Herceptin
Active material: Trastuzumab
When ATH: L01XC03
CCF: Anticancer drug. Monoklonalynыe antibodies
ICD-10 codes (testimony): C50
When CSF: 22.05
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Valium for solution for infusion from white to light yellow in color; prepared solution is clear or slightly opalescent, colorless to pale yellow.
| 1 fl. | |
| Trastuzumab | 150 mg |
Excipients: L-histidine hydrochloride, L-histidine, a,a-трегалоза (digidrat), polysorbate 20.
Bottles of colorless glass single dose (1) – packs cardboard.
Valium for concentrate for solution for infusion from white to light yellow in color; prepared solution is clear or slightly opalescent, colorless to pale yellow.
| 1 fl. | |
| Trastuzumab | 440 mg |
Excipients: L-histidine hydrochloride, L-histidine, a,a-трегалоза (digidrat), polysorbate 20.
Solvent: bacteriostatic water d / and (20 ml), contains 1.1% benzilovogo alcohol preservative in quality antimikrobnogo.
Bottles of colorless glass multidose (1) together with the solvent (fl. 1 PC.) – packs cardboard.
Pharmacological action
Anticancer drug. Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody, which selectively interact with the extracellular domain of the epidermal growth factor receptor of human 2 type (HER2). These antibodies are IgG1, consisting of human regions (the constant regions of the heavy chains) and complementarity determining regions of mouse antibodies p185 HER2-HER2.
HER2 (also neu or c-er B2) protooncogene is from the family of the epidermal growth factor receptor - receptor tyrosine kinases. Retseptoropodobny HER2 encodes a transmembrane protein with a molecular weight 185 kDa, which is structurally similar to other members of the family of epidermal growth factor receptor. Amplification of the HER2 gene leads to overexpression of the HER2 protein on the membrane of tumor cells, what, in turn, It causes permanent activation of the HER2 receptor. HER2 overexpression is found in the tissues of primary breast cancer 25-30% patients.
Amplification / overexpression of HER2 independently associated with lower disease-free survival compared with tumors without amplification / overexpression of HER2.
Trastuzumab blocks the proliferation of human tumor cells c HER2-positive. In vitro antibody-dependent cellular cytotoxicity Trastuzumab predominantly directed against tumor cells overexpressing HER2.
Monotherapy Gertseptinom®, undertaken as a therapy second and third line of women with HER2-positive metastatic breast cancer, It gives total response rate, equal 15%, and median survival 13 Months.
The use of Herceptin® in combination with paclitaxel as first-line therapy in women with metastatic breast cancer and HER2-positive increased the median time to progression in the 3.9 Months (from 3 to 6.9 Months), response rate and annual survival compared using one paclitaxel.
The use of Herceptin® in combination with docetaxel as a first-line therapy in patients with HER2-positive metastatic breast cancer significantly increases the response rate (61% compared with 34%), increases the median time to progression in the 5.6 months, and median survival (from 22.7 Months before 31.2 Months) compared to docetaxel monotherapy. The use of Herceptin® in combination with anastrozole as first-line therapy in patients with metastatic breast cancer with HER2-overexpressing and positive estrogen and / or progesterone receptors prolongs progression-free survival with 2.4 months (monotherapy anastrozolom) to 4.8 months (combination with anastrozole Gertseptinom®). With the combination of Herceptin and anastrozole® increases the overall frequency effect (from 6.7% to 16.5%), the frequency of clinical improvement (from 27.9% to 42.7%), term until disease progression. Also increases the overall median survival time in the 4.6 of the month. The increase was not statistically significant, but clinically significant, tk. more 50% patients, initially treated with anastrozole alone, after disease progression were transferred for treatment with Herceptin®. Appointment of Herceptin® after surgery and adjuvant chemotherapy in patients with early-stage breast cancer and HER2-positive significantly increases disease-free survival (p<0.0001, regarding risk 0.54), disease-free survival (p<0.0001, regarding risk 0.51) and survival without distant metastases (p<0.0001, regarding risk 0.5).
Trastuzumab antibodies were found to have a 903 patients, with the phenomenon of allergy to Herceptin® her absent.
Pharmacokinetics
With the introduction of the drug in patients with metastatic breast cancer and early stage breast cancer in short / in infusion at a dose of 10, 50, 100, 250 and 500 mg 1 once a week pharmacokinetics is dose-dependent. The clearance of trastuzumab on the background of the equilibrium state after a loading dose of trastuzumab (4 mg / kg) and weekly maintenance therapy dose 2 mg / kg was 0.225 l / day, Vd – 2.95 l, T1/2 terminal phase – 28.5 days (95% confidence interval, range 25.5-32.8 days). K 20 week trastuzumab concentration in serum reaches equilibrium, AUC – 578 mg X d / l, Cmax and Cmin were 110 mg / ml 66 mg / ml, respectively. The same time is required for removal after the drug trastuzumab.
With increasing doses of the average T1/2 increases, and clearance of the drug decreases.
In the appointment of Herceptin® in the adjuvant setting in patients with early-stage breast cancer three-week scheme (nagruzochnaya dose 8 mg / kg, followed by 6 mg / kg every 3 of the week) Cssmin is 63 mg / l to 13 cycle therapy and is comparable to that in patients with metastatic breast cancer.
Pharmacokinetics in special clinical situations
Appointment of combination chemotherapy (anthracycline / cyclophosphamide, paclitaxel), anastrozole not affect the pharmacokinetics of trastuzumab.
A pharmacokinetic study in elderly patients and patients with renal or hepatic impairment have not been conducted.
Age does not affect the distribution of trastuzumab.
Testimony
Metastatic breast cancer with HER2-positive tumor:
- Monotherapy after one or more chemotherapy regimens;
- In combination with paclitaxel or docetaxel in the absence of prior chemotherapy (first line therapy);
- In combination with aromatase inhibitors positive hormone receptor (estrogen or progesterone).
Early stage breast cancer with HER2-positive tumor in the form of adjuvant therapy: after surgery, completion of chemotherapy (neoadjuvant or adjuvant) and radiation therapy.
Dosage regimen
Testing for HER2 expression tumor before treatment with Herceptin® It is mandatory.
Gerceptin® introduced only in / in the drip; introduce the drug in / bolus or bolus can not be!
The standard dosing regimen
During each introduction of trastuzumab must carefully observe the patient for the appearance of chills, fever and other infusion reactions.
Metastatic Breast Cancer, weekly administration
1. When monotherapy or combination therapy with paklitakselom or dotsetakselom nagruzochnaya dose: 4 mg / kg of body weight in a 90-min / drip infusion. In case of fever, chills or other infusion reactions infusion interrupted. After the disappearance of the symptoms of infusion resume.
Maintenance dose: 2 mg / kg body weight 1 once a week. If the previous dose was well tolerated, the drug can be administered as a 30 minute infusion drip. The drug is prescribed to disease progression.
2. In combination therapy with an aromatase inhibitor loading dose: 4 mg / kg of body weight in a 90-min / drip infusion.
Maintenance dose: 2 mg / kg body weight 1 once a week. If the previous dose was well tolerated, the drug can be administered as a 30 minute / drip infusion, until disease progression.
Early-stage breast cancer, through the introduction of 3 of the week
Loading dose: 8 mg / kg, through 3 week administered drug dose 6 mg / kg, hereinafter maintenance dose: 6 mg / kg every 3 of the week, as 90-min / drip infusion.
If you pass in the planned introduction of trastuzumab was 7 days or less, should be as fast as possible to enter the drug dose 6 mg / kg (without waiting for the next scheduled administration) and then enter it 1 once every 3 the week according to the set schedule. If a break in the introduction of the drug was more than 7 days, you must re-enter the loading dose of trastuzumab 8 mg / kg, and then continue introduction mode 6 mg / kg every 3 of the week.
Patients with early breast cancer should receive treatment with Herceptin® during 1 year or until progression of disease.
Dose adjustment
During the occurrence of reversible myelosuppression, chemotherapy-induced, Herceptin therapy® can be continued after chemotherapy dose reduction or temporary cancel it, with careful monitoring of complications, due to neutropenia.
Dose reduction elderly patients not required.
Preparation of the solution
Gerceptin® incompatible with 5% dextrose solution due to the possibility of protein aggregation.
Gerceptin® It can not be mixed together with other drugs.
Herceptin solution® compatible with the infusion bags, made of polyvinyl chloride and polyethylene.
Preparations for the introduction of the drug must be carried out under aseptic conditions.
The contents of one vial 440 mg diluted in 20 mL supplied with the preparation of bacteriostatic water for injection, contains 1.1% benzilovogo alcohol preservative in quality antimikrobnogo. Sterile syringes slowly introduced 20 ml bacteriostatic water for injection into the vial with 440 mg Herceptin®, directing a jet of fluid directly on lyophilisate. For the dissolution of the vial should be gently shake rotational movements. Do not shake!
The dissolution of the drug is often a small amount of foam. Excessive foam formation may hamper set the desired dose of the drug from the vial. To avoid this, you must give the solution to stand about 5 minutes.
The result is a concentrated solution, reusable, comprising 21 mg trastuzumab 1 ml and having a pH 6.0. The use of other solvents should be avoided.
The prepared concentrate must be clear and colorless, or have a pale yellow color.
The bottle with the concentrate solution of Herceptin®, prepared on bacteriostatic water for injection, stable for 28 days at a temperature of from 2 ° to 8 ° C.. Through 28 days, the unused balance of the solution should be discarded. The concentrate can not freeze.
You can use as a solvent of Herceptin® 440 mg Sterile water for injection (without preservative) in the same way. In this case a concentrate is desirable to use immediately after preparation. If necessary, the solution can be stored for more than 24 hours at a temperature of from 2 ° to 8 ° C.. The concentrate can not freeze.
Bottle with 150 mg of the drug is used only once.
The contents of one vial of Herceptin® 150 mg diluted in 7.2 ml of sterile water for injection (as described above) and then immediately used for solution for infusion. Cooked concentrated solution should be clear and colorless or have a pale yellow color.
If further dilution is not performed, said concentrate can be stored no more than 24 hours at a temperature of from 2 ° to 8 ° C.; Do not freeze. Responsibility for ensuring the sterility of the solution lies with the specialist, final concentrate.
Instructions for further dilution of the drug
Solution volume, required for loading dose trastuzumab, of equal 4 mg / kg body weight, or maintenance dose, of equal 2 mg / kg, determined by the following formula:
weight (kg) × dose (4 mg / kg loading or 2 mg / kg maintenance)/21 (mg / ml, the concentration of the prepared solution)
Solution volume, required for loading dose trastuzumab, of equal 8 mg / kg body weight, or maintenance dose, of equal 6 mg / kg, determined by the following formula:
weight (kg) × dose (8 mg / kg loading or 6 mg / kg maintenance)/21 (mg / ml, the concentration of the prepared solution)
From the bottle to the concentrate (concentrated solution) by dialing an appropriate volume and enter it into an infusion bag with 250 ml 0.9% sodium chloride solution. Then the infusion bag should be gently invert to mix the solution, avoiding foaming. Before the introduction of the solution must be tested (visually) for mechanical impurities and discoloration. The solution for infusion should be administered immediately after preparation. If dilution was carried out under aseptic conditions, solution for infusion in a packet can be stored at 2 ° to 8 ° C for up to 24 no. Ready solution should not be frozen.
Side effect
Development of possible side effects in about 50% patients. The most common side effects include infusion reactions.
Infusion Reactions: during the first infusion is often – chills, fever, nausea, vomiting, pain, tremor, headache, cough, dizziness, breathlessness, hypertension, skin rash and weakness; rarely – hypotension, wheezing in the lungs, bronchospasm, tachycardia, decrease in hemoglobin oxygen saturation, respiratory distress syndrome.
From the body as a whole: often (in 10% and more patients) – weakness, pain and chest discomfort, pain in the breast, fever, chills, peripheral edema, mukozit, weight gain, limfangiektatichesky swelling, flu-like symptoms; rarely (occur in more than 1% but less 10% patients) – back pain, infection, catheter-associated infections, Pain in the neck, malaise, weight loss, herpes zoster, flu; rarely – sepsis; in a few cases – coma.
From the digestive system: often – diarrhea (27%), nausea, vomiting, disgevziya, constipation, stomatitis, gastritis, stomach ache, epigastric pain, gepatotoksichnostь; in a few cases – pancreatitis, hepatic failure, jaundice.
On the part of the musculoskeletal system: often – arthralgia, myalgia, pain in the limbs, ossalgia, cramps and muscle cramps.
Dermatological reactions: often – rash, эritema, alopecia, violation of the structure of nails, onihoreksis or increased fragility of the nail plate; rarely – itch, increased perspiration, xerosis, acne, maculo-papular rash; in a few cases – dermatitis, hives, fibrous cellulitis, erysipelas.
Cardio-vascular system: rarely – vasodilation, tides, supraventricular tachycardia, hypotension, heart failure, cardiomyopathy, heartbeat; rarely – reduction in ejection fraction, pericardial effusion, bradycardia, cerebrovascular disorders; in a few cases – cardiogenic shock, perikardit, arterial hypertension.
From the hematopoietic system: rarely – leukopenia; less 1% – thrombocytopenia, anemia; rarely – neutropenia, febrile neutropenia, leukemia; in a few cases – gipoprotrombinemii.
From the central and peripheral nervous system: often – paresthesia, gipestezii, headache, anorexia, Muscle hypertonicity; rarely – alarm, depression, dizziness, lethargy, drowsiness, insomnia, perifericheskaya neuropathy; rarely – ataxia, tremor, paresis; in a few cases – meningitis, swelling of the brain, thought disorders.
The respiratory system: often – cough, breathlessness, sore throat and larynx, nose bleed, nasal discharge, nazofaringit; rarely – suffocation, pharyngitis, rhinitis, sinusitis, lung function, decrease in hemoglobin oxygen saturation, pleural effusion, upper respiratory tract infection; rarely – bronchospasm, respiratory distress syndrome, acute pulmonary edema, respiratory insufficiency; in a few cases – gipoksiya, laryngeal edema, pulmonary infiltrates, pneumonia, pneumonitis, fibrosis.
From the urinary system: rarely – cystitis, urinary tract infection, dizurija; in a few cases – Glomerulonephropathy, renal failure.
From the senses: increased lacrimation, conjunctivitis, deafness.
Allergic reactions: rarely – angioedema, anaphylactic shock.
Infusion Reactions
Usually, these symptoms are mild or moderate, and with repeated infusions of Herceptin® are rare. They may improve with analgesics or antipyretics such as meperidine or paracetamol, or an antihistamine, eg, difengidramina. Sometimes the reaction to the infusion of Herceptin®, which are manifested by shortness of breath, hypotension, the appearance of wheezing in the lungs, bronchospasm, taxikardiej, decrease in hemoglobin oxygen saturation and respiratory distress syndrome, It may be severe and lead to potentially adverse outcome.
Cardiotoxicity
During therapy with Herceptin® may develop symptoms of heart failure, such as shortness of breath, orthopnoea, increased cough, pulmonary edema, The tripartite rhythm (gallop), reduced ejection fraction.
In accordance with the criteria, determining myocardial dysfunction, incidence of heart failure in the treatment of Herceptin® in combination with paclitaxel was 9-12%, compared with paclitaxel alone – 1-4%, Herceptin monotherapy® – 6-9%. The highest incidence of cardiac dysfunction was observed in patients, receiving Herceptin® with antratsiklinom / tsiklofosfamidom (27-28%), which is significantly higher than the number of reported adverse events among patients, receiving only an anthracycline / cyclophosphamide (7-10%). The examination of the cardiovascular system during treatment with Herceptin® Symptomatic heart failure was observed in 2.2% patients, treated with Herceptin® and dotsetakselom, and was not observed in the docetaxel.
Patients, receiving Herceptin® in the adjuvant therapy for 1 year, the incidence of chronic heart failure III-IV NYHA functional class was 0.6%.
T. to. Average T1/2 is 28.5 days (range 25.5-32.8 days), Trastuzumab may be determined in the serum after cessation of therapy for the 18-24 weeks. Appointment anthracycline during this period could increase the risk of heart failure, Therefore, along with careful monitoring of the cardiovascular system, necessary to assess the perceived risk / benefit of treatment.
Hematologic toxicity
In therapy Herceptin® gematotoksichnosti manifestations are rare. Leukopenia, thrombocytopenia and anemia 3 extent of WHO marked less, than 1% patients. Signs gematotoksichnosti 4 degree mentioned.
Patients, receiving Herceptin® in combination with paklitakselom, there was an increase in the incidence of gematotoksichnosti compared to patients, poluchavshimi monoterapiyu paklitakselom (34% and 21% respectively). Most likely, this was due to longer receiving paclitaxel in the combination therapy group, because this group of patients time to disease progression was great, than with paclitaxel monotherapy.
The frequency of hematologic toxicity also increased in patients, receiving Herceptin® and docetaxel, compared to docetaxel monotherapy (32% and 22% 3 and 4 the severity of neutropenia, respectively, on Common Toxicity Criteria of the National Cancer Institute). The incidence of febrile neutropenia / neutropenic sepsis was increased in patients, treated with Herceptin® in combination with dotsetakselom (23% and 17% respectively).
The frequency of hematologic toxicity III and IV degree of severity in patients with early-stage breast cancer, receiving Herceptin®, made 0.4%.
Plunk- and nephrotoxicity
When Herceptin monotherapy® gepatotoksichnostь 3 or 4 extent of WHO noted in 12% patients with metastatic breast cancer. In 60% hepatotoxicity of these phenomena accompanied the progression of metastatic liver disease. Patients, receiving Herceptin® and paclitaxel, gepatotoksichnostь 3 and 4 degree occurred less frequently, than with paclitaxel monotherapy (7% and 15% respectively). Nephrotoxicity 3 and 4 degree was developed.
Diarrhea
When Herceptin monotherapy® diarrhea was observed in 27% patients with metastatic breast cancer. Increasing the frequency of diarrhea, mainly, mild to moderate severity, It was also noted in patients, treated with the combination of Herceptin® with paklitakselom, compared to patients, poluchavshimi monoterapiyu paklitakselom.
In patients with early breast cancer diarrhea occurs with a frequency 7%.
Infection
The rate of infection, mainly, light upper respiratory tract infections, did not have important clinical implications, and a catheter-related infection was greater in the treatment with Herceptin® in combination with paklitakselom, than with paclitaxel monotherapy.
In patients with metastatic breast cancer with HER2-overexpressing and positive estrogen and / or progesterone receptor with the combination of Herceptin® with anastrozole New adverse events did not develop, and increasing the frequency of occurrence of known adverse events was observed.
Contraindications
- Hypersensitivity to the drug, incl. for benzyl alcohol.
FROM caution use in patients with coronary artery disease, hypertension, Heart Failure, related lung disease or lung metastases, previous therapy with cardiotoxic drugs, incl. antratsiklinami / tsiklofosfamidom.
In the treatment of the early stages of breast cancer with tumor HER2-positive patients with documented congestive heart failure history; with arrhythmias, resistant to therapy; with angina, requiring drug therapy; with clinically significant heart defects; with transmural myocardial infarction on ECG; with treatment-resistant hypertension.
Pregnancy and lactation
Category B. Research on the use of Herceptin® in pregnant women were not conducted. Herceptin® Pregnancy should be avoided, unless the potential benefit of therapy for the mother does not exceed the potential risk to the fetus.
Unknown, Does trastuzumab on the fetus when assigning pregnant women and whether it is allocated with breast milk in humans.
Because human immunoglobulins of class G (Gerceptin® molecule is a subclass IgG1) secreted in breast milk, and the possible damaging effect on the child is unknown, during treatment with Herceptin® and for 6 months after the last injection to avoid breast-feeding.
Reproduction study, conducted on monkeys kind Cynomolgus, at doses, in 25 times exceeds the weekly maintenance dose for humans (2 mg / kg), have not revealed teratogenic effects of the drug. In the early (20-50 day of pregnancy) and late (120-150 day of pregnancy) the timing of the fetus observed trastuzumab penetrate the placental barrier. Displaying, that trastuzumab is secreted in breast milk. The presence of trastuzumab in the serum of infant monkeys had no negative impact on their growth and development from birth to the age of one month.
Benzyl alcohol, part of the water as a bacteriostatic preservative, causes toxicity to infants and children up to 3 years.
Cautions
Treatment with Herceptin® should only be undertaken under the supervision of an oncologist.
Occasionally the introduction of Herceptin® there are severe adverse reactions Infusion, which requires discontinuation of the drug and close monitoring of the patient to eliminate these symptoms. For relief of successfully apply oxygen inhalation, beta adrenostimulyatorov, GCS. The risk of fatal infusion reactions is higher in patients with shortness of breath at rest, caused by metastases to the lungs or comorbidities, so the treatment of these patients need to exercise extreme caution, carefully weigh the benefits of the drug with its risk.
Serious adverse reactions with unfavorable outcome of the respiratory system in the appointment of Herceptin® We were uncommon and occurred both during the infusion, as manifestations of infusion reactions, and after administration. The risk of severe adverse reactions in the respiratory system higher in patients with metastatic lung and shortness of breath at rest.
Heart failure (II-IV functional class NYHA classification), observed after treatment with Herceptin® as monotherapy or in combination with paclitaxel chemotherapy anthracycline (doxorubicin or эpirubitsin), in some cases can lead to death.
When treating patients with existing heart failure, hypertension or established coronary artery disease, and in patients with early breast cancer and left ventricular ejection fraction (LVEF) 55% and less should be particularly careful. Patients, which it is planned appointment of Herceptin®, particularly those, who have previously received anthracyclines and drugs cyclophosphamide, must first undergo a thorough cardiac evaluation, including medical history, physical examination, and one or more of the following methods of instrumental examination – ECG, echocardiography, radioizotopnuû ventrikulografiû. Prior to treatment with Herceptin® must carefully compare the possible benefits and risks of its purpose.
During treatment with Herceptin® necessary to examine every function of the heart 3 of the month. In asymptomatic cardiac dysfunction advisable to more frequent monitoring of (eg, every 6-8 weeks). If there is a persistent decline in LVEF, even in the absence of clinical symptoms, you must consider whether interrupting therapy Herceptin®, provided, that particular patient, it does not give explicit clinical effect. If you have symptoms of heart failure during treatment with Herceptin® you must assign standard therapy. In patients with clinically significant symptoms of heart failure therapy Herceptin® to interrupt, unless the benefits of its use for a particular patient does not significantly exceed the risk.
With a decrease in the LVEF 10 points from baseline value and / or to 50% less, Herceptin therapy® should be interrupted and a re-investigation by LVEF 3 of the week. If LVEF has not improved, therapy should be discontinued, unless the benefits of its use for a particular patient does not significantly exceed the risk.
Status most patients, who developed heart failure, improved during standard medical therapy, including diuretics, cardiac glycosides, and / or ACE inhibitors. The majority of patients with cardiac symptoms, in whom treatment with Herceptin® effectively, continued weekly therapy with Herceptin® without impairing the function of the heart.
In the appointment of Herceptin® patient with hypersensitivity to benzyl alcohol product must be diluted with water for injection, wherein each of the multi-dose vial can select only one dose. The remaining medication should be discarded.
Use in Pediatrics
The efficacy and safety of the drug in children have not been established.
Overdose
In clinical trials, cases of overdose have been identified. The introduction of Herceptin® in single doses more 10 mg / kg have not been studied.
Drug Interactions
Specific drug interaction studies of Herceptin® in humans have not been conducted. In clinical studies no clinically significant interaction with the simultaneous use of drugs not indicated.
Cyclophosphamide, doxorubicin, epirubicin increase the risk of cardiotoxicity.
Pharmaceutical interaction
Gerceptin® incompatible with 5% dextrose solution due to the possibility of protein aggregation.
Gerceptin® It can not be mixed together with other drugs.
Herceptin solution® compatible with the infusion bags, made of polyvinyl chloride and polyethylene.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children at a temperature of 2 ° to 8 ° C. Shelf life – 4 year.
