Herceptin440 mg/20 ml

Herceptin is a HER2-targeted monoclonal antibody indicated for the treatment of certain HER2-overexpressing cancers, confirmed by an approved HER2 test prior to initiation.

Established / FDA-approved uses

• Adjuvant breast cancer: HER2-overexpressing, node-positive or high-risk node-negative breast cancer, as part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, or with docetaxel and carboplatin, or as a single agent following multi-modality anthracycline-based therapy.
• Metastatic breast cancer: HER2-overexpressing metastatic breast cancer, in combination with paclitaxel for first-line treatment, or as a single agent in patients who have received one or more prior chemotherapy regimens for metastatic disease.
• Metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma: HER2-overexpressing metastatic gastric or GEJ adenocarcinoma, in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil), in patients who have not received prior treatment for metastatic disease.

Herceptin must only be used in patients whose tumors have confirmed HER2 overexpression or gene amplification, as efficacy depends entirely on HER2-positive status.

Trastuzumab is a recombinant humanized IgG1 monoclonal antibody produced by mammalian cell (Chinese hamster ovary) culture, directed against the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein.

It is supplied as a sterile, preservative-free, white to pale yellow lyophilized powder for reconstitution, commonly available in single-use vials of 150 mg or 440 mg per vial for intravenous infusion. Some markets also offer a subcutaneous fixed-dose combination of Trastuzumab with hyaluronidase, which is a distinct product from the intravenous formulation.

Herceptin is an anti-HER2 humanized monoclonal antibody used in oncology to treat cancers that overexpress the HER2 protein on the surface of tumor cells. By binding selectively to the HER2 receptor, Herceptin interferes with the growth signals that drive proliferation of HER2-positive tumor cells and also flags these cells for destruction by the immune system.

Herceptin is administered only by intravenous infusion under the supervision of a qualified oncology healthcare team, typically as part of a combination chemotherapy regimen or, in some settings, as a single agent. Treatment requires confirmed HER2-positive status, baseline and periodic cardiac monitoring, and close observation during infusions because of the risk of serious infusion reactions.

Herceptin belongs to the class of anti-HER2 monoclonal antibodies, a subgroup of targeted antineoplastic (anticancer) biologic agents.

Mechanism of action: Trastuzumab is a humanized monoclonal antibody that binds with high affinity to subdomain IV of the extracellular segment of the human epidermal growth factor receptor 2 (HER2/neu, ErbB2) protein.

• It inhibits proliferation of tumor cells that overexpress HER2 by blocking HER2-mediated intracellular signaling pathways involved in cell growth and survival.
• It mediates antibody-dependent cellular cytotoxicity (ADCC), directing immune effector cells to preferentially destroy HER2-overexpressing tumor cells.
• It may also inhibit shedding of the HER2 extracellular domain, which otherwise generates a truncated, more active form of the receptor.

Pharmacokinetics: Following intravenous administration, Trastuzumab exhibits dose-dependent, nonlinear pharmacokinetics with an elimination half-life of approximately 1 to 32 days depending on dose, consistent with target-mediated drug disposition. Steady-state concentrations are typically reached by approximately 16 to 20 weeks of every-3-week dosing.

Herceptin is for intravenous infusion only and must not be given as an IV push or bolus.

• The initial (loading) dose is infused over approximately 90 minutes, with the patient observed for fever, chills, and other infusion-related symptoms.
• If the initial infusion is well tolerated, subsequent maintenance doses may be infused over 30 minutes.
• Do not mix or dilute Herceptin with dextrose (glucose)-containing solutions, as this can cause protein aggregation; dilute only as directed, typically in 0.9% sodium chloride.
• Vital signs should be monitored closely during and after each infusion, particularly the first one, because of the risk of serious infusion reactions.
• Herceptin is administered in a healthcare setting equipped to manage severe infusion or hypersensitivity reactions.

Formal drug-interaction studies with Herceptin are limited because it is a monoclonal antibody rather than a small molecule metabolized through cytochrome P450 pathways. The clinically important interactions relate mainly to combined toxicity with other cancer therapies:

• Anthracyclines (e.g., doxorubicin, epirubicin): Concurrent or sequential use with Herceptin substantially increases the risk of cardiotoxicity and clinical heart failure; concurrent anthracycline use with Herceptin is generally avoided outside of clinical trials (see Precautions and Warnings for cardiac monitoring).
• Paclitaxel: Co-administration has been reported to increase plasma concentrations of both agents; the combination is used therapeutically under close monitoring for toxicity.
• Other cardiotoxic or myelosuppressive chemotherapy agents: May have additive toxicity when combined with Herceptin; blood counts and cardiac function should be monitored appropriately.

Serious adverse effects of Herceptin — cardiomyopathy, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity — are described fully in Precautions and Warnings and are not repeated here.

Common side effects

• Fever, chills, and flu-like symptoms, especially with the first infusion
• Headache and fatigue
• Nausea, vomiting, and diarrhea
• Infections (including upper respiratory and urinary tract infections)
• Rash
• Insomnia
• Neutropenia, anemia, and thrombocytopenia (more common when combined with chemotherapy)
• Stomatitis and weight loss (particularly reported in gastric cancer treatment)

Patients should promptly report shortness of breath, swelling of the legs, palpitations, unusual bruising or bleeding, or persistent fever to their treating physician.

Pregnancy: Herceptin can cause fetal harm, including oligohydramnios that may manifest as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Herceptin should not be used during pregnancy. Pregnancy status should be verified before starting treatment, and females of reproductive potential should use effective contraception during treatment and for at least 7 months after the final dose. If Herceptin is used during pregnancy, or if a patient becomes pregnant while receiving it, the physician must be informed immediately and the potential risk to the fetus discussed.

Lactation: There is limited information on the presence of Herceptin in human milk or its effects on the breastfed infant. Because of the potential for serious adverse reactions in a nursing infant, a decision should be made to discontinue breastfeeding or discontinue Herceptin, taking into account the benefit of treatment to the mother; a physician should always be consulted before breastfeeding during or shortly after Herceptin therapy.

Herceptin carries the following boxed (black box) warnings, which require careful attention from the prescribing physician:

Cardiomyopathy

Herceptin can cause a decline in left ventricular ejection fraction (LVEF) and clinical heart failure. The risk is increased with concurrent or prior anthracycline use. Left ventricular function should be evaluated before starting treatment and monitored at regular intervals during treatment; Herceptin should be withheld or discontinued in patients who develop significant left ventricular dysfunction.

Infusion reactions

Serious infusion reactions, including anaphylaxis, angioedema, and acute respiratory distress syndrome, have occurred, sometimes fatally. Reactions are most common with the first infusion. Patients should be observed closely and the infusion interrupted or discontinued for signs of a serious reaction, with facilities available to manage such events.

Pulmonary toxicity

Severe pulmonary toxicity, including interstitial pneumonitis, acute respiratory distress syndrome, pulmonary fibrosis, and pulmonary failure, has occurred, sometimes fatally, especially in patients with pre-existing lung disease or extensive tumor involvement of the lungs.

Embryo-fetal toxicity

See Pregnancy and Lactation for full detail; Herceptin must be strictly avoided in pregnancy and effective contraception used during and after treatment.

Other precautions

• HER2 status must be confirmed by an approved test before starting Herceptin, as efficacy depends entirely on HER2 overexpression.
• Use with caution in patients with pre-existing cardiac disease or risk factors for cardiac dysfunction; a careful risk-benefit assessment and closer cardiac monitoring is warranted in such patients.

There is no established antidote for Herceptin overdose. Doses higher than recommended have not been extensively studied. In case of a suspected overdose of Herceptin, the patient should be monitored closely for exaggerated adverse effects, particularly cardiac dysfunction, infusion-related reactions, and pulmonary symptoms.

If an overdose is suspected, seek immediate medical attention or contact emergency services / a poison control center; treatment is supportive and symptomatic, and should be managed at a facility equipped for oncology or critical care.

Store unopened Herceptin vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Keep out of reach of children.

Once reconstituted, Herceptin solution should generally be used promptly; if not used immediately, follow the product-specific reconstituted and diluted solution storage times provided in the manufacturer's instructions (commonly refrigerated storage for a limited number of hours to a few weeks depending on the formulation), and any unused portion should be discarded appropriately as cytotoxic waste.

• Pediatric patients: Safety and efficacy of Herceptin have not been established in pediatric patients.
• Geriatric patients: Available data suggest no overall difference in effectiveness compared with younger patients, but elderly patients may be at higher risk of cardiac dysfunction; cardiac monitoring should be applied consistently regardless of age.
• Renal impairment: No formal dose adjustment has been established; use with caution.
• Hepatic impairment: No formal dose adjustment has been established; use with caution.
• Pregnancy and lactation: See Pregnancy and Lactation section — Herceptin must be strictly avoided in pregnancy.

Duration of Herceptin therapy depends on the indication:

• Adjuvant breast cancer: A total treatment duration of 52 weeks (one year), regardless of the specific dosing schedule used.
• Metastatic breast cancer and metastatic gastric/GEJ adenocarcinoma: Treatment is continued until disease progression or until unacceptable toxicity occurs, as determined by the treating oncologist.

Herceptin lyophilized powder for injection must be reconstituted before intravenous use, according to the manufacturer's instructions for the specific product/vial strength:

• A 150 mg single-use vial is typically reconstituted with approximately 7.2–7.4 mL of the diluent specified by the manufacturer (commonly sterile or bacteriostatic water for injection), yielding a solution of approximately 21 mg/mL.
• Reconstitute by directing the diluent stream at the lyophilized cake; swirl the vial gently to aid dissolution — do not shake, as this can cause foaming and protein denaturation.
• Allow the vial to stand for a few minutes if foaming occurs, then inspect the reconstituted solution; it should be clear to slightly opalescent and colorless to pale yellow, without visible particulates.
• The calculated dose of reconstituted Herceptin is further diluted into an infusion bag of 0.9% sodium chloride (not dextrose-containing solutions) before administration.
• Follow the specific product insert for exact diluent volumes, storage time of the reconstituted vial, and discard instructions, as these can vary slightly between Herceptin brands/biosimilars.

Monoclonal antibodies; Anti-HER2 targeted therapy; Antineoplastic (anticancer) biologic agents.

Trastuzumab is a humanized IgG1 monoclonal antibody that binds selectively and with high affinity to subdomain IV of the extracellular domain of the HER2 (human epidermal growth factor receptor 2) protein, which is overexpressed on the surface of certain tumor cells.

• By binding HER2, Trastuzumab blocks downstream intracellular signaling pathways (such as the PI3K/AKT and MAPK pathways) that drive uncontrolled tumor cell proliferation and survival.
• Trastuzumab triggers antibody-dependent cellular cytotoxicity (ADCC), recruiting immune effector cells (such as natural killer cells) to recognize and destroy HER2-overexpressing tumor cells.
• Trastuzumab may inhibit proteolytic cleavage (shedding) of the HER2 extracellular domain, preventing formation of a constitutively active truncated receptor fragment.

D

The safety and efficacy of Herceptin have not been established in pediatric patients. Clinical trials supporting approval of Herceptin were conducted in adult patients with HER2-overexpressing breast or gastric/GEJ cancer, and no pediatric dosing regimen has been validated.

Herceptin should only be used in a pediatric patient in the rare circumstance where a treating pediatric oncologist determines it is clinically necessary, with close specialist monitoring for cardiac, pulmonary, and infusion-related toxicity.