Herzuma®
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product Herzuma®
Composition:
Active substance: trastuzumab;
1 multidose vial of lyophilisate contains: 440 mg trastuzumab;
Excipients: L-histidine hydrochloride, L-histidine, α,α-trehalose dihydrate, polysorbate 20;
Solvent: bacteriostatic water for injections 20 ml, containing 1.1% benzyl alcohol (as antimicrobial preservative) and water for injections.
Pharmaceutical form. Lyophilisate for concentrate for solution for infusions.
Main physicochemical properties: lyophilized powder ranging from white to pale yellow. The reconstituted solution is a clear or slightly opalescent liquid, colorless or light yellow. The solvent is a clear, colorless or almost colorless liquid.
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 erbB2) encodes a transmembrane receptor-like single-chain protein with a molecular weight of 185 kDa, structurally similar to the epidermal growth factor receptor. HER2 overexpression occurs 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 positive 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.
Studies in animals and in vitro experiments have demonstrated that trastuzumab inhibits proliferation of human tumor cells overexpressing HER2. Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity. In vitro, trastuzumab-induced antibody-dependent cell-mediated cytotoxicity is primarily directed against tumor cells overexpressing HER2.
Determination of HER2 overexpression or HER2 gene amplification in breast cancer
Trastuzumab should only be used 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 method of administration"). HER2 gene amplification is determined by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) in 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:
| Assessment of staining intensity in scores |
Type of staining |
Assessment of HER2 overexpression |
| 0 |
No staining observed or staining of membranes in < 10% of tumor cells. |
Negative |
| 1+ |
Faint/ barely perceptible staining of membranes in > 10% of tumor cells. Membranes are stained only partially in cells. |
Negative |
| 2+ |
Complete staining of membranes in > 10% of tumor cells, ranging from weak to moderate. |
Equivoval |
| 3+ |
Complete staining of membranes in > 10% of tumor cells, ranging from moderate to strong. |
Positive |
In general, the FISH test is considered positive if the ratio of the number of HER2 gene copies in a 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 a tumor cell when chromosome 17 testing is not performed. In general, 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 validated and reliable methodologies should be used to determine HER2 overexpression or HER2 gene amplification. IHC is recommended as the initial testing method. 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 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 a HER2-positive status defined as IHC 3+ or FISH-positive. Clinical trial results showed a positive treatment effect of the drug 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 should be determined by in situ hybridization methods, such as FISH or SISH, using fixed tumor blocks.
Recommended scoring system for evaluating HER2 overexpression by IHC:
| Score |
Surgical specimen – staining type |
Biopsy specimen – staining type |
HER2 overexpression assessment |
| 0 |
No staining or membrane reactivity in < 10 % of tumor cells. |
Absence of reactivity or membranous reactivity in any tumor cell |
Negative |
| 1+ |
Faint/barely perceptible membrane reactivity in > 10 % of tumor cells; only part of the membrane stained |
Cluster of tumor cells with faint/barely perceptible membrane reactivity, regardless of the percentage of stained cells |
Negative |
| 2+ |
Faint to moderate complete basolateral membrane reactivity in > 10 % of tumor cells |
Cluster of tumor cells with faint to moderate complete basolateral or lateral membrane reactivity, regardless of the percentage of stained cells |
Equívocal |
| 3+ |
Strong complete basolateral or lateral membrane reactivity in > 10 % of tumor cells |
Cluster of tumor cells with strong complete basolateral or lateral membrane reactivity, regardless of the percentage of stained cells |
Positive |
In general, 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 predominantly observed in the intestinal histological subtype. In contrast to breast cancer, immunohistochemical staining methods are largely ineffective in gastric cancer.
HER2 can 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 1,582 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 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.
Linear clearance was 0.136 L/day in breast cancer patients. The maximum elimination rate (Vmax) in 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 values (with 5th to 95th percentiles) and pharmacokinetic parameter values at clinically relevant drug concentrations (Cmax and Cmin) 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 exposure values during cycle 1 (median with 5–95 percentiles) for intravenous treatment regimens in patients with breast cancer and metastatic gastric cancer
| Dosing |
Type of primary tumor |
N (number of patients) |
Cmin (μg/mL) |
Cmax (μg/mL) |
AUC0–21 day (μg·day/mL) |
| 8 mg/kg + 6 mg/kg once every 3 weeks |
Metastatic breast cancer/ |
805 |
28.7 (2.9–46.3) |
182 (134–280) |
1376 (728–1998) |
| Early-stage breast cancer |
390 |
30.9 (18.7–45.5) |
176 (127–227) |
1390 (1039–1895) |
|
| Metastatic gastric cancer |
274 |
23.1 |
132 |
1109 |
|
| 4 mg/kg + 2 mg/kg once weekly |
Metastatic breast cancer/ |
805 |
37.4 |
76.5 |
1073 |
| Early-stage breast cancer |
390 |
38.9 (25.3–58.8) |
76.0 (54.7–104) |
1074 (783–1502) |
Table 2
Predicted population pharmacokinetic exposure values at steady state (with median 5–95 percentiles) for intravenous trastuzumab regimens in patients with breast cancer, early-stage breast cancer, and metastatic gastric cancer
| Doses |
Type of primary tumor |
N (number of patients) |
Cmin,ss* (μg/mL) |
Cmax,ss** (μg/mL) |
AUC (μg·day/mL) |
Time to reach steady state *** (weeks) |
| 8 mg/kg + 6 mg/kg once every 3 weeks |
metastatic breast cancer |
805 |
44.2 (1.8–85.4) |
179 (123–266) |
1736 (618–2756) |
12 |
| early-stage breast cancer |
390 |
53.8 (28.7–85.8) |
184 (134–247) |
1927 (1332–2771) |
15 |
|
| metastatic gastric cancer |
274 |
32.9 |
131 |
1338 |
9 |
|
| 4 mg/kg + 2 mg/kg once weekly |
metastatic breast cancer |
805 |
63.1 |
107 |
1710 |
12 |
| early-stage breast cancer |
390 |
72.6 (46–109) |
115 (82.6–160) |
1893 (1309–2734) |
14 |
* Cmin,ss = Cmin at steady state
** Cmax,ss = Cmax at steady state
*** time to reach 90% of steady state
Population predicted PK parameters at steady state for intravenous regimens of trastuzumab in patients with metastatic breast cancer, early breast cancer, and metastatic gastric cancer
| Dosage |
Type of primary tumor |
N (number of patients) |
Overall clearance, range from Cmax,ss to Cmin,ss (L/day) |
T1/2, range from Cmax,ss to Cmin,ss (days) |
| 8 mg/kg + 6 mg/kg once every 3 weeks |
Metastatic breast cancer |
805 |
0.183–0.302 |
15.1–23.3 |
| Early-stage breast cancer |
390 |
0.158–0.253 |
17.5–26.6 |
|
| Metastatic gastric cancer |
274 |
0.189–0.337 |
12.6–20.6 |
|
| 4 mg/kg + 2 mg/kg once weekly |
Metastatic breast cancer |
805 |
0.213–0.259 |
17.2–20.4 |
| Early-stage breast cancer |
390 |
0.184–0.221 |
19.7–23.2 |
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 of the drug were < 1 mcg/mL seven months after the last dose (approximately 3% of the population-predicted Cmin,ss, or approximately 97% elimination).
Soluble extracellular domain of the HER2 receptor
Covariate analysis of data obtained from a subgroup of patients showed that individuals with higher baseline levels of circulating extracellular domain of the HER2 receptor exhibited a faster nonlinear clearance (at concentrations below 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 (MGC) were comparable to those in patients with metastatic breast cancer and early-stage breast cancer, and no significant impact on trastuzumab clearance was observed.
Clinical characteristics.
Indications.
Breast cancer
Prior to initiating treatment with the medicinal product Herzuma®, it is necessary to confirm the presence of HER2 protein overexpression in tumor tissue in patients — either by immunohistochemical analysis (staining must be assessed 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 protein 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 received adjuvant treatment for early-stage breast cancer with Herzuma®.
HER2-positive early-stage breast cancer:
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 treatment with 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
The medicinal product 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 protein overexpression, i.e., with an expression level of 2+ as determined by immunohistochemical (IHC) analysis and a positive result by FISH or silver in situ hybridization (SISH), or with an expression level of 3+ by IHC analysis. Validated and accurate analytical methods must be used.
Contraindications.
The medicinal product Herzuma® is contraindicated in patients with hypersensitivity to trastuzumab, proteins from Chinese hamster ovary cells, any other components of the medicinal product, or any components of the diluent.
In metastatic breast cancer as well as in adjuvant treatment, the medicinal product Herzuma® and anthracyclines should not be administered simultaneously. 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 measures.
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 administered 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 (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 (administered at an initial loading dose of 8 mg/kg or 4 mg/kg intravenously, followed by 6 mg/kg intravenously every 3 weeks or 2 mg/kg weekly, respectively). However, trastuzumab may increase 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 a non-comparative study (JP16003) evaluating the effect of trastuzumab (loading dose 4 mg/kg intravenously, followed by 2 mg/kg intravenously weekly) and docetaxel (60 mg/m² intravenously) in Japanese women with HER2-positive MBC indicated that concomitant administration of trastuzumab had no effect on the pharmacokinetics of a single dose of docetaxel. Study JP19959 was a sub-study 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 drug interaction sub-study indicate 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 capecitabine concentrations and a longer elimination half-life 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 serum trastuzumab concentration modeling after monotherapy with trastuzumab (loading dose 4 mg/kg, followed by 2 mg/kg intravenously weekly) 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 concurrently, and two phase II studies where 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 no clear effect of concomitant paclitaxel administration on trastuzumab pharmacokinetics was observed.
No evidence of an effect of concomitant docetaxel administration on trastuzumab pharmacokinetics was found in a comparative analysis of plasma trastuzumab concentration modeling after its administration (as monotherapy with a weekly intravenous loading dose) and plasma trastuzumab concentrations in Japanese female patients with HER2-positive MBC (study JP16003). In phase 2 clinical trials involving HER2-positive female patients with MBC, and in a phase 3 clinical trial combining trastuzumab and paclitaxel, pharmacokinetic results were compared. Mean trough trastuzumab concentrations varied within and across clinical trials, but the impact of concomitant paclitaxel administration on trastuzumab pharmacokinetics was not clearly defined. Concomitant administration of anastrozole with trastuzumab did not affect trastuzumab pharmacokinetics.
Special precautions for use
Herzuma® for multiple use (benzyl alcohol)
Benzyl alcohol (a preservative contained in bacteriostatic water for injection) may cause allergic reactions. The use of benzyl alcohol is associated with a risk of serious adverse reactions, including respiratory disorders (so-called "gasping syndrome") in young children. The medicinal product should not be used in newborns and young children. For patients with hypersensitivity to benzyl alcohol, the lyophilisate for concentrate for solution for infusion should be reconstituted exclusively with water for injection; only a single dose should be drawn from the vial, and any unused portion of the medicinal product must be discarded.
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 treatment with Herzuma®. These events may represent infusion-related reactions and may have a delayed onset. Most of these events occurred during or within 2.5 hours after 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.
To reduce the risk of infusion-related reactions, premedication may be administered. Patients should be closely monitored and informed about the necessity to report such reactions immediately. If such reactions occur, infusion of Herzuma® should be stopped, and the patient should be monitored 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 infusions of trastuzumab were administered.
Serious reactions have been successfully managed with supportive therapy, such as oxygen, beta-antagonists, and corticosteroids (see section "Adverse reactions"). Rarely, such reactions have been associated with potentially fatal clinical outcomes. The risk of developing fatal infusion reactions is increased in patients with dyspnea at rest 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 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 factors to consider.
Patients receiving trastuzumab therapy have an increased risk of developing congestive heart failure of NYHA functional classes II–IV or asymptomatic cardiac 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 vary from moderate to severe and may lead to fatal outcomes (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).
Trastuzumab and anthracyclines should not be administered concurrently in metastatic breast cancer or in the adjuvant treatment regimen. In the neoadjuvant setting, concomitant use 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 therapy should not exceed 180 mg/m² (doxorubicin) or 360 mg/m² (epirubicin). If patients have received neoadjuvant low-dose anthracyclines and trastuzumab concomitantly, 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 used. Overall, their frequency 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 vascular system for up to 27 weeks after treatment discontinuation.
The risk of cardiotoxicity is increased in patients receiving anthracyclines after discontinuation of Herzuma®. If possible, anthracycline-based therapy should be avoided for 7 months after the last dose of Herzuma®.
All patients should undergo a thorough cardiac evaluation prior to initiation of Herzuma® therapy, especially those who have previously received anthracyclines. The 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 chemotherapy with anthracyclines, 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 should be reassessed after approximately 3 weeks. If LVEF does not improve or further declines, or if clinically significant heart failure develops, Herzuma® should be discontinued unless the benefit for the individual patient outweighs the risk. In patients who develop asymptomatic cardiac dysfunction, monitoring should be intensified (e.g., every 6–8 weeks). Persistent left ventricular dysfunction, even in the absence of clinical symptoms, should prompt consideration of discontinuing trastuzumab therapy 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 cases of symptomatic heart failure developing during trastuzumab therapy, standard heart failure treatments should be used. The condition of most patients with heart failure or asymptomatic cardiac dysfunction in baseline studies improved with the use of 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 effect on trastuzumab distribution.
Adjuvant and neoadjuvant therapy
Patients with a history of myocardial infarction, untreated angina, congestive heart failure (including history of NYHA functional class II–IV), other cardiomyopathies, arrhythmias requiring treatment, 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 frequency of symptomatic and asymptomatic cardiac events was higher when Herzuma® was administered after anthracycline-containing chemotherapy compared to regimens with docetaxel or carboplatin that did not include anthracyclines. The frequency of such events was higher with concomitant use 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 advanced age (>50 years), low baseline LVEF (<55%), reduced 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 administered before starting Herzuma® and high 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 anticancer agents capable of causing interstitial lung disease, such as taxanes, gemcitabine, vinorelbine, and radiation therapy. Patients with dyspnea at rest due to extensive malignant disease or comorbid 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 unfavorable 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). No adverse effects on fertility or fetal harm were observed. Trastuzumab was shown to cross the placenta during both early (gestational age 20–50 days) and late (gestational age 120–150 days) stages of 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 worsening renal function associated with oligohydramnios have been reported in pregnant women receiving trastuzumab, some of which were accompanied by fetal lung hypoplasia and fatal outcomes. Women of childbearing potential should be advised to use effective contraception during trastuzumab therapy and for at least 7 months after completion of treatment. Women who become pregnant during trastuzumab therapy 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.
A lactation study 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 reaction speed when driving or operating machinery.
Herzuma® has a minor influence on the ability to drive or 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.
Method of Administration and Dosage
It is important that treatment with Herceptin® be initiated under the supervision of a qualified physician experienced in the treatment of oncology patients.
Prior to initiating therapy, HER2 status must be determined (see section "Indications").
To avoid medication errors in the use of prescribed medicinal products, it is essential to verify the labels on the injection vials to ensure that the prepared and administered product is indeed Herceptin® (trastuzumab), and not trastuzumab emtansine. Herceptin® should be administered as an intravenous infusion. Intravenous bolus or rapid push administration of the drug is not permitted!
Recommended initial and maintenance doses for both monotherapy and combination therapy regimens are outlined below.
Metastatic Breast Cancer: Weekly Regimen
Monotherapy
Loading Dose
The recommended loading dose of Herceptip® 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 the event of infusion-related reactions, the infusion should be interrupted. The infusion may be resumed once symptoms have resolved.
Maintenance Doses
The recommended weekly maintenance dose of Herceptin® 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 the event of infusion-related reactions, the infusion should be interrupted. The infusion may be resumed once symptoms have resolved.
Combination Therapy with Paclitaxel or Docetaxel
The dosage of Herceptin® in combination therapy does not differ from that used in monotherapy. Administration of paclitaxel or docetaxel should occur the day after the first dose of Herceptin®. Subsequently, paclitaxel or docetaxel may be administered every 3 weeks immediately after maintenance doses of Herceptin®, provided prior administrations were well tolerated.
For dosing recommendations for paclitaxel or docetaxel, refer to the respective product instructions.
Combination with an Aromatase Inhibitor
The dosage of Herceptin® in combination therapy does not differ from that used in monotherapy. In the pivotal study, Herceptin® and anastrozole were administered on Day 1. No restrictions on the interval between administration of these agents were established. For anastrozole dosing information, refer to the respective product instructions. If the patient was previously receiving tamoxifen, its use should be discontinued at least one day prior to initiating combination therapy.
Metastatic Breast Cancer: Administration 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 Herceptin® is 8 mg/kg body weight, followed 3 weeks later by a dose of 6 mg/kg body weight. Subsequent maintenance doses of Herceptin® 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 reduced to 30 minutes.
Early-Stage Breast Cancer
The treatment regimens with Herceptin® described below should be continued until recurrence or for a total of 52 weeks (1 year), whichever occurs 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 Every 3 Weeks
With the 3-weekly regimen, the recommended loading dose of Herceptin® is 8 mg/kg body weight. The recommended maintenance dose of Herceptin® administered every 3 weeks is 6 mg/kg body weight, starting 3 weeks after the initial dose.
If monotherapy with Herceptin® is continued after combination with chemotherapy, a dose of 6 mg/kg every 3 weeks should be administered.
For information on studies of Herceptin® 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 3 weeks later by a dose of 6 mg/kg body weight. Maintenance doses of Herceptin® 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 reduced to 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 Herceptin® until disease progression. Patients with early-stage breast cancer should receive treatment for 1 year or until 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 Herceptin® infusion is delayed 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 Herceptin® (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 Herceptin® infusion for more than 1 week, a new loading dose should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg body weight; 3-weekly regimen: 8 mg/kg body weight). Subsequent maintenance doses of Herceptin® (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 reductions were not performed in clinical trials. Treatment with Herceptin® 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 Herceptin® is not age-dependent (see section "Pharmacokinetics"). Dose adjustments were not made in clinical trials involving elderly patients.
Children
The safety and efficacy of Herceptin® in children and adolescents have not been studied.
Preparation of Herceptin® 440 mg for Multiple Dosing
Preparation for Administration
Appropriate aseptic techniques must be used. The Herceptin® vial should be reconstituted with 20 mL of bacteriostatic water for injection containing 1.1% benzyl alcohol. This results in a solution for multiple use containing 21 mg/mL of trastuzumab at a pH of approximately 6.0. Other solvents should be avoided.
For patients hypersensitive to benzyl alcohol, the drug may also be reconstituted with sterile water for injection (not included in the package). Such solutions should be used immediately, and any unused portion should be discarded.
To prevent precipitation and subsequent loss of dissolved Herceptin®, shaking and excessive foaming during reconstitution and preparation of the diluted infusion solution should be avoided. Rapid injection from a syringe should also be avoided.
Reconstitution
- Using a sterile syringe, slowly inject 20 mL of bacteriostatic water into the vial containing the lyophilized powder for the concentrate solution for infusion of Herceptin®.
- 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 remain. The color of the prepared solution ranges from clear to pale yellow.
Further Dilution of Herceptin® in Single- and Multiple-Dose Vials
The volume of reconstituted solution required for a specific patient is calculated as follows:
-
For administration of an initial 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 an initial dose of trastuzumab of 8 mg/kg body weight or subsequent doses 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 440 mg multi-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 confirm the absence of particles and discoloration.
Storage of Reconstituted Solution and Infusion Solution
Any unused reconstituted solution or infusion solution prepared under non-controlled and non-validated aseptic conditions must be discarded.
Herceptin® 440 mg for Multiple Use
The contents of the Herceptin® vial reconstituted with bacteriostatic water for injection contain a preservative (1.1% benzyl alcohol) and are stable for 28 days when stored at 2–8°C. The reconstituted solution contains a preservative and is therefore suitable for multiple use. Any residual reconstituted solution remaining after 28 days must be discarded. Do not freeze the reconstituted solution.
If the patient is hypersensitive to benzyl alcohol (see section "Special Warnings and Precautions for Use: Herceptin® for Multiple Use (Benzyl Alcohol)"), the drug should be reconstituted with sterile water for injection, and only one dose may be withdrawn from the vial. The prepared solution must be used immediately. Any unused portion should be discarded.
Infusion Solution of Herceptin®
The reconstituted Herceptin® solution for infusion, prepared with bacteriostatic water for injection and diluted in polyvinyl chloride, polyethylene, or polypropylene bags containing 0.9% sodium chloride, is physically and chemically stable for 48 hours at 2–8°C (do not freeze). From a microbiological standpoint, the Herceptin® infusion solution should be used immediately unless it was prepared under controlled, validated aseptic conditions.
Children.
The safety and efficacy of Herceptin® in children and adolescents have not been studied.
Overdose.
Cases of overdose have not been reported in clinical trials. Single doses exceeding 10 mg/kg body weight have not been studied.
Adverse Reactions
The most serious and/or frequently observed adverse reactions during treatment with HerzuMA® are cardiotoxicity, infusion reactions, hematotoxicity (especially neutropenia), infections, and pulmonary adverse reactions.
Heart failure of NYHA class II–IV is a common adverse event during treatment with trastuzumab and, in some cases, may be fatal (see section "Special Warnings and Precautions for Use").
Infusion reactions of any type occur in approximately 40% of patients receiving trastuzumab. However, most infusion-related adverse effects are mild to moderate in severity (according to National Cancer Institute Common Toxicity Criteria, NCI-CTC) and primarily occur 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 occur very rarely, usually during the first or second infusion of trastuzumab (see section "Special Warnings and Precautions for Use").
Leukopenia, febrile neutropenia, anemia, and thrombocytopenia are very commonly observed. Neutropenia is considered a common adverse effect. The frequency of hypoprothrombinemia is unknown. Serious pulmonary adverse reactions during trastuzumab treatment occur rarely, 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 for Use").
List of Adverse Reactions
The following classification is used to describe the frequency of adverse reactions 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), and 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, neutropenic sepsis, 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, thinking abnormalities;
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 – paresis, ataxia, cerebral edema, lethargy, coma, cerebrovascular disorders.
Eye disorders:
Very common – lacrimation increased (> 10%), conjunctivitis (> 10%);
Common – dry eye;
Frequency not known – optic disc edema, retinal hemorrhage, madarosis.
Ear and labyrinth disorders:
Uncommon – deafness;
Frequency not known – paresis, ataxia, cerebral edema, lethargy, coma, cerebrovascular disorders.
Eye disorders:
Very common – increased lacrimation (> 10%), conjunctivitis (> 10%);
Common – dry eye;
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%), hot flushes (> 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, hiccups, 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 dysesthesia (> 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 reactions (40%), pain (12%), pyrexia (12%), peripheral edema (> 10%), mucosal inflammation (> 10%);
Common – malaise, edema.
Immunogenicity
During neoadjuvant/adjuvant treatment, anti-trastuzumab antibodies were detected in 8.1% of patients (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 functional 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 reduced 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) of grade 3/4 according to the NCI-CTC scale (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 concomitantly 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, NYHA class III–IV heart failure 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 after 1 year of 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 treatment.
In pivotal metastatic trials of intravenous trastuzumab, the incidence of cardiac dysfunction ranged from 9% to 12% when administered concomitantly 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 concomitantly 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 plus docetaxel, compared to 0% in those 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 concomitantly 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 concomitantly 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 different studies, depending on the indication, data collection methodology, and whether trastuzumab was administered concomitantly 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 administered with docetaxel following anthracycline-based 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 the cardiac event) 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 cardiac 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: a decline in LVEF of ≥ 10% to below 50% was observed in 18.5% of the AC→PH group. Reversibility of left ventricular dysfunction was observed in 64.5% of AC→PH patients who had symptomatic CHF and were asymptomatic at last observation, and in 90.3% of patients who showed 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 – bacteriostatic water for injection) is 28 days when stored at 2 to 8 °C. Do not freeze. Any unused portion of reconstituted solution must be discarded after 28 days.
The shelf life of the reconstituted (diluent – bacteriostatic water for injection) and further diluted solution in polyvinyl chloride, polyethylene, or polypropylene bags containing 0.9% sodium chloride is physically and chemically stable for 48 hours when stored at 2 to 8 °C.
Incompatibilities
No incompatibility of HerzuMA® with polyvinyl chloride, polyethylene, or polypropylene bags has been reported.
Glucose 5% solution should not be used due to protein aggregation.
HerzuMA® must not be mixed with other medicinal products or reconstituted in them.
Packaging
440 mg of lyophilisate in a vial made of colorless glass, closed with a stopper and a flip-off cap. 20 mL of diluent in a vial made of colorless glass, closed with a stopper and a flip-off cap. One vial of lyophilisate and one vial of diluent in a carton.
Prescription Category
Prescription only.
Manufacturer
CELLTRION, Inc.
Manufacturer's Address and Place of Business
20, Academy-ro 51 beon-gil, Yeonsu-gu, Incheon, 22014, Republic of Korea.
Marketing Authorization Holder
Celltrion Healthcare Co., Ltd.
Address 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 Ltd., Hungary.