Trastuzumab

Usage

• Trastuzumab is prescribed for the treatment of HER2-positive breast cancer, both early-stage and metastatic, and HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. It is also indicated for use in the adjuvant setting after surgery.
• Pharmacological classification: Monoclonal antibody, targeted therapy, antineoplastic agent.
• Mechanism of Action: Trastuzumab selectively targets the human epidermal growth factor receptor 2 (HER2) protein, which is overexpressed in certain types of cancer cells. By binding to HER2, trastuzumab inhibits cell proliferation and promotes antibody-dependent cell-mediated cytotoxicity (ADCC), leading to tumor cell death.

Alternate Names

• International/Regional Variations: None specifically noted.
• Brand Names: Herceptin, Herzuma, Kanjinti, Ontruzant, Zercepac, Trazimera, Ogivri, Phesgo (combination with pertuzumab).

How It Works

• Pharmacodynamics: Trastuzumab binds with high affinity to the extracellular domain of the HER2 receptor. This binding inhibits downstream signaling pathways involved in cell growth and survival, ultimately triggering apoptosis (programmed cell death) in HER2-overexpressing cancer cells. It also enhances the immune system’s ability to destroy tumor cells through ADCC.
• Pharmacokinetics: Administered intravenously or subcutaneously. Trastuzumab exhibits dose-proportional pharmacokinetics in the range of doses from 1 to 20 mg/kg. Distribution: Distributed mainly into the vascular and extravascular spaces. Metabolism: Metabolized through proteolytic degradation into small peptides and amino acids. Elimination: Predominantly eliminated through intracellular catabolism. For the intravenous route, the half-life is approximately 5-6 days and clearance decreases with increasing doses.
• Mode of Action: Receptor binding (HER2), inhibition of cell signaling pathways, antibody-dependent cell-mediated cytotoxicity.
• Elimination Pathways: Intracellular catabolism, minor renal excretion of metabolites.

Dosage

Standard Dosage

Adults:

• Metastatic Breast Cancer: Loading dose: 8 mg/kg IV infusion over 90 minutes, followed by 6 mg/kg IV infusion every 3 weeks over 30-90 minutes. Alternatively, 4 mg/kg IV loading dose over 90 minutes, followed by 2 mg/kg IV weekly over 30 minutes.
• Adjuvant Breast Cancer: May be given concurrently with chemotherapy. Dosage and duration depend on specific regimen.
• Metastatic Gastric Cancer: 8 mg/kg IV loading dose over 90 minutes, followed by 6 mg/kg IV every 3 weeks over 30-90 minutes.
• Subcutaneous (SC) administration: 600 mg SC every 3 weeks, injected over 2-5 minutes.

Children:

• Not routinely used in children. If used, dosage is adjusted based on body surface area and administered under strict specialist supervision.

Special Cases:

• Elderly Patients: No specific dosage adjustments are typically required.
• Patients with Renal Impairment: No specific dosage adjustments are required, as renal clearance is a minor elimination pathway.
• Patients with Hepatic Dysfunction: No specific dosage adjustments are recommended, as the liver is not the primary route of metabolism.
• Patients with Comorbid Conditions: Close monitoring is required for patients with cardiac dysfunction or other comorbidities.

Clinical Use Cases

Trastuzumab is typically used in oncology settings. Its use in settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations is not indicated.

Dosage Adjustments

• Dose adjustments are not usually needed for renal or hepatic impairment.
• If severe adverse reactions occur, particularly cardiac toxicity or infusion reactions, the dose may be reduced or treatment temporarily interrupted.

Side Effects

Common Side Effects

Fever, chills, nausea, vomiting, diarrhea, fatigue, headache, cough, shortness of breath, rash, pain in muscles or joints, low white blood cell counts, anemia. Infusion reactions (fever, chills, rigors, nausea, vomiting, pain, headache, dizziness, rash, dyspnea) can occur during or shortly after infusion.

Rare but Serious Side Effects

Cardiomyopathy (weakening of the heart muscle), heart failure, severe infusion reactions (including anaphylaxis, angioedema, interstitial pneumonitis, and acute respiratory distress syndrome), lung problems (including pneumonitis), fetal harm during pregnancy.

Long-Term Effects

Potential long-term effects include cardiac dysfunction, pulmonary toxicity, and secondary malignancies (rare).

Adverse Drug Reactions (ADR)

Clinically significant ADRs that necessitate immediate intervention include anaphylaxis, severe cardiotoxicity, and pulmonary toxicity.

Contraindications

• Absolute: Severe hypersensitivity to trastuzumab or any component of the formulation.
• Relative: Pre-existing severe cardiac dysfunction, uncontrolled hypertension, pregnancy (unless benefits clearly outweigh risks).

Drug Interactions

• Clinically Significant Interactions: Anthracyclines (increased risk of cardiotoxicity), other HER2-targeted therapies (potential for additive toxicity).
• CYP450 Interactions: Not metabolized by CYP450 enzymes, so CYP450-related interactions are not expected.
• Other Interactions: Numerous potential drug interactions exist, with some being major and others moderate. Always consult a drug interaction checker for a comprehensive assessment.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D
• Fetal Risks: Trastuzumab can cause fetal harm, including oligohydramnios, pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Contraindicated in pregnancy unless the potential benefit justifies the potential risk to the fetus.
• Breastfeeding: Trastuzumab is likely present in breast milk and has the potential to cause adverse effects in nursing infants. Breastfeeding is contraindicated during trastuzumab treatment and for 7 months after the last dose.

Drug Profile Summary

• Mechanism of Action: HER2 receptor antagonist, inhibits cell growth and promotes ADCC.
• Side Effects: Fever, chills, nausea, vomiting, diarrhea, fatigue, cardiotoxicity, infusion reactions.
• Contraindications: Severe hypersensitivity, severe cardiac dysfunction, pregnancy.
• Drug Interactions: Anthracyclines (increased cardiotoxicity), other HER2-targeted therapies.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Variable, dependent on indication and administration route (IV or SC). See dosage section for details.
• Monitoring Parameters: Cardiac function (ejection fraction), complete blood counts, pulmonary function tests.

Popular Combinations

• Trastuzumab is often combined with other chemotherapeutic agents, such as taxanes (paclitaxel, docetaxel), pertuzumab, and aromatase inhibitors, for treating HER2-positive breast cancer.
• The combination regimens are designed to enhance efficacy and improve patient outcomes.

Precautions

• General Precautions: Assess cardiac function before and during treatment. Monitor for signs of infusion reactions and other adverse effects.
• Specific Populations: Pregnancy (contraindicated), breastfeeding (contraindicated), elderly (monitor closely for cardiac events).

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Trastuzumab?

A: Dosage varies depending on the indication (metastatic breast cancer, adjuvant breast cancer, metastatic gastric cancer) and administration route (IV or SC). Please refer to the detailed dosage section above for specific recommendations.

Q2: What are the most common side effects of Trastuzumab?

A: Common side effects include fever, chills, nausea, vomiting, diarrhea, fatigue, headache, and infusion reactions.

Q3: What are the serious side effects of Trastuzumab?

A: Serious side effects include cardiotoxicity (heart failure), severe infusion reactions (anaphylaxis, angioedema), and pulmonary toxicity.

Q4: Can Trastuzumab be used during pregnancy or breastfeeding?

A: No, Trastuzumab is contraindicated during pregnancy and breastfeeding due to potential risks to the fetus and infant.

Q5: What are the major drug interactions with Trastuzumab?

A: Anthracyclines can increase the risk of cardiotoxicity when used with Trastuzumab.

Q6: How is Trastuzumab administered?

A: Trastuzumab can be administered intravenously (IV) or subcutaneously (SC).

Q7: How does Trastuzumab work against cancer?

A: Trastuzumab targets the HER2 receptor, inhibiting cancer cell growth and promoting their destruction by the immune system.

Q8: How should cardiac function be monitored during Trastuzumab treatment?

A: Left ventricular ejection fraction (LVEF) should be assessed before and during treatment using echocardiography or MUGA scan.

Q9: What should be done if a patient experiences an infusion reaction?

A: Infusion reactions can range from mild to severe. Mild reactions may be managed with supportive care, such as antihistamines, antipyretics, and corticosteroids. Severe reactions require immediate discontinuation of the infusion and appropriate medical intervention.

Q10: What are the signs and symptoms of cardiotoxicity associated with Trastuzumab?

A: Signs and symptoms of cardiotoxicity may include shortness of breath, fatigue, swelling in the legs or ankles, and rapid weight gain. Patients should be instructed to report any of these symptoms immediately.