutions due to the potential for protein aggregation.

Packaging
150 mg in a vial, 1 vial in a carton.

Prescription status

Prescription only.

Manufacturer

Accord Healthcare Polska Sp. z o.o. Importer's Warehouse/Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and place of business

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorization Holder

Accord Healthcare S.L.U.

Inquiries regarding substandard quality of the medicinal product, safety concerns, improper use, or complaints are accepted 24/7 via phone: +380993100335 or by email: [email protected]

Marketing Authorization Holder's address

World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain.