Download Trastuzumab

T Trastuzumab
Trade Names
Herceptin, Anti-HER-2-antibody
Classification
Monoclonal antibody
Category
Biologic response modifier agent
Drug Manufacturer
Genentech
Mechanism of Action
Recombinant humanized monoclonal antibody directed against the
extracellular domain of the HER-2/neu human epidermal growth
factor receptor. This receptor is overexpressed in several human
cancers, including 25%–30% of breast cancers.
Precise mechanism(s) of action remains unknown.
Downregulates expression of HER-2/neu receptor.
Inhibits HER-2/neu intracellular signaling pathways.
Induction of apoptosis through as yet undetermined mechanisms.
Immunologic mechanisms may also be involved in antitumor
activity, and they include recruitment of antibody-dependent cellular
cytotoxicity (ADCC) and/or complement-mediated cell lysis.
Mechanism of Resistance
Mutation in the HER-2/neu growth factor receptor leading to
decreased binding affinity to trastuzumab.
Decreased expression of HER-2/neu receptors.
Activation/induction of alternative cellular signaling pathways, such
as IGF-1R.
Distribution
Distribution in body is not well characterized.
Metabolism
Metabolism of trastuzumab has not been extensively characterized.
Half-life is on the order of 5–6 days with minimal clearance by the liver or
kidneys, as has been observed for other monoclonal antibodies and peptides
used in the clinic.
Indications
Metastatic breast cancer—First-line therapy in combination with
paclitaxel. Patient’s tumor must express HER-2/neu protein to be
treated with this monoclonal antibody.
Metastatic breast cancer—Second- and third-line therapy as a single
agent in patients whose tumors overexpress the HER-2/neu protein.
FDA-approved for the adjuvant therapy of node-positive, HER2overexpressing breast cancer as part of a treatment regimen containing
doxorubicin, cyclophosphamide, and either paclitaxel 0r docetaxel.
Dosage Range
Recommended loading dose of 4 mg/kg IV administered over
90 minutes, followed by maintenance dose of 2 mg/kg IV on a
weekly basis.
Alternative schedule is to give a loading dose of 8 mg/kg IV administered
over 90 minutes, followed by maintenance dose of 6 mg/kg IV
every 3 weeks.
Drug Interactions
Anthracyclines, taxanes—Increased risk of cardiotoxicity when trastuzumab
is used in combination with anthracyclines and/or taxanes.
Special Considerations
Caution should be exercised in treating patients with pre-existing
cardiac dysfunction. Careful baseline assessment of cardiac function
(LVEF) before treatment and frequent monitoring (every 3 months)
of cardiac function while on therapy. Trastuzumab should be held
for _16% absolute decrease in LVEF from a normal baseline value.
Trastuzumab therapy should be stopped immediately in patients who
develop clinically significant congestive heart failure. When trastuzumab
is used in the adjuvant setting, cardiac function should be
assessed every 6 months for at least 2 years following the completion
of therapy.
Carefully monitor for infusion reactions, which typically occur during
or within 24 hours of drug administration. Administer initial
loading dose over 90 minutes and then observe patient for 1 hour
following completion of the loading dose. May need to treat with
Benadryl and acetaminophen. Rarely, in severe cases, may need to
treat with IV fluids and/or pressors.
Maintenance doses are administered over 30 minutes if loading dose
was well tolerated without fever and chills. However, if fever and
chills were experienced with loading dose, need to administer over
90 minutes.
Pregnancy category B.
Toxicity 1
Infusion-related symptoms with fever, chills, urticaria, flushing, fatigue,
headache, bronchospasm, dyspnea, angioedema, and hypotension. Occur in
40%–50% of patients. Usually mild to moderate in severity and observed
most commonly with administration of the first infusion.
Toxicity 2
Nausea and vomiting, diarrhea. Generally mild.
Toxicity 3
Cardiotoxicity in the form of dyspnea, peripheral edema, and reduced left
ventricular function. Significantly increased risk when used in combination
with an anthracycline-based regimen. In most instances, cardiac dysfunction
is readily reversible.
Toxicity 4
Myelosuppression. Increased risk and severity when trastuzumab is
administered with chemotherapy.
Toxicity 5
Generalized pain, asthenia, and headache.
Toxicity 6
Pulmonary toxicity in the form of increased cough, dyspnea, rhinitis,
sinusitis, pulmonary infiltrates, and/or pleural effusions.