Trastuzumab - instructions for use, doses, side effects, contraindications

Clinical and pharmacological group: & nbsp

Antineoplastic agents - monoclonal antibodies

Included in the formulation

Herceptin®

solution PC

Hoffmann-La Roche Ltd. Switzerland

Herceptin®

lyophilizate d / infusion

Hoffmann-La Roche Ltd. Switzerland

Herceptin®

lyophilizate d / infusion

Hoffmann-La Roche Ltd. Switzerland

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

ONLS

АТХ:

L.01.X.C Monoclonal antibodies

L.01.X.C.03 Trastuzumab

Pharmacodynamics:Recombinant DNA derivatives isolated from Chinese hamster ovary cells, humanized IgG1 monoclonal antibodies containing human framework regions and complementarily determining regions of murine p185 human epidermal growth factor-2 (HER2) antibodies bind to the extracellular domain of the HER2 protein overexpressed by 25-30% of primary breast cancer, which inhibits the growth of tumor cells and mediates the antibody-dependent cellular cytotoxicity of cancer cells that overexpress HER2.

Pharmacokinetics:

Half-life(dose-dependent) - 1.7 and 12 days at a dose of 10 mg and 500 mg once a week, respectively; minimum and maximum concentrations66 and 110 mg / ml, respectively. Creatinine clearance 0.225 l / day (decreases with increasing dose). When combined with paclitaxel, the clearance is reduced by half.

Indications:

Metastatic breast cancer with tumor overexpression HER2:

- in the form of 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 with positive hormonal receptors (estrogen and / or progesterone) in postmenopausal women.

Early stages of breast cancer with tumor overexpression HER2:

- in the form of adjuvant therapy after surgical intervention, completion of chemotherapy (neoadjuvant or adjuvant), and radiation therapy;

- in combination with paclitaxel or docetaxel after adjuvant chemotherapy with doxorubicin and cyclophosphamide;

- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin;

- in combination with neoadjuvant chemotherapy and subsequent adjuvant trastuzumab monotherapy, with a locally advanced (including inflammatory form) disease or in cases where the tumor size exceeds 2 cm in diameter.

ICD-10

II.C50 Malignant neoplasm of breast)

Contraindications:

Hypersensitivity; marked shortness of breath at rest.

Carefully:

Dyspnoea at rest due to metastatic damage or concomitant lung diseases (risk of lethal infusion reactions), patients at risk for developing cardiotoxicity (patients with chronic heart failure, arterial hypertension, coronary heart disease, after previous treatment with cardiotoxic drugs, including anthracycline and cyclophosphamide), pregnancy, breast-feeding.

Pregnancy and lactation:

Controlled studies in humans are not conducted. Trastuzumab penetrates the placental barrier in monkeys on early (20-50 days) and late (120-150th day) gestation periods. Monkeys do not damage the fetus in doses that exceed 25 times the support for humans. Many embryonic tissues, including the nervous and cardiac muscle, express HER2 in significant amounts, and early studies have shown early death of embryos of mutant mice that do not express HER2. There is no evidence of penetration into breast milk, but human IgG is excreted last. Trastuzumab is excreted by the milk of lactating macaques receiving a drug in a dose 25 times larger than that for human, but its presence in the blood plasma of the young macaque did not affect their development and growth during the first 3 months after birth. It was recommended to stop breastfeeding during treatment with trastuzumab and within 6 months after its last administration.

Recommendations for FDA - Category B.

Dosing and Administration:

Standard dosing regimen: subcutaneously, at a fixed dose of 600 mg / 5 mL (regardless of the patient's body weight), for 2-5 minutes, every 3 weeks. A loading dose is not required.

Side effects:

Infectious and parasitic diseases: very often - nasopharyngitis; often - pneumonia, neutropenic sepsis, cystitis, Herpes zoster, infections, influenza, sinusitis, skin infections, rhinitis, upper respiratory tract infections, urinary tract infections, erysipelas, inflammation of subcutaneous fat; infrequently sepsis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): unknown - progression of malignant neoplasm, progression of neoplasm.

Infringements from blood and lymphatic system: very often - febrile neutropenia, anemia, neutropenia, leukopenia, thrombocytopenia; unknown - hypoprothrombinemia.

Infringements from immune system: often - hypersensitivity reactions; unknown - anaphylactic reactions, anaphylactic shock.

Infringements from metabolism: very often - weight loss, anorexia; unknown - hyperkalemia.

Violations mentality: very often insomnia; often - anxiety, depression, disturbance of thinking.

Infringements from nervous system: very often - tremor, dizziness, headaches, paresthesia, dysgeusia (distortion of taste perception); often - peripheral neuropathy, muscle hypertonia, drowsiness, ataxia; rarely - paresis; unknown - edema of the brain.

Infringements from organ of vision: very often - conjunctivitis, increased tearing; often - dry eyes; unknown - edema of the optic disc, hemorrhage in the retina.

Infringements from the organ of hearing and labyrinthine disorders: infrequently, deafness.

Infringements from of cardio-vascular system: very often - a decrease and increase in blood pressure,heart rhythm disturbance, palpitations, flutter (atria or ventricles), reduction of left ventricular ejection fraction, "hot flashes"; often - heart failure (chronic, supraventricular tachyarrhythmia, cardiomyopathy, arterial hypotension, vasodilation, infrequent - pericardial effusion, unknown - cardiogenic shock, pericarditis, bradycardia, rhythm of "gallop".

Infringements from respiratory system, chest and mediastinal organs: very often - wheezing, shortness of breath, cough, nosebleeds, rhinorrhea; often - bronchial asthma, pulmonary function, pharyngitis; infrequently - pleural effusion; rarely - pneumonitis; unknown - pulmonary fibrosis, respiratory failure, lung infiltration, acute pulmonary edema, acute respiratory distress syndrome, bronchospasm, hypoxia, decreased hemoglobin oxygen saturation, laryngeal edema, orthopnea, pulmonary edema, interstitial lung disease.

Infringements from gastrointestinal tract: very often - diarrhea, vomiting, nausea, swelling of the lips, abdominal pain, indigestion, constipation, stomatitis; often - pancreatitis, hemorrhoids, dry mouth.

Infringements from liver and bile ducts: often - hepatitis, tenderness in the liver, hepatocellular injury; rarely jaundice; unknown - hepatic insufficiency.

Infringements from skin and subcutaneous tissues: very often - erythema, rashes, face swelling, alopecia, a violation of the structure of the nails, palmar-plantar syndrome; often - acne, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, itching, onychoclasia, dermatitis; infrequently - hives; unknown - angioedema.

Infringements from musculoskeletal and connective tissue: very often - arthralgia, muscle stiffness, myalgia; often - arthritis, back pain, ossalgia, muscle spasms, neck pain, pain in the limbs.

Infringements from kidney and urinary tract: often - kidney disease; it is not known - membranous glomerulonephritis, glomerulonephropathy, renal failure.

Influence on the current pregnancy, postpartum and perinatal conditions: unknown - oligohydramnion, fatal hypoplasia of the lungs and hypoplasia and / or impaired renal function in the fetus.

Infringements from genital organs and breast: often - inflammation of the breast / mastitis.

General disorders and disorders at the site of administration: very often - asthenia, chest pain, chills, weakness, flu-like syndrome, reactions associated with the administration of the drug, pain, fever, mucositis, peripheral edema; often - malaise, swelling.

Trauma, intoxication and complications of manipulation: often - a bruise.

Overdose:

No data.

Interaction:

Trastuzumab in a subcutaneous dosage form is a ready-to-use solution that can not be dissolved in other medications or mixed.

Special instructions:

Since the half-life of trastuzumab is about 28-38 days, the drug can be in the blood up to 27 weeks after completion of therapy. Patients who receive anthracyclines after the end of treatment with trastuzumab may increase the risk of heart dysfunction. Where possible, physicians should avoid the appointment of anthracycline-based chemotherapy within 27 weeks after the end of therapy with trastuzumab. With the use of anthracycline drugs, careful monitoring of heart function should be carried out.

It should be assessed the need for a standard cardiac examination in patients with suspected cardiovascular disease. All patients should monitor cardiac function during treatment (for example, every 12 weeks).

As a result of monitoring, it is possible to identify patients who have developed cardiac dysfunction.

In patients with asymptomatic cardiac dysfunction, it may be useful to monitor more frequently (for example, every 6-8 weeks). With prolonged worsening of left ventricular function, which is not manifested symptomatically, it is advisable to consider the question of drug cancellation if the clinical benefit from its use is absent. The safety of continuation or resumption of trastuzumab therapy in patients who developed a violation of the function of the heart has not been studied.

If the left ventricular ejection fraction is reduced by> 10 units from the baseline and below the value of 50%, treatment should be suspended. Reassessment Left ventricular ejection fraction should be carried out in about 3 weeks. If there is no improvement in the indicator Left ventricular ejection fraction, or its further decrease, or when symptoms of chronic heart failure appear, consideration should be given to discontinuing trastuzumab treatment, unless the benefit to the individual patient exceeds the risks. All these patients should be referred to a cardiologist for a survey and be monitored.

If symptomatic heart failure develops with trastuzumab, appropriate standard medical therapy chronic heart failure. Most patients with chronic heart failure or asymptomatic heart dysfunction in baseline studies, there was an improvement in the background of standard drug therapy: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. In the presence of clinical benefit from the use of trastuzumab, most patients with adverse cardiac reactions continued therapy without manifestation of additional clinically significant reactions from the heart.

It is not recommended to apply the drug trastuzumab together in combination with anthracyclines for the treatment of metastatic breast cancer.

The risk of developing heart dysfunction in patients with metastatic breast cancer is elevated with prior anthracycline therapy, but it is lower in comparison with that with simultaneous use of anthracyclines and trastuzumab.

Patients with early breast cancer should undergo a cardiac examination before the start of treatment, every 3 months during therapy and every 6 months after the end of treatment, within 24 months of the administration of the last dose of the drug. Longer monitoring is recommended after treatment with trastuzumab in combination with anthracyclines at a frequency of 1x per year for 5 years from the last dose of trastuzumab or further if there is a constant decrease Left ventricular ejection fraction.

Treatment with trastuzumab is not recommended for patients in the early stages of breast cancer (adjuvant and neoadjuvant therapy) with: a history of myocardial infarction; angina pectoris requiring treatment; chronic heart failure (NYHA functional class II-IV) in the history or at present; Left ventricular ejection fraction below 55%; other cardiomyopathies; arrhythmias requiring treatment; clinically significant heart defects; poorly controlled hypertension, with the exception of arterial hypertension, amenable to standard drug therapy; and hemodynamically significant pericardial effusion, since the efficacy and safety of the drug in these patients have not been studied.

It is not recommended to apply trastuzumab together in combination with anthracyclines in adjuvant therapy. In patients with early stages of breast cancer who received trastuzumab (intravenously) after anthracycline-based chemotherapy, there was an increase in the incidence of symptomatic and asymptomatic cardiovascular adverse events compared with those receiving chemotherapy with docetaxel and carboplatin (regimes not containing anthracycline-based drugs). However, the difference was greater in cases of co-administration of trastuzumab and taxanes than with consecutive use.

Regardless of the regime used, most symptomatic cardiac events occurred in the first 18 months of treatment.A prolonged increase in the cumulative incidence of symptomatic cardiac events or events associated with a decrease in the left ventricular ejection fraction is observed in 2.37% of patients receiving trastuzumab together with taxanes after anthracycline therapy, compared with 1% of patients in the comparison groups (in the anthracycline and cyclophosphamide, further taxanes, and in the taxanes, carboplatin and trastuzumab group).

The identified risk factors for the development of adverse cardiac events with adjuvant therapy with trastuzumab are: age> 50 years, low baseline left ventricular ejection fraction (<55%) before and after treatment with paclitaxel, a decrease Left ventricular ejection fraction for 10-15 units, the preceding or concomitant administration of antihypertensive drugs.

Risk of impaired cardiac function in patients who received trastuzumab after completion of adjuvant chemotherapy, was associated with a higher total dose of anthracyclines before starting treatment with trastuzumab and with a body mass index> 25 kg / m².

For patients with early stages of breast cancer,who can be assigned neoadjuvant-adjuvant therapy, the use of trastuzumab in conjunction with anthracyclines is recommended only if they have not previously received chemotherapy and only with low-dose regimens of anthracycline therapy (maximum total doxorubicin dose of 180 mg / m²or epirubicin 360 mg / m²).

In patients who received a full course of low-dose anthracyclines and trastuzumab in the neoadjuvant therapy, additional cytotoxic chemotherapy is not recommended after surgical intervention. In all other cases, the decision on the need for additional cytotoxic chemotherapy is taken on the basis of individual factors.

The experience with trastuzumab in conjunction with low-dose regimens for anthracycline therapy is limited to two studies. When trastuzumab was used in conjunction with neoadjuvant chemotherapy, which included three to four cycles of neoadjuvant therapy with anthracyclines (total dose of doxorubicin 180 mg / m² or epirubicin 300 mg / m²), the incidence of symptomatic cardiac dysfunction was low (1.7%).

Clinical experience in patients older than 65 years is limited.

Premedication can be used to reduce the risk of reactions to administration.

Despite the fact that serious reactions (including dyspnea, arterial hypotension, wheezing in the lungs, bronchospasm, tachycardia, decreased oxygen saturation of hemoglobin, and respiratory distress syndrome) associated with the administration for trastuzumab in a subcutaneous dosage form have not been reported, caution, since these phenomena were observed when the intravenous drug form of trastuzumab was administered.

It is possible to take analgesics, antipyretics, such as paracetamol, or antihistamines, such as diphenhydramine. Serious reactions associated with intravenous administration of trastuzumab successfully responded to treatment, which consisted of beta-adrenostimulants, glucocorticosteroids, and oxygen inhalation. In rare cases, these reactions were associated with a fatal outcome. The risk of developing lethal reactions associated with the administration is higher in patients with dyspnea at rest caused by metastases to the lungs or concomitant diseases, so such patients should not be treated with trastuzumab.

Caution should be exercised when using trastuzumab in a subcutaneous dosage form, as when using trastuzumab in the dosage form for intravenous administration, severe pulmonary events have been reported in the postgrade period, which have sometimes been fatal. These phenomena can occur both with the administration of the drug and delayed. In addition, cases of interstitial lung disease, including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema and respiratory failure. Risk factors associated with interstitial lung disease, include previously conducted or concomitant therapy with other antitumor drugs that are known to be associated with interstitial lung disease (taxanes, gemcitabine, vinorelbine and radiation therapy). The risk of severe lung reactions is higher in patients with metastatic lung involvement, concomitant diseases accompanied by dyspnea at rest, so such patients should not receive trastuzumab. Care should be taken, especially in patients receiving concomitant taxane therapy, because of the potential for pneumonitis.

Needles and syringes can not be reused. Used needles and syringes are placed in a puncture-proof container (container). Dispose of trastuzumab and consumables in accordance with local regulations.

Studies to study the effect of the drug on the ability to drive a car and work with mechanisms have not been carried out. In case of reactions associated with the administration of the drug, patients should not drive the car or work with the mechanisms until the symptoms are completely resolved.

Instructions

Trastuzumab (Trastuzumabum)