Herceptin
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HERCEPTIN® (HERCEPTIN®)
Composition:
Active substance: trastuzumab;
One single-dose vial of lyophilisate contains trastuzumab 150 mg; one multi-dose vial of lyophilisate contains trastuzumab 440 mg;
1 ml of prepared (reconstituted) solution contains trastuzumab 21 mg;
Excipients: L-histidine hydrochloride monohydrate, L-histidine, α,α-trehalose dihydrate, polysorbate 20;
Solvent: bacteriostatic water for injections – 20 ml, containing 1.1% benzyl alcohol and water for injections.
Pharmaceutical form. Lyophilisate for concentrate for solution for infusion, 150 mg or 440 mg.
Main physicochemical properties: the product is a lyophilisate ranging from white to pale yellow. The reconstituted solution is a clear or slightly opalescent liquid, colorless or pale yellow. The solvent is a clear, colorless or almost colorless liquid.
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
Mechanism of Action
Trastuzumab is a recombinant humanized kappa monoclonal IgG1 antibody 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 c-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 is observed in 15–20% of all cases of primary breast cancer. The overall frequency of HER2-positive metastatic gastric cancer observed during screening for study BO18255 was 15% based on positive IHC3+ or IHC2+/FISH+ test results, or 22.1% when using a broader definition according to which either IHC3+ or FISH+ results are sufficient to define HER2-positive status. Amplification of the HER2 gene leads to increased expression of the HER2 protein on the surface of these tumor cells, resulting in strong activation of the HER2 receptor.
Studies in patients with breast cancer have shown that patients with HER2-overexpressing tumors have shorter disease-free survival compared to patients without tumor HER2 overexpression.
Studies in animals and in vitro experiments have demonstrated that trastuzumab inhibits proliferation of human tumor cells overexpressing HER2. Trastuzumab mediates antibody-dependent cellular cytotoxicity. In vitro, trastuzumab-induced antibody-dependent cellular cytotoxicity is primarily directed against tumor cells overexpressing HER2.
Pharmacokinetics
The pharmacokinetics of trastuzumab were evaluated through a population pharmacokinetic analysis using a model based on pooled data from 1,582 patients who received Herceptin® intravenously (18 Phase I, II, and III studies).
Absorption
Not applicable.
Distribution
Tables 1 and 2 present population-predicted pharmacokinetic exposure values (with 5th to 95th percentiles) and pharmacokinetic parameter values at clinically relevant drug concentrations (Cmax and Cmin) for patients with breast cancer and metastatic gastric cancer receiving treatment according to approved weekly and every-three-week regimens.
Table 1
Population-predicted pharmacokinetic exposure values during Cycle 1 (with median 5th–95th percentiles) for intravenous treatment regimens in patients with breast cancer and metastatic gastric cancer
| Dosing |
Type of primary tumor |
N |
Cmin (μg/mL) |
Cmax (μg/mL) |
AUC (μg·day/mL) |
| 8 mg/kg + 6 mg/kg once every 3 weeks |
Metastatic breast cancer/early-stage breast cancer |
1195 |
29.4 (5.8–59.5) |
178 (117–291) |
1373 (736–2245) |
| Metastatic gastric cancer |
274 |
23.1 |
132 |
1109 |
|
| 4 mg/kg + 2 mg/kg once weekly |
Metastatic breast cancer/early-stage breast cancer |
1195 |
37.7 |
88.3 |
1066 |
Table 2
Predicted population pharmacokinetic exposure values at steady state (with median 5–95 percentiles) for intravenous treatment regimens in patients with breast cancer and metastatic gastric cancer
| Doses |
Type of primary tumor |
N |
Cmin,ss (μg/mL) |
Cmax,ss (μg/mL) |
AUC (μg·day/mL) |
Time to reach steady state (weeks) |
Overall steady-state clearance range (L/day) |
| 8 mg/kg + 6 mg/kg every 3 weeks |
metastatic breast cancer/early-stage breast cancer |
1195 |
47.4 (5 – 115) |
179 (107 – 309) |
1794 (673 – 3618) |
12 |
0.173 – 0.283 |
| metastatic gastric cancer |
274 |
32.9 |
131 |
1338 |
9 |
0.189 – 0.337 |
|
| 4 mg/kg + 2 mg/kg once weekly |
metastatic breast cancer/early-stage breast cancer |
1195 |
66.1 |
88.3 |
1765 |
12 |
0.201 – 0.244 |
Metabolism
Not applicable.
Elimination
The elimination half-life of trastuzumab was estimated following intravenous and subcutaneous administration using appropriate population pharmacokinetic (PK) models. Results from these studies demonstrate that in at least 95 % of patients, serum trastuzumab concentrations were < 1 mcg/mL 7 months after the last dose (approximately 3 % of the predicted population Cmin,ss, or about 97 % elimination).
Circulating antigens in blood
Breast cancer: measurable concentrations of circulating extracellular domain of HER2 receptors (shed antigen) are observed in serum of 64 % of patients with HER2-positive breast cancer (up to 1880 ng/mL; median value – 11 ng/mL). Patients with higher baseline levels of shed antigen are more likely to have lower minimum trastuzumab concentrations. With weekly administration of the drug, target serum trastuzumab concentrations were achieved by week 6 in the majority of patients with elevated shed antigen levels. No significant correlation was observed between baseline shed antigen levels and clinical response to treatment.
Data on shed antigen levels in patients with gastric cancer or gastroesophageal junction cancer are not available.
Linearity/Non-linearity
The trastuzumab concentration-time profile was characterized by a two-compartment model with parallel linear and non-linear elimination from the central compartment. Due to the non-linear elimination, total clearance increases as concentration decreases. Linear clearance was 0.127 L/day in breast cancer (metastatic breast cancer/early-stage breast cancer) and 0.176 L/day in metastatic gastric cancer. The maximum elimination rate (Vmax) for non-linear 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.
Special patient groups
Patients with hepatic impairment
Detailed pharmacokinetic studies have not been conducted in patients with hepatic impairment.
Patients with renal impairment
Detailed pharmacokinetic studies have not been conducted in patients with renal impairment.
Population pharmacokinetic analysis showed that renal impairment does not affect trastuzumab disposition. Serum creatinine levels have been shown not to influence the pharmacokinetic profile of trastuzumab.
Elderly patients
Detailed pharmacokinetic studies have not been conducted in elderly patients. Patient age does not affect the pharmacokinetics of trastuzumab.
Clinical characteristics.
Indications.
Breast cancer
Prior to initiating treatment with Herceptin**®**, the presence of HER2 overexpression in tumor tissue must be confirmed – either by immunohistochemical analysis (staining should be scored as 3+), or by molecular biology methods (detection of HER2 gene amplification by fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]).
Metastatic breast cancer with HER2 tumor overexpression:
- as monotherapy in patients who have already received one or more chemotherapy regimens for metastatic disease;
- in combination with paclitaxel or docetaxel in patients who have not yet received chemotherapy for metastatic disease;
- in combination with an aromatase inhibitor in postmenopausal patients with metastatic breast cancer and hormone receptor-positive status who have not yet received chemotherapy for metastatic disease.
There are no data available for patients with breast cancer who have previously received adjuvant therapy with Herceptin**®** in early-stage disease.
HER2-overexpressing breast cancer (early stages):
- following surgical intervention, completion of chemotherapy (neoadjuvant or adjuvant), and, if applicable, radiotherapy;
- in combination with paclitaxel or docetaxel following adjuvant chemotherapy with doxorubicin and cyclophosphamide;
- in combination with adjuvant chemotherapy containing docetaxel and carboplatin;
- in combination with neoadjuvant chemotherapy, followed by continuation of Herceptin**®** 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
Herceptin**®** 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. Herceptin**®** should only be administered to patients with metastatic gastric cancer exhibiting HER2 tumor overexpression, i.e., with an expression level of 2+ by immunohistochemical (IHC) analysis and a positive FISH or silver in situ hybridization (SISH) result, or with an expression level of 3+ by a validated IHC assay.
Contraindications.
Hypersensitivity to trastuzumab, proteins of Chinese hamster ovary cells, or any other component of the medicinal product or solvent.
Concomitant administration of Herceptin® and anthracyclines is not recommended for the treatment of metastatic breast cancer or as adjuvant therapy. In neoadjuvant treatment regimens, concomitant use of Herceptin® and anthracyclines should be performed with caution and only in patients who have not previously received chemotherapy.
Dyspnea at rest due to lung metastases or concomitant diseases.
Interaction with other medicinal products and other forms of interaction.
Specific studies on interactions between Herceptin® and other medicinal products in humans have not been conducted. No clinically significant interactions with medicinal products used concomitantly with Herceptin® in clinical settings have been observed.
Pharmacokinetic interactions
In vivo data
In studies where Herceptin® was administered at therapeutic doses in combination with docetaxel, carboplatin, or anastrozole, no changes in the pharmacokinetics of these agents or trastuzumab were observed.
Concentrations of paclitaxel and doxorubicin (as well as their main metabolites 6-α-hydroxy-paclitaxel [POH] and doxorubicinol [DOL]) remained unchanged in the presence of trastuzumab. However, trastuzumab may increase the total exposure of one metabolite of doxorubicin – 7-deoxy-13-dihydro-doxorubicin (D7D). The bioavailability of D7D and the clinical significance of increased levels of this metabolite are unknown. No changes in trastuzumab concentrations were observed in the presence of paclitaxel and doxorubicin.
Results from a sub-study evaluating interactions with other medicinal products, assessing the pharmacokinetics of capecitabine and cisplatin with or without trastuzumab, indicate that the exposure to biologically active metabolites (e.g., 5-FU) of capecitabine was not altered when co-administered with cisplatin or cisplatin in combination with trastuzumab. However, higher concentrations and a prolonged elimination half-life of capecitabine were observed when administered in combination with trastuzumab. The data also show that the pharmacokinetics of cisplatin were not altered by concomitant administration of capecitabine or capecitabine with trastuzumab.
Special precautions for use.
Herceptin® in multidose vial (benzyl alcohol)
The solvent for Herceptin® (bacteriostatic water for injection supplied with the 440 mg vial) contains 220 mg benzyl alcohol/20 mL as a preservative. Benzyl alcohol may cause allergic reactions. The use of benzyl alcohol is associated with a risk of serious adverse reactions, including respiratory disturbances (so-called "gasping syndrome") in young children. The medicinal product must not be used in newborns and young children.
When prescribing Herceptin® to patients with hypersensitivity to benzyl alcohol, the drug should be reconstituted exclusively with water for injection, and only a single dose should be withdrawn from each vial. Any unused portions of the drug must be discarded.
Sterile water for injection used to reconstitute the contents of the single-dose 150 mg vial does not contain benzyl alcohol.
Infusion reactions
Serious infusion-related adverse reactions, including typical symptoms such as dyspnea, arterial hypotension, nausea, fever, bronchospasm, tachycardia, decreased oxygen saturation, urticaria, and rash, have been rarely reported in patients during treatment with Herceptin**®**. These events may represent infusion reactions and may have a delayed onset. Premedication may be used to reduce the risk of infusion reactions.
Patients should be monitored for infusion reactions. Interrupting the infusion may help control such symptoms. The infusion may be resumed once symptoms have subsided. Analgesic/antipyretic agents such as meperidine or paracetamol, or antihistamines such as diphenhydramine, may be used to treat these symptoms. Severe reactions have been successfully managed with symptomatic therapy, including oxygen, beta-agonists, and corticosteroids. Rarely, such reactions have been associated with potentially fatal clinical outcomes. The risk of developing fatal infusion reactions is increased in patients with resting dyspnea due to lung metastases or concomitant diseases; therefore, Herceptin**®** is contraindicated in such patients (see section "Contraindications"). Infusion reactions may sometimes be difficult to distinguish from hypersensitivity reactions.
Cardiotoxicity
During treatment with Herceptin®, an increased risk of developing New York Heart Association (NYHA) Class II–IV congestive heart failure or asymptomatic cardiac dysfunction has been observed. These events have occurred during treatment with Herceptin® as monotherapy or in combination with taxanes following anthracycline therapy (doxorubicin or epirubicin). Heart failure may be moderate or severe and may lead to death (see section "Adverse reactions"). Caution should be exercised when treating patients at increased risk of cardiovascular complications (e.g., patients with hypertension, documented ischemic heart disease, congestive heart failure, diastolic dysfunction, or elderly patients).
Concomitant administration of Herceptin® and anthracyclines is not recommended for the treatment of metastatic breast cancer or as adjuvant therapy. In neoadjuvant treatment regimens, concomitant use of Herceptin® and anthracyclines should be performed with caution and only in patients who have not previously received chemotherapy (see section "Contraindications"). The maximum cumulative dose of low-dose anthracyclines must not exceed 180 mg/m² (doxorubicin) or 360 mg/m² (epirubicin). If patients have received concomitant low-dose anthracyclines and Herceptin® as neoadjuvant therapy, additional cytotoxic chemotherapy after surgery is not required. Clinical experience with neoadjuvant therapy in patients over 65 years of age is limited.
Most symptomatic cardiac adverse reactions occurred within the first 18 months, regardless of the treatment regimen. No increase in cumulative incidence was observed after 3 years. In most cases, left ventricular function improved after discontinuation of Herceptin® and/or initiation of cardiac medication.
Population pharmacokinetic modeling simulations indicate that trastuzumab may remain in the circulation for up to 7 months after discontinuation of Herceptin® following intravenous or subcutaneous administration (see section "Pharmacokinetics"). Patients receiving anthracyclines after discontinuation of Herceptin**®** may have an increased risk of developing cardiotoxicity.
If possible, anthracycline-based therapy should be avoided for 7 months following discontinuation of Herceptin®.
All patients should undergo a thorough cardiac evaluation before starting Herceptin**®, especially those who have previously received anthracyclines. This evaluation should include medical history, physical examination, ECG, echocardiography, and/or radionuclide ventriculography (MUGA). Monitoring for early detection of patients developing cardiac dysfunction should include baseline cardiac assessment, every 3 months during treatment, and every 6 months after treatment completion for 24 months from the last dose of Herceptin®. In patients receiving anthracycline-containing chemotherapy, continued monitoring is recommended, repeated annually for up to 5 years after the last dose of Herceptin®**, or longer if a persistent decrease in left ventricular ejection fraction (LVEF) is observed.
If LVEF decreases by 10 or more percentage points from baseline or falls below 50%, treatment with Herceptin**®** should be discontinued and LVEF reassessed approximately 3 weeks later. If LVEF does not improve or further deteriorates within this period, or if clinically significant heart failure develops, Herceptin**®** should be discontinued unless the benefit for the individual patient outweighs the risk. In patients who develop asymptomatic cardiac dysfunction, monitoring should be performed more frequently (e.g., every 6–8 weeks). Persistent reduction in left ventricular function, even in the absence of symptoms, should prompt consideration of discontinuing Herceptin® unless the benefit outweighs the risk. Such patients should be referred to a cardiologist and continued monitoring should be maintained.
The safety of resuming or continuing Herceptin**®** treatment in patients who have developed cardiotoxicity has not been prospectively studied. Symptomatic heart failure occurring during Herceptin**®** therapy should be managed with standard heart failure treatments. The condition of most patients who developed heart failure or asymptomatic cardiac dysfunction in clinical trials improved with the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and beta-blockers.
Adjuvant and neoadjuvant therapy
Patients with a history of myocardial infarction, treatment-requiring angina, history or current congestive heart failure (NYHA Class II–IV), other cardiomyopathies, treatment-requiring arrhythmias, clinically significant valvular heart disease, poorly controlled 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 Herceptin**®** therapy for breast cancer.
In patients with early-stage breast cancer, the incidence of symptomatic and asymptomatic cardiac events was higher when Herceptin**®** was administered after anthracycline-containing chemotherapy compared to regimens with docetaxel or carboplatin that did not include anthracyclines. The incidence of such events was higher with concomitant use of Herceptin® and taxanes than with sequential administration. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months.
Risk factors for cardiac events included older age (>50 years), low baseline LVEF, reduced LVEF (<55%), decreased LVEF before or after paclitaxel or Herceptin**®** initiation, and prior or concomitant use of antihypertensive medications. In patients who received Herceptin**®** after completion of adjuvant chemotherapy, the risk of cardiac dysfunction was associated with higher cumulative anthracycline dose administered before starting Herceptin**®** and higher body mass index (BMI > 25 kg/m²).
Pulmonary reactions
Severe adverse pulmonary reactions have been reported during post-marketing use of Herceptin**®** (see section "Adverse reactions"); these events were sometimes fatal and could occur as manifestations of infusion reactions with delayed onset. Additionally, cases of interstitial lung disease have 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. Patients with resting dyspnea due to lung metastases or concomitant diseases are at risk of pulmonary reactions and should not receive Herceptin®.
Use during pregnancy or breastfeeding.
Pregnancy
Women of reproductive potential should use effective contraception during treatment with Herceptin**®** and for 7 months after completion of treatment with this drug (see section "Pharmacokinetics").
The medicinal product has an unfavorable pharmacological effect on pregnancy and/or the fetus and/or the newborn.
Herceptin® should not be used during pregnancy unless clearly necessary and only if the potential benefits to the pregnant woman outweigh the potential risks to the fetus.
During post-marketing use, cases of impaired fetal kidney development (e.g., renal hypoplasia) and/or function, associated with oligohydramnios and sometimes linked to fatal pulmonary hypoplasia of the fetus, have been reported in women who received Herceptin® during pregnancy.
Women who become pregnant should be informed of the potential harmful effects on the fetus. If a pregnant woman receives Herceptin® or if a patient becomes pregnant during Herceptin® treatment or within 7 months after the last dose, intensive multidisciplinary medical monitoring is indicated.
Breastfeeding
In a study in lactating cynomolgus monkeys, trastuzumab was shown to be excreted into milk when administered at doses up to 25 times the weekly maintenance dose in humans (2 mg/kg body weight). The presence of trastuzumab in neonatal serum was not associated with any negative effects on growth or development from birth to one month of age. It is unknown whether trastuzumab is excreted in human breast milk. However, since human IgG is secreted into breast milk and the potential harm to the infant is unknown, breastfeeding is not recommended during treatment with Herceptin®.
Fertility
It is unknown whether Herceptin**®** may affect fertility when administered to pregnant women.
A fertility study was conducted in cynomolgus monkeys receiving Herceptin® at doses up to 25 times the weekly maintenance dose in humans (2 mg/kg body weight). Transplacental transfer of trastuzumab was observed during both early (20–50 days of gestation) and late (120–150 days of gestation) fetal development. However, no evidence of fetal harm or impaired fertility was observed.
Ability to affect reaction speed when driving or operating machinery.
Herceptin**®** has a minor influence on the ability to drive and operate machinery. Dizziness and somnolence may occur during treatment with Herceptin® (see section "Adverse reactions"). Patients experiencing symptoms related to the use of the drug (see section "Special precautions for use") should be advised not to drive or operate machinery until symptoms have completely resolved.
Administration and Dosage
Treatment with Herceptin**®** should be initiated under the supervision of a physician experienced in the treatment of oncology patients.
Testing for HER2 tumor expression prior to starting treatment with Herceptin**®** is mandatory (see section "Indications").
Herceptin**®** must be administered only by intravenous infusion. Intravenous bolus or rapid push injection of the drug is not permitted!
To avoid medication errors, it is essential to check the labels on the vials to ensure that Herceptin® (trastuzumab) is being prepared and administered, and not Kadcyla® (trastuzumab emtansine).
For traceability of biological medicinal products, it is recommended to document the brand name and batch number each time the product is prescribed.
Below are the recommended initial and maintenance doses for monotherapy and combination therapy.
Metastatic Breast Cancer – Weekly Regimen
Monotherapy
Loading dose: 4 mg/kg body weight administered as a 90-minute intravenous infusion.
Maintenance doses: 2 mg/kg body weight weekly. If the loading dose is well tolerated, subsequent infusions may be given as a 30-minute infusion.
Combination Therapy with Paclitaxel or Docetaxel
When used in combination, Herceptin**®** is administered at the same doses as in monotherapy. Paclitaxel or docetaxel should be administered the day after the first Herceptin**®** infusion. Subsequently, paclitaxel or docetaxel may be administered every 3 weeks immediately after the maintenance dose of Herceptin**®**, provided the previous infusion was well tolerated. Doses of paclitaxel or docetaxel are specified in the respective product information for these medicinal products.
Combination Therapy with Aromatase Inhibitors
When used in combination, Herceptin**®** is administered at the same doses as in monotherapy. In the pivotal study, Herceptin**®** and anastrozole were administered on Day 1. There were no restrictions on the relative timing of administration when used concomitantly. Anastrozole dosing is specified in its product information. If a patient is receiving tamoxifen, it should be discontinued at least one day before starting combination therapy.
Metastatic Breast Cancer – Every 3 Weeks Regimen
Monotherapy and Combination Therapy
As an alternative to weekly administration, administration of Herceptin**®** every 3 weeks is recommended for monotherapy and in combination with paclitaxel, docetaxel, or an aromatase inhibitor.
Loading dose: 8 mg/kg body weight; after 3 weeks, administer 6 mg/kg body weight; thereafter, maintenance dose: 6 mg/kg body weight every 3 weeks. The drug is administered as an infusion over approximately 90 minutes. If the loading dose is well tolerated, subsequent infusions may be given as a 30-minute intravenous infusion.
Early-Stage Breast Cancer
With the regimens described below, Herceptin**®** is administered until disease recurrence or for a total of 52 weeks.
Weekly Administration
For weekly administration, the initial dose is 4 mg/kg body weight, followed by weekly doses of 2 mg/kg body weight.
Administration Every 3 Weeks
Loading dose: 8 mg/kg body weight.
Maintenance dose: 6 mg/kg body weight; the first maintenance dose is administered 3 weeks after the initial dose.
If Herceptin**®** is continued as monotherapy following combination with chemotherapy, administer 6 mg/kg body weight every 3 weeks.
Metastatic Gastric Cancer or Gastroesophageal Junction Cancer – Every 3 Weeks Regimen
Loading dose: 8 mg/kg body weight; after 3 weeks, administer 6 mg/kg body weight.
Maintenance dose: 6 mg/kg body weight, repeated every 3 weeks. The drug is administered as an infusion over approximately 90 minutes. If the loading dose is well tolerated, maintenance doses may be administered as a 30-minute infusion.
Treatment Duration
Patients with metastatic breast cancer, metastatic gastric cancer, or gastroesophageal junction cancer should continue treatment with Herceptin® until disease progression or until unmanageable toxicity occurs. In patients with early-stage breast cancer, treatment duration should be 1 year or until disease recurrence or unmanageable toxicity, whichever occurs first. Treatment of early-stage breast cancer with Herceptin® should not exceed 1 year.
Missed Doses
If a scheduled trastuzumab dose is missed by 7 days or less, administer the drug as soon as possible (without waiting for the next scheduled cycle) at the standard maintenance dose (weekly regimen: 2 mg/kg body weight once weekly; 3-weekly regimen: 6 mg/kg body weight once every 3 weeks). Subsequent maintenance doses of Herceptin**®** should be administered according to the established schedule weekly or every 3 weeks.
If the interruption in dosing exceeds 7 days, a new loading dose of trastuzumab should be administered as a 90-minute intravenous infusion as soon as possible (weekly regimen: 4 mg/kg body weight once weekly; 3-weekly regimen: 8 mg/kg body weight once every 3 weeks). Subsequent maintenance doses of Herceptin**®** (2 mg/kg body weight for weekly administration, 6 mg/kg body weight for administration every 3 weeks) should be administered 7 or 21 days later, respectively, according to the established schedule (weekly or every 3 weeks).
Dose Adjustment for Adverse Effects
In the event of an infusion reaction (IR), reduce the infusion rate of Herceptin® for intravenous infusion or discontinue the infusion and monitor the patient until all observed symptoms resolve (see section "Special Warnings and Precautions for Use").
In clinical studies, the dose of Herceptin**®** was not reduced. Patients may continue treatment with Herceptin**®** during reversible myelosuppression caused by chemotherapy, provided complications related to neutropenia are carefully monitored. Specific guidelines for dose reduction or delay of chemotherapy should be followed.
If the left ventricular ejection fraction (LVEF) decreases by 10 or more percentage points from baseline or falls below 50%, treatment with Herceptin® should be temporarily discontinued, and LVEF should be reassessed approximately 3 weeks later. If LVEF does not improve or worsens further, or if symptomatic congestive heart failure (CHF) develops, the decision to permanently discontinue Herceptin® should be carefully considered, unless the benefit of continued treatment outweighs the risks for the individual patient. Such patients should be referred for cardiology evaluation and ongoing monitoring.
Special Patient Populations
Elderly Patients
Data indicate no change in the bioavailability of Herceptin**®** related to patient age (see section "Pharmacokinetics. Special Patient Populations"). Patients aged ≥ 65 years did not receive reduced doses of Herceptin® in clinical studies.
Children and Adolescents
The safety and efficacy of Herceptin**®** in children and adolescents (under 18 years of age) have not been established.
Preparation and Storage of the Solution
Single-Dose Vials of 150 mg
The contents of one 150 mg vial of Herceptin**®** should be reconstituted (diluted) with 7.2 mL of sterile water for injection (not supplied with the product). Other solvents must not be used. This results in a single dose of 7.4 mL with a trastuzumab concentration of 21 mg/mL and a pH of approximately 6.0.
To prevent the formation of any precipitate and subsequent reduction in the amount of dissolved Herceptin**®**, avoid shaking and excessive foaming during reconstitution and preparation of the diluted infusion solution. Rapid injection from a syringe should also be avoided.
Instructions for Reconstituting the 150 mg Concentrate in the Vial
Using a sterile syringe, slowly inject 7.2 mL of sterile water for injection into the vial containing the lyophilized powder of Herceptin® to prepare a concentrate for infusion solution. Gently swirl the vial from side to side. Do not shake!
A small amount of foam is commonly formed 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 contain practically no visible particles.
Multi-Dose Vials of 440 mg
Appropriate aseptic techniques must be followed during preparation. The contents of one 440 mg vial of Herceptin**®** should be reconstituted with 20 mL of bacteriostatic water for injection (supplied with the product and containing 1.1% benzyl alcohol). This results in a concentrate solution suitable for multiple use, containing 21 mg/mL trastuzumab with a pH of approximately 6.0. The use of other solvents should be avoided.
For patients with hypersensitivity to benzyl alcohol, sterile water for injection (not supplied with the product) may also be used to prepare a single dose. Such preparations should be used immediately, and any unused portions must be discarded. The use of other solvents should be avoided.
To prevent the formation of any precipitate and subsequent reduction in the amount of dissolved Herceptin**®**, avoid shaking and excessive foaming during reconstitution and preparation of the diluted infusion solution. Rapid injection from a syringe should also be avoided.
Instructions for Reconstituting the 440 mg Concentrate in the Vial
Using a sterile syringe, slowly inject 20 mL of bacteriostatic water for injection into the vial containing the lyophilized powder of Herceptin**®** to prepare a concentrate for infusion solution. Gently swirl the vial from side to side. Do not shake!
A small amount of foam is commonly formed 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 and contain practically no visible particles.
Instructions for Further Dilution of the Drug in Single-Dose and Multi-Dose Vials
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 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 (from either the 150 mg single-dose vial or 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. Care must be taken to maintain sterility during the preparation of the concentrate and the final infusion solution. Parenteral products should be visually inspected prior to administration to ensure the absence of particles and discoloration.
The infusion solution should be used immediately after preparation. If dilution is performed 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
Any unused portions of reconstituted solutions or infusion solutions prepared under uncontrolled and non-validated aseptic conditions must be discarded.
Herceptin® in 150 mg Single-Dose Vials
After reconstitution with sterile water for injection, the solution remains physically and chemically stable for 48 hours at 2–8 °C (do not freeze). From a microbiological standpoint, the reconstituted Herceptin® solution should be used immediately, except when dilution was performed under controlled and validated aseptic conditions.
Herceptin® in 440 mg Multi-Dose Vials
The contents of the Herceptin® vial reconstituted with bacteriostatic water for injection (supplied with the product) are stable for 28 days at 2–8 °C. The reconstituted solution contains a preservative and may therefore be used multiple times. Any remaining solution after 28 days must be discarded.
For patients with hypersensitivity to benzyl alcohol (see section "Special Warnings and Precautions for Use"), Herceptin® should be reconstituted with sterile water for injection, and only a single dose should be withdrawn from the vial. The diluted solution should be used immediately. Any unused solution must be discarded.
Do not freeze the reconstituted solution.
Herceptin®, Infusion Solution
Reconstituted infusion solutions of Herceptin® in polyvinyl chloride, polyethylene, or polypropylene infusion bags with 0.9% sodium chloride solution are physically and chemically stable for 24 hours at temperatures not exceeding 30 °C. Since the product contains no preservatives, from a microbiological standpoint, the infusion solution should be used immediately. If the infusion solution is prepared under aseptic conditions, it may be stored for up to 24 hours at 2–8 °C.
Any unused medicinal product or waste material must be disposed of in accordance with local requirements.
Children.
The safety and efficacy of Herceptin**®** in children and adolescents (under 18 years of age) have not been established.
Overdose.
Cases of overdose have not been reported in clinical studies. Single doses exceeding 10 mg/kg body weight have not been studied.
Adverse Reactions
The most serious and/or commonly observed adverse reactions during treatment with Herceptin® are cardiotoxicity, infusion reactions, hematotoxicity (particularly neutropenia), infections, and pulmonary adverse reactions.
NYHA Class II–IV heart failure is an adverse reaction frequently associated with Herceptin® therapy and, in some cases, may lead to fatal outcomes (see section "Special Warnings and Precautions for Use").
Infusion reactions of any type occur in approximately 49–54% (metastatic breast cancer) and 18–54% (early-stage breast cancer) of patients receiving Herceptin®. However, the majority of these infusion-related adverse reactions are mild to moderate in severity (according to the National Cancer Institute Common Toxicity Criteria [NCI-CTC]) and typically occur during the initial phases of treatment, particularly during the first three infusions; their frequency decreases with continued administration. Such reactions include chills, fever, nausea, urticaria, rash, dyspnea, bronchospasm, tachycardia, and hypotension (see section "Special Warnings and Precautions for Use").
Serious anaphylactic reactions requiring immediate intervention occur very rarely and usually during the first or second infusion of Herceptin® (see section "Special Warnings and Precautions for Use").
Leukopenia, febrile neutropenia, anemia, and thrombocytopenia are very common. Neutropenia is a common adverse reaction. The frequency of hypoprothrombinemia is unknown.
Serious pulmonary adverse reactions during Herceptin® therapy occur rarely but may occasionally be fatal. These include pulmonary 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").
The following categories, based on MedDRA terminology, are used to describe the frequency of adverse reactions: 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 not known (frequency cannot be estimated from available data).
Below are adverse effects and events reported with intravenous administration of Herceptin® as monotherapy or in combination with chemotherapy in pivotal clinical trials and during post-marketing surveillance.
The frequency data provided reflect the highest percentage of adverse effects observed in pivotal clinical trials.
Infections and infestations: very common – infection (24%), nasopharyngitis (17%); common – cystitis, influenza, pharyngitis, skin infections, sinusitis, upper respiratory tract infections, urinary tract infections, sepsis, neutropenic sepsis; frequency not known – meningitis, bronchitis.
Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency not known – progressive malignant neoplasm, progressive neoplasm.
Blood and lymphatic system disorders: very common – neutropenia (47%), anemia (28%), febrile neutropenia (23%), thrombocytopenia (16%), leukopenia (15%); frequency not known – hypoprothrombinemia, leukemia, immune thrombocytopenia.
Immune system disorders: common – hypersensitivity; rare – anaphylactic reactions, anaphylactic shock.
Metabolism and nutrition disorders: very common – anorexia (46%), weight loss (23%), decreased appetite (20%), weight gain (15%); frequency not known – hyperkalemia, tumor lysis syndrome.
Psychiatric disorders: very common – insomnia (11%); common – depression, anxiety; frequency not known – lethargy, paraneoplastic cerebellar degeneration.
Nervous system disorders: very common – paresthesia (50%), headache (25%), dizziness (21%), dysgeusia (19%), hypesthesia (11%), tremor; common – taste disturbance, increased muscle tone, peripheral neuropathy, vertigo, somnolence; frequency not known – lethargy, coma, cerebrovascular disorders.
Eye disorders: very common – conjunctivitis (38%), increased lacrimation (21%); common – dry eyes; frequency not known – optic disc edema, retinal hemorrhage, madarosis.
Ear and labyrinth disorders: uncommon – deafness.
Cardiac disorders: very common – decreased ejection fraction (11%), atrial fibrillation, irregular heartbeat; common – supraventricular tachyarrhythmia, congestive heart failure, cardiomyopathy, rapid heartbeat; uncommon – pericardial effusion; frequency not known – cardiogenic shock, gallop rhythm, tachycardia.
Vascular disorders: very common – flushing (17%), lymphedema (11%); common – hypotension, hypertension, vasodilation.
Respiratory, thoracic and mediastinal disorders: very common – epistaxis (18%), rhinorrhea (18%), cough (16%), oropharyngeal pain (15%), dyspnea (14%), wheezing; common – bronchial asthma, lung disorders, pleural effusion, pneumonia; uncommon – pneumonitis, severe breathing difficulty; frequency not known – interstitial lung disease, including pulmonary infiltrates, pulmonary fibrosis, respiratory failure, apnea, acute pulmonary edema, acute respiratory distress, bronchospasm, laryngeal edema, orthopnea, dyspnea on exertion, hiccups, acute respiratory distress syndrome, respiratory distress syndrome, decreased oxygen saturation, hypoxia, Cheyne-Stokes respiration.
Gastrointestinal disorders: very common – nausea (78%), diarrhea (50%), vomiting (50%), stomatitis (40%), constipation (27%), abdominal pain (20%), dyspepsia (14%), lip swelling; common – dry mouth, hemorrhoids; uncommon – pancreatitis; frequency not known – gastritis.
Hepatobiliary disorders: common – hepatocellular disorders, hepatitis, hepatic tenderness on palpation; rare – jaundice.
Skin and subcutaneous tissue disorders: very common – alopecia (94%), palmar-plantar erythrodysesthesia (26%), rash (24%), erythema (23%), nail disorders (17%), toxic nail effects (11%), facial swelling; common – acne, dermatitis, dry skin, subcutaneous hemorrhage, hyperhidrosis, maculopapular rash, pruritus, nail brittleness (onychoclasis); uncommon – urticaria; frequency not known – angioneurotic edema, onychorexis, Stevens-Johnson syndrome.
Musculoskeletal and connective tissue disorders: very common – myalgia (35%), arthralgia (28%), muscle rigidity; 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.
General disorders and administration site conditions: very common – infusion reactions (74%), fatigue (53%), asthenia (51%), influenza-like symptoms (23%), mucosal inflammation (23%), peripheral edema (17%), chills (15%), pain (12%), fever (12%), chest pain (11%); common – edema, malaise.
$ The stated frequency represents the sum of several individual terms. Percentage data for individual adverse events are not available.
Post-marketing adverse effects
In rare cases during post-marketing use of the drug, severe immune thrombocytopenia with bleeding has been observed, which may occur within several hours after infusion.
Description of selected adverse effects
Immunogenicity
In the neoadjuvant/adjuvant therapy trial (BO22227), antibodies to trastuzumab were detected in 10.1% (30/296) of patients with a median follow-up of over 70 months (treatment-induced antibodies and antibodies that increased in titer during treatment). Neutralizing antibodies were detected in post-baseline samples from 2 of the 30 patients who received Herceptin®. The clinical significance of these antibodies is unknown. However, there was no negative impact of anti-trastuzumab antibodies on the pharmacokinetics, efficacy (defined as pathological complete response [pCR]), or safety (assessed by frequency of infusion reactions) of trastuzumab.
*Long-term cardiac monitoring in early-stage breast cancer
After a median follow-up of 8 years, the incidence of severe chronic heart failure (NYHA Class III and IV) following 1 year of Herceptin® treatment in study BO16348 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 onset of cardiac dysfunction) was observed in 71.4% of patients with CHF. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated in 79.5% of patients with this condition. Approximately 17% of heart failure-related events occurred after completion of Herceptin® therapy.
In a pooled analysis of two trials, NSABP B-31 and NCCTG N9831, with a median follow-up of 8.1 years, the incidence of left ventricular dysfunction (defined by LVEF) in the AC→PH group (doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab) remained unchanged compared to the analysis at 2.0 years median follow-up: LVEF decline of ≥ 10% to below 50% occurred in 18.5% of AC→PH patients. Recovery of left ventricular dysfunction was reported in 64.5% of AC→PH patients who had symptomatic CHF but were asymptomatic at last follow-up, and in 90.3% of patients who showed complete or partial recovery of LVEF.
Reporting of adverse reactions after drug registration is of great importance. It enables ongoing 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.
Storage conditions.
Store at 2 to 8 °C. Keep out of the reach and sight of children.
Incompatibilities.
Herceptin® is incompatible with 5% glucose solution due to the potential for protein aggregation.
In the absence of compatibility studies, Herceptin® must not be mixed or diluted with other medicinal products.
The reconstituted solution of Herceptin® is compatible with polyvinyl chloride, polyethylene, and polypropylene infusion bags.
Packaging.
150 mg of lyophilisate for concentrate for infusion solution in vial No. 1 in a cardboard box.
440 mg of lyophilisate for concentrate for infusion solution in vial No. 1 together with 20 mL of solvent in vial No. 1 in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
For 150 mg and 440 mg dosage:
F. Hoffmann-La Roche Ltd
Manufacturer's location and address of place of business.
Wurmisweg, 4303 Kaiseraugst, Switzerland
Manufacturer.
For 150 mg dosage:
Roche Diagnostics GmbH
Manufacturer's location and address of place of business.
Sandhofer Strasse 116, 68305 Mannheim, Germany