Herceptin, lyophilizate 150 mg

Pharmacodynamics

Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that interacts selectively with the extracellular domain of human epidermal growth factor receptor type 2 (HER2). These antibodies are IgG1 antibodies consisting of human regions (constant heavy chain sites) and determinant complementary murine p185 HER2 antibody sites to HER2.

The proto-oncogene HER2 or c-erB2 encodes a transmembrane receptor-like protein with a molecular weight of 185 kDa that is structurally similar to other members of the epidermal growth factor receptor family. Hyperexpression of HER2 is detected in the tissue of primary breast cancer (BC) in 25-30% of patients and in the tissue of advanced gastric cancer in 6.8-42.6% of patients. Amplification of the HER2 gene leads to overexpression of the HER2 protein on the membrane of tumor cells, which in turn causes continuous activation of the HER2 receptor.

Studies show that breast cancer patients with amplification or overexpression of HER2 in tumor tissue have a lower survival rate without evidence of disease compared to patients without amplification or overexpression of HER2 in tumor tissue.

Trastuzumab blocks the proliferation of human tumor cells with HER2 hyperexpression in vivo and in vitro. In vitro antibody-dependent cellular cytotoxicity of trastuzumab predominantly targets tumor cells with HER2 hyperexpression.

Immunogenicity

An antibody to trastuzumab was detected in one of 903 women with breast cancer who received the drug as monotherapy or in combination with chemotherapy, and she was not allergic to Herceptin®.

There are no data on immunogenicity in the use of Herceptin® for the treatment of gastric cancer.

Pharmacokinetics

The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer and early stages of breast cancer as well as in patients with advanced gastric cancer. No special studies on the study of interdrug interactions have been conducted.

Breast cancer

The pharmacokinetics were nonlinear when the drug was administered as short IV infusions at doses of 10, 50, 100, 250 and 500 mg once a week. The clearance of the drug decreased with increasing dose.

The elimination half-life (T1/2)

The T1/2 is 28-38 days; therefore, the elimination period after drug withdrawal is up to 27 weeks (190 days or 5 half-lives).

The pharmacokinetics of trastuzumab in equilibrium.

The equilibrium state should be reached after approximately 25 weeks. Using a population-based pharmacokinetic method (two-chamber model, model-dependent analysis) to evaluate data from phase I, phase II, and phase III studies in metastatic breast cancer, the median expected AUC at equilibrium after 3 weeks was 1677 mg×day/L after administration of 3 doses (2 mg/kg) weekly and 1793 mg×day/L when administered after 3 weeks at a dose of 6 mg/kg. The calculated medians of Cmax were 104 mg/L and 189 mg/L, and Cmin were 64.9 mg/L and 47.3 mg/L, respectively. Using model-independent or “non-compartmental” analysis (NCA), the median Cmin at equilibrium by cycle 13 (week 37) was 63 mg/L in patients with early-stage breast cancer who received trastuzumab at a loading dose of 8 mg/kg, then at a maintenance dose of 6 mg/kg, 3 weeks later, and was comparable to that in patients with mRBC who received trastuzumab weekly.

Clearance

The typical clearance of trastuzumab (for a patient with a body weight of 68 kg) was 0.241 L/day.

The volume of distribution

In all clinical studies, the central chamber (Vc) volume of distribution was 3.02 L and the peripheral chamber (Vp) volume was 2.68 L for a typical patient.

The circulating extracellular domain of the HER2-receptor (“sloughing” from the cell antigen)

The circulating extracellular domain of the HER2-receptor (“sloughing” from the cell antigen) was detected in the serum of some patients with breast cancer and HER2 hyperexpression. In 64% of the patients examined, the “sloughing off” antigen was detected in baseline serum samples at a concentration as high as 1880 ng/ml (median, 11 ng/ml). Patients who had high levels of the sloughing off cell antigen probably could have had a lower Cmin. However, in the majority of patients with an elevated sloughing off-cell antigen level, the target serum concentration of trastuzumab was reached by week 6 when the drug was administered weekly. There was no significant association between baseline cell-derived antigen levels and clinical response.

Disseminated gastric cancer

. Pharmacokinetics of trastuzumab at equilibrium state To assess the pharmacokinetics of trastuzumab at equilibrium state in patients with advanced gastric cancer after administration of trastuzumab at a loading dose of 8 mg/kg, followed by administration of 6 mg/kg every 3 weeks, a nonlinear two-chamber population pharmacokinetic method was used using data from a phase III study.

The observed serum concentration levels of trastuzumab were lower, thus finding that overall clearance of the drug was higher in patients with advanced gastric cancer than in breast cancer patients receiving trastuzumab at the same dose. The reason for this is unknown.

At high concentrations, total clearance is predominantly linear and the T1/2 is about 26 days.

The median estimated AUC (at equilibrium over a 3 week period) is 1213 mg×day/L, the median Cmax at equilibrium is 132 mg/L, and the median Cmin is 27.6 mg/L.

There are no data on circulating extracellular domain levels of the HER2 receptor (“sloughing off” antigen from the cell) in the serum of patients with gastric cancer.

Pharmacokinetics in special patient groups

Separate pharmacokinetic studies have not been performed in elderly patients and patients with renal or hepatic impairment. Age has no effect on the distribution of trastuzumab.

Indications

Breast Cancer

Metastatic breast cancer with tumor overexpression of HER2:

The early stages of breast cancer with tumor overexpression of HER2:

Active ingredient

Composition

Active ingredients: trastuzumab 150 mg.

Excipients: L-histidine hydrochloride – 3.36 mg, L-histidine – 2.16 mg, α,α-trehalose dihydrate – 136.2 mg, polysorbate 20 – 0.6 mg.

How to take, the dosage

Testing for tumorigenic HER2 expression before starting treatment with Herceptin® is mandatory.

Herceptin® is only given by IV drip! Herceptin® must not be given by IV drip or bolus!

Herceptin® is not compatible with 5% dextrose solution because of the possibility of protein aggregation. Herceptin® should not be mixed or diluted with other medicinal products.

The Herceptin® drug solution is compatible with infusion bags made of polyvinyl chloride, polyethylene and polypropylene.

Preparation of the solution

Preparation of the drug for administration should be performed under aseptic conditions.

Instruction for preparation of concentrate

The contents of the vial of Herceptin® is diluted in 20 ml of the bacteriostatic water for injection supplied with the drug and containing 1.1% benzyl alcohol as an antimicrobial preservative. The result is a reusable solution concentrate containing 21 mg of trastuzumab in 1 ml with pH=6.0.

Please handle the drug carefully during dissolution. Excessive foaming should be avoided during dissolution as it may make it difficult to draw the correct dose from the vial.

It is not uncommon for a small amount of foam to form while dissolving the product. In order to avoid this it is necessary to let the solution stand for about 5 min. The prepared concentrate should be clear and colorless or pale yellow in color.

The Herceptin® concentrate solution prepared with bacteriostatic water for injection is stable for 28 days at 2-8°C. The prepared concentrate contains a preservative and can therefore be used repeatedly. After 28 days unused residual concentrate should be discarded. Do not freeze!

The sterile water for injection (without preservative) may be used as a solvent for Herceptin® 440 mg. The use of other solvents should be avoided. If sterile water for injection is used as a solvent, the concentrate is physically and chemically stable for only 24 hours at 2-8°C and must be discarded after this time. Do not freeze!

Instructions for preparing the solution for infusion

Determine the volume of the solution:

Volume (ml) = body weight (kg)× dose (4 mg/kg loading dose or 2 mg/kg maintenance)/21 (mg/mL, concentration of prepared solution);

Interaction

No specific drug interaction studies of Herceptin® in humans have been conducted.

In clinical studies no clinically significant interactions with concomitant drugs (including doxorubicin, paclitaxel, docetaxel, capecitabine or cisplatin) have been observed.

Herceptin® is not compatible with 5% dextrose solution due to the possibility of protein aggregation.

Herceptin® should not be mixed or dissolved with other drugs.

There has been no evidence of incompatibility between Herceptin® solution and infusion bags made of polyvinyl chloride, polyethylene or polypropylene.

Special Instructions

The treatment with Herceptin® should only be performed under the supervision of an oncologist. HER2 testing should be performed by a specialized laboratory that can provide quality control of the testing procedure.

Herceptin® should only be used in patients with metastatic or early-stage breast cancer when tumor HER2 hyperexpression as determined by immunohistochemical reaction (IHC) or HER2 gene amplification as determined by in situ hybridization (FISH or SISH). Accurate and validated detection methods should be used.

Herceptin® should only be used in patients with metastatic gastric cancer when tumor HER2 overexpression determined by IHC as IHC2+ and confirmed by SISH or FISH or IHC3+. Accurate and validated detection methods should be used.

There are currently no data from clinical studies of patients who received Herceptin® repeatedly after use in adjuvant therapy.

Infusion reactions and hypersensitivity reactions

Infrequent serious infusion adverse reactions have occurred with Herceptin®: shortness of breath, arterial hypotension, wheezing in the lungs, arterial hypertension, bronchospasm, supraventricular tachyarrhythmia, decreased hemoglobin oxygen saturation, anaphylaxis, respiratory distress syndrome, urticaria, and angioedema. Most of them occurred during the infusion or within 2.5 h from the beginning of the first infusion. If an infusion reaction occurs, the infusion should be stopped. The patient should be closely monitored until all symptoms have resolved. Effective therapy of severe reactions consists in the use of oxygen inhalation, beta-adrenergic stimulants, GCS. In case of severe and life-threatening infusion reactions, discontinuation of further therapy with Herceptin® should be considered.

In rare cases, these reactions have been associated with a fatal outcome. The risk of fatal infusion reactions is higher in patients with dyspnea at rest caused by pulmonary metastases or comorbidities, so these patients should not be treated with Herceptin®.

There have been reported cases in which deterioration has occurred after initial improvement, as well as cases with delayed rapid deterioration. Lethal outcome occurred within hours or one week after infusion. In very rare cases, patients have had symptoms of infusion reactions or pulmonary symptoms (more than 6 hours after initiation of Herceptin®). Patients should be warned about the possible delayed development of these symptoms and the need to contact their physician immediately if they occur.

Lung disorders

Serious lung events, sometimes accompanied by death, have been reported with Herceptin® in the post-registration period. In addition, cases of interstitial lung disease (ILD), including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory failure were observed. Risk factors associated with IBD include: previous or concomitant therapy with other anti-neoplastic drugs known to be associated with IBD (taxanes, gemcitabine, vinorelbine, and radiation therapy). These phenomena may occur either during the infusion (as manifestations of infusion reactions) or delayed. The risk of severe pulmonary reactions is higher in patients with metastatic lung lesions, comorbidities accompanied by dyspnea at rest. Therefore, such patients should not receive Herceptin®. Caution should be exercised, especially in patients receiving concomitant therapy with taxanes, because of the development of pneumonitis.

Cardiotoxicity

General guidelines

Heart failure (NYHA functional class II-IV) seen after therapy with Herceptin® as monotherapy or in combination with paclitaxel or docetaxel, especially after chemotherapy containing anthracyclines (doxorubicin or epirubicin) may be moderate to severe and in some cases may be fatal.

Patients planning to receive Herceptin®, especially those previously treated with anthracyclines and cyclophosphamide, should first undergo a thorough cardiology work-up, including history taking, physical examination, ECG, echocardiography and/or radioisotopic ventriculography or MRI.

The possible benefits and risks of Herceptin® should be carefully compared before starting treatment with Herceptin®.

Because the T1/2 of Herceptin® is about 28-38 days, the drug may remain in the blood up to 27 weeks after completion of therapy. Patients who receive anthracyclines after completion of Herceptin® treatment may have an increased risk of cardiotoxicity. Whenever possible, physicians should avoid prescribing anthracycline-based chemotherapy for 27 weeks after completion of Herceptin® therapy. Careful monitoring of cardiac function should be performed when using anthracyclines.

The necessity of a standard cardiac examination in patients with suspected cardiovascular disease during the pre-treatment evaluation should be evaluated.

In all patients, cardiac function should be monitored during treatment (e.g., every 12 weeks).

Monitoring can identify patients who develop cardiac dysfunction.

Patients with asymptomatic impaired heart function may benefit from more frequent monitoring (e.g., every 6-8 weeks). If left ventricular function impairment persists and is not symptomatic, it is appropriate to consider discontinuing the drug if there is no clinical benefit from its use. Caution should be exercised during treatment of patients with symptomatic heart failure, arterial hypertension or documented history of coronary artery disease, and early breast cancer patients with left ventricular ejection fraction ≤55%.

If LVEF falls to values below 50% and by 10 points relative to the value before therapy, treatment should be suspended and the LVEF should be reassessed at least 3 weeks later. If LVEF has not improved or has continued to decline, discontinuation of the drug should be considered if the benefit in this patient does not outweigh the risk. Such patients should be evaluated and monitored by a cardiologist.

If symptomatic heart failure develops with Herceptin® therapy, appropriate standard drug therapy should be given. Consideration should be given to discontinuing Herceptin® when clinically significant heart failure develops unless the benefit to the individual patient outweighs the risk.

The safety of continuing or resuming Herceptin® therapy in patients who develop cardiotoxicity has not been studied in prospective clinical trials. Most patients improved with standard drug therapy in baseline studies. Diuretics, cardiac glycosides, beta-adrenoblockers and/or ACE inhibitors were used as standard therapy. In the presence of clinical benefit from Herceptin®, most patients with adverse cardiac reactions continued therapy without additional clinically significant cardiac reactions.

Metastatic breast cancer

Herceptin® is not recommended in combination with anthracyclines for the treatment of metastatic breast cancer.

The risk of cardiotoxicity in patients with metastatic breast cancer is increased with prior therapy with anthracyclines, but is lower compared to that with concomitant use of anthracyclines and Herceptin®.

Early-stage breast cancer

Patients with early-stage breast cancer should have a cardiac evaluation before starting treatment, every 3 months during therapy, and every 6 months after completion of therapy for 24 months from the last dose of the drug. Longer follow-up after treatment with Herceptin® in combination with anthracyclines is recommended, with a frequency of examinations once per year for 5 years from the last dose of Herceptin® or thereafter if there is a prolonged decrease in LVEF.

Adjuvant therapy

The use of Herceptin® in combination with anthracyclines in adjuvant therapy is not recommended. Patients with early breast cancer who received Herceptin® after anthracycline-based chemotherapy had an increased incidence of symptomatic and asymptomatic cardiac adverse events compared to those who received docetaxel and carboplatin chemotherapy (nonanthracycline regimens). The difference was greater when Herceptin® and taxanes were used together than when they were used sequentially.

Contraindications

With caution: use in CHD, arterial hypertension, heart failure, comorbid lung disease or pulmonary metastases, prior therapy with cardiotoxic drugs including anthracyclines/cyclophosphamide.

Side effects

Currently, the most serious and/or frequent adverse reactions reported with Herceptin® are: cardiotoxicity, infusion reactions, hematotoxicity (particularly neutropenia) and pulmonary disorders.

The following classification is used to describe the incidence of adverse reactions in this section:

Overdose

No cases of drug overdose have been observed in clinical trials. Administration of Herceptin® in single doses greater than 10 mg/kg has not been studied. Herceptin® in doses ≤10 mg/kg was well tolerated.

Pregnancy use

Women of childbearing age should use reliable contraceptive methods during treatment with Herceptin® and for at least 6 months after completion of treatment.

In case of pregnancy, the woman should be warned about the possibility of harmful effects on the fetus. If the pregnant woman continues to receive therapy with Herceptin®, she should be closely monitored by doctors of various specialties. It is not known whether Herceptin® affects fertility in women. The results of animal experiments showed no evidence of impaired fertility or negative effects on the fetus.

Breastfeeding is not recommended during treatment and for at least 6 months after completion of Herceptin® therapy.

The benzyl alcohol contained as a preservative in the bacteriostatic water for injection included with each 440 mg multi-dose vial has toxic effects in infants and children less than 3 years of age.