Trastuzumab (Lyophilisate) Instructions for Use

ATC Code

L01FD01 (Trastuzumab)

Active Substance

Trastuzumab (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents, monoclonal antibodies and their drug conjugates; HER2 receptor (human epidermal growth factor receptor 2) inhibitors

Pharmacological Action

Antitumor agent. Recombinant DNA-derived humanized monoclonal antibodies that selectively interact with the extracellular domain of the human epidermal growth factor receptor 2 (HER2). These antibodies belong to the IgG1 subclass and consist of six murine complementarity-determining regions grafted onto a fully human immunoglobulin framework (constant regions of light and heavy chains) without loss of specific reactivity.

There is evidence indicating that the use of trastuzumab according to indications as monotherapy and as part of combination therapy with docetaxel and paclitaxel increases patient survival.

Pharmacokinetics

In patients with metastatic breast cancer receiving trastuzumab as short intravenous infusions at doses of 10 mg, 50 mg, 100 mg, 250 mg, and 500 mg once weekly, the pharmacokinetics were dose-dependent. With increasing dose, the mean T_1/2 increased and clearance decreased.

Steady-state serum concentrations of trastuzumab were achieved between weeks 16 and 32, with mean C_ss^min and C_ss^max being approximately 79 µg/ml and 123 µg/ml, respectively.

In clinical studies, following administration of a trastuzumab loading dose (4 mg/kg) and weekly maintenance therapy at a dose of 2 mg/kg, the mean T_1/2 was 5.8 days (range 1-32 days).

Indications

Breast cancer with tumor HER2 overexpression – as monotherapy or as part of combination therapy.

Advanced adenocarcinoma of the stomach or gastroesophageal junction with tumor HER2 overexpression – as part of combination therapy.

ICD codes

Dosage Regimen

Administer as an intravenous infusion. Do not administer as an intravenous push or bolus. Determine the dosage regimen individually based on indication and treatment phase.

Reconstitute the 60 mg vial with 5.3 mL of Bacteriostatic Water for Injection, containing 1.1% benzyl alcohol, to yield a concentration of 11.4 mg/mL. Gently swirl the vial until completely dissolved. Avoid shaking. The reconstituted solution is a colorless to pale yellow transparent liquid.

For the loading dose, administer 4 mg/kg body weight as a 90-minute intravenous infusion. Observe the patient for fever and chills during the initial infusion.

For subsequent weekly maintenance doses, administer 2 mg/kg body weight as a 30-minute intravenous infusion if the initial infusion was well-tolerated.

An alternative three-weekly regimen is also approved. Administer an initial loading dose of 8 mg/kg as a 90-minute infusion. Follow with 6 mg/kg every three weeks as a 30- to 90-minute infusion.

Dilute the calculated dose in 250 mL of 0.9% Sodium Chloride solution in a PVC or polyethylene bag. Do not use dextrose (5%) solution. Gently invert the bag to mix. Use the solution immediately after preparation.

Do not mix or co-infuse with other medicinal products. Do not freeze the reconstituted or diluted solution. Store reconstituted vials at 2°C to 8°C for up to 28 days if using Bacteriostatic Water for Injection.

Permanently discontinue administration for clinically significant chemotherapy-induced myelotoxicity, severe infusion reactions, or symptomatic congestive heart failure.

Adverse Reactions

Infections and infestations: very common – nasopharyngitis; common – neutropenic sepsis, cystitis, Herpes zoster, influenza, sinusitis, skin infections, rhinitis, upper respiratory tract infections, urinary tract infections, erysipelas, cellulitis, pharyngitis; uncommon – sepsis.

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

Blood and lymphatic system disorders: very common – febrile neutropenia, anemia, neutropenia, leukopenia, thrombocytopenia; frequency unknown – hypoprothrombinemia, immune thrombocytopenia.

Immune system disorders: common – hypersensitivity reactions; frequency unknown – anaphylactic reactions, anaphylactic shock.

Metabolism and nutrition disorders: very common – weight decreased, anorexia; frequency unknown – hyperkalemia.

Psychiatric disorders: very common – insomnia; common – anxiety, depression, thinking impaired.

Nervous system disorders: very common – tremor, dizziness, headache, paresthesia, dysgeusia; common – peripheral neuropathy, muscle hypertonia, somnolence, ataxia; rare – paresis; frequency unknown – brain edema.

Eye disorders: very common – conjunctivitis, lacrimation increased; common – dry eye; frequency unknown – optic disc edema, retinal hemorrhage.

Ear and labyrinth disorders: uncommon – deafness.

Cardiac disorders: very common – decreased and increased blood pressure, arrhythmia, palpitations, flutter, decreased left ventricular ejection fraction, flushing; common – cardiac failure (congestive), supraventricular tachyarrhythmia, cardiomyopathy, vasodilation; uncommon – pericardial effusion; frequency unknown – cardiogenic shock, pericarditis, bradycardia, gallop rhythm.

Respiratory, thoracic and mediastinal disorders: very common – lung wheezing, dyspnea, cough, epistaxis, rhinorrhea; common – pneumonia, asthma, lung function abnormal, pleural effusion; rare – pneumonitis; frequency unknown – pulmonary fibrosis, respiratory failure, lung infiltration, acute pulmonary edema, acute respiratory distress syndrome, bronchospasm, hypoxia, oxygen saturation of hemoglobin decreased, laryngeal edema, orthopnea, pulmonary edema, interstitial lung disease.

Gastrointestinal disorders: very common – diarrhea, vomiting, nausea, abdominal pain, dyspepsia, constipation, stomatitis; common – hemorrhoids, dry mouth.

Hepatobiliary disorders: common – hepatocellular injury, hepatitis, liver tenderness; rare – jaundice; frequency unknown – hepatic failure.

Skin and subcutaneous tissue disorders: very common – erythema, rash, face edema, alopecia, nail disorder, palmar-plantar erythrodysesthesia syndrome; common – acne, dry skin, ecchymosis, hyperhidrosis, maculo-papular rash, pruritus, onychoclasis, dermatitis; uncommon – urticaria; frequency unknown – angioedema.

Musculoskeletal and connective tissue disorders: very common – arthralgia, muscle stiffness, myalgia; common – arthritis, back pain, bone pain, muscle spasms, neck pain, pain in extremity.

Renal and urinary disorders: common – renal function abnormal; frequency unknown – membranous glomerulonephritis, glomerulonephropathy, renal failure.

Breast disorders: common – mastitis.

General disorders and administration site conditions: very common – asthenia, chest pain, chills, fatigue, influenza-like illness, infusion related reaction, pain, pyrexia, mucositis, peripheral edema; common – malaise, edema.

Contraindications

Hypersensitivity to trastuzumab; severe dyspnea at rest caused by lung metastases, or requiring supportive oxygen therapy; patients with early-stage breast cancer with a history of myocardial infarction, angina requiring treatment, congestive heart failure (NYHA functional class II-IV), LVEF <55%, cardiomyopathy, arrhythmia, clinically significant heart valve disease, uncontrolled arterial hypertension, hemodynamically significant pericardial effusion; concurrent use with anthracyclines as part of adjuvant therapy in patients with early-stage breast cancer; pregnancy, lactation (breastfeeding); children and adolescents under 18 years of age.

With caution

Coronary artery disease, arterial hypertension, heart failure, concomitant lung diseases or lung metastases, prior therapy with cardiotoxic drugs, including anthracyclines/cyclophosphamide, LVEF <50%, elderly age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Women of childbearing potential must use reliable methods of contraception during treatment with trastuzumab and for 7 months after the end of treatment. Breastfeeding is not recommended during treatment and for 7 months after the end of therapy.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Treatment with trastuzumab should be carried out under the supervision of a specialist experienced in anticancer chemotherapy. The drug must be administered only if there is access to an emergency kit.

Patients receiving Trastuzumab as monotherapy or in combination with paclitaxel or docetaxel, especially after chemotherapy including anthracyclines (doxorubicin or epirubicin), have an increased risk of developing congestive heart failure (NYHA functional class II-IV) or asymptomatic cardiac dysfunction. The severity of these events can range from moderate to severe. These events can be fatal. In addition, caution should be exercised when treating patients with high cardiovascular risk, for example, elderly patients, patients with arterial hypertension, documented coronary artery disease, congestive heart failure, LVEF <55%.

Before starting treatment with trastuzumab, the expected benefit and potential risk of its use should be carefully weighed. Cardiac function should be monitored during trastuzumab administration.

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

Trastuzumab must not be mixed or diluted together with other drugs.

Drug Interactions

Cyclophosphamide, doxorubicin, epirubicin increase the risk of cardiotoxic effects.

Paclitaxel increases the plasma concentration and effect of trastuzumab.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.