Trastuzumab (Systemic)
VA CLASSIFICATION
Primary: AN900
Commonly used brand name(s): Herceptin.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Monoclonal antibody; antineoplastic—
Indications
General considerations
Patient eligibility was determined by immunohistochemical assessment of tumor tissue for human epidermal growth factor receptor 2 [HER2] protein overexpression using the Clinical Trial Assay (CTA). Patients with 2+ or 3+ HER2 protein overexpresssion were eligible for treatment with trastuzumab. The results from both clinical trials suggest that patients with the highest level (3+) of HER2 protein overexpression may benefit most from treatment with trastuzumab {01}.
Accepted
Carcinoma, breast (treatment)—Trastuzumab is indicated as a single agent for the treatment of metastatic breast cancer in patients whose tumors overexpress the HER2 protein and who have received at least one chemotherapy regimen previously. Trastuzumab also is indicated, in combination with paclitaxel, for treatment of metastatic breast cancer in patients whose tumors overexpress the HER2 protein and who have not previously received chemotherapy for metastatic disease {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Recombinant DNA-derived humanized monoclonal antibody derived from a mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing gentamicin (although gentamicin does not appear in the final product) {01}.
Molecular weight—
148 kilodaltons {01}
pH
Approximately 6 (after reconstitution) {01}.
Binding affinity
High for the extracellular domain of the human epidermal growth factor receptor 2 [HER2] protein {01}.
Mechanism of action/Effect:
Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, binds to the extracellular domain of the HER2 protein, which is overexpressed in 25 to 30% of primary breast cancers. By binding to the HER2 protein, trastuzumab inhibits the growth of tumor cells and mediates antibody-dependent cellular cytotoxicity (ADCC) in cancer cells that overexpress the HER2 protein {01}.
Distribution:
Volume of distribution—Approximately 44 mL per kg of body weight (approximates serum volume) {01}.
Half-life:
Dose-related—1.7 and 12 days for doses of 10 and 500 mg once a week, respectively {01}.
5.8 days (range 1 to 32) for a loading dose of 4 mg per kg of body weight (mg/kg) followed by a maintenance dose of 2 mg/kg once a week {01}.
Peak serum concentration:
At steady state—123 micrograms per mL for a loading dose of 4 mg per kg of body weight (mg/kg) followed by a maintenance dose of 2 mg/kg once a week {01}.
377 micrograms per mL for a dose of 500 mg once a week {01}.
Trough serum concentration
At steady state—79 micrograms per mL for a loading dose of 4 mg per kg of body weight (mg/kg) followed by a maintenance dose of 2 mg/kg once a week {01}.
In combination with paclitaxel—The average trough serum concentration is approximately 1.5-fold greater than the trough serum concentration associated with trastuzumab used in combination with an anthracycline and cyclophosphamide {01}.
Time to peak effect:
At a loading dose of 4 mg per kg of body weight (mg/kg) followed by a maintenance dose of 2 mg/kg once a week, steady-state serum concentrations are reached between 16 and 32 weeks {01}.
Elimination:
In combination with paclitaxel—Clearance of trastuzumab was decreased twofold in primate studies {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to Chinese hamster ovary cell proteins or components of the product formulation may also be sensitive to trastuzumab {01}.
Carcinogenicity
Studies have not been done to evaluate the carcinogenic potential of trastuzumab {01}.
Mutagenicity
Trastuzumab, at concentrations of up to 5000 micrograms per mL (mcg/mL), was not mutagenic in Ames tests, using six test strains of bacteria, with and without metabolic activation. Mutagenicity was also not detected in an in vitro test of human peripheral blood lymphocytes treated with concentrations of up to 5000 mcg/mL trastuzumab, with and without metabolic activation. An in vivo micronucleus assay detected no evidence of chromosomal damage to mouse bone marrow cells following bolus doses of 118 mg per kg of body weight {01}.
Pregnancy/Reproduction
Fertility—
Studies in monkeys at doses of up to 25 times the weekly human maintenance dose found no effect on fertility {01}.
Pregnancy—
Trastuzumab crosses the placenta in monkeys during early (days 20 to 50) and late (days 120 to 150) gestation. Adequate and well-controlled studies in humans have not been done {01}.
Studies in monkeys at doses of up to 25 times the weekly human maintenance dose found no harmful effects in the fetus. However, many embryonic tissues, including neural and cardiac tissues, express high amounts of HER2 protein and animal studies have shown that early embryo death occurs in mutant mice that lack HER2 protein. {01}
FDA Pregnancy Category B {01}.
Breast-feeding
It is not known if trastuzumab is distributed into breast milk. Human immunoglobulin G (IgG) is distributed into human milk, although the potential for absorption and consequent immunosuppression in the infant is unknown {01}. Trastuzumab is distributed into the milk of lactating monkeys given 25 times the weekly human maintenance dose; however, the presence of trastuzumab in infant monkey serum did not adversely affect development or growth during the first 3 months after birth {01}.
It is recommended that women treated with trastuzumab not breast-feed during therapy and for 6 months after the last dose of trastuzumab {01}.
Pediatrics
No information is available on the relationship of age to the effects of trastuzumab in pediatric patients. Safety and efficacy have not been established {01}.
Geriatrics
Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of trastuzumab in the elderly. However, elderly patients are more likely to have age-related cardiac dysfunction, which may require caution in patients receiving trastuzumab {01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
» Cyclophosphamide {01} or
» Doxorubicin {01} or
» Epirubicin {01} (concurrent use increases risk of developing cardiac dysfunction)
Paclitaxel {01} (concurrent use may increase serum levels and effects of trastuzumab)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Cardiac disease {01} (increased risk of developing cardiomyopathy [ventricular dysfunction and congestive heart failure]; extreme caution is recommended for patients with pre-existing cardiac dysfunction)
» Pre-existing pulmonary compromise{02} (increased risk of serious events including hypersensitivity reactions, infusion reactions, and pulmonary events, including adult respiratory distress syndrome and death; extreme caution is recommended for patients with pulmonary compromise secondary to intrinsic lung disease and/or malignant pulmonary involvement)
Previous cardiotoxic drug or radiation therapy to chest wall {01} (may increase risk for cardiotoxicity)
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Baseline cardiac assessment, including history and physical {01} (recommended prior to initiation of therapy)
Delayed severe reactions{02} (patients should be informed and monitored for the possibility of hypersensitivity, infusion, and pulmonary reactions which may occur 24 hours or more after the infusion)
Echocardiogram or {01}
Electrocardiogram (ECG) studies or {01}
Multigated angiogram scan (MUGA) {01} (recommended prior to initiation of therapy and frequently during therapy )
Side/Adverse Effects
Note: The side/adverse effects and frequencies reported below occur when trastuzumab is administered as a single agent. These effects may occur at a higher rate of frequency when trastuzumab is administered in combination with chemotherapy {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent (³ 20%)
Infusion reaction {01}{02} (dizziness; fever or chills; headache; nausea or vomiting; shortness of breath; skin rash; weakness)— usually mild to moderate in severity, however, some reactions have resulted in fatal outcomes
Note: An infusion reaction may occur during the first dose, but infrequently occurs with subsequent doses. {01}Severe reactions may be delayed for 24 hours or more after infusion{02}.
Incidence less frequent (5 to 19%)
Cardiotoxicity, usually in the form of congestive heart failure{01} (fast or irregular heartbeat ; increased cough; shortness of breath; swelling of feet and lower legs)
Note: Severe congestive heart failure, including cardiac failure, mural thrombosis leading to stroke, and death, has been reported {01}.
Incidence rare (< 5%)
Allergic reaction {01}{02} (chills; hives; fever; shortness of breath ; tightness in chest; trouble in breathing; wheezing; skin rash )—may result in fatal outcome
angioedema {02}(large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs )
urticaria {02}(hives or welts; itching; redness of skin; skin rash)
adult respiratory distress syndrome {02}(shortness of breath; tightness in chest; troubled breathing ; wheezing)
bronchospasm {02}(cough; difficulty breathing; noisy breathing ; shortness of breath; tightness in chest; wheezing)
anemia (unusual tiredness or weakness )
dyspnea {02}(shortness of breath; difficult or labored breathing; tightness in chest; wheezing)
hypotension ( blurred vision; confusion; dizziness, faintness, or light-headedness when getting up from a lying or sitting position; sudden sweating; unusual tiredness or weakness)
leukopenia {01} (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic
noncardiogenic pulmonary edema {02}(chest pain; difficult, fast, noisy breathing, sometimes with wheezing; blue lips and fingernails; pale skin; increased sweating; coughing; shortness of breath)
pleural effusions {02}(chest pain; shortness of breath), pulmonary infiltrates {02}(cough; chest pain; unusual tiredness or weakness )
pulmonary insufficiency and hypoxia requiring supplemental oxygen or ventilatory support {02}
wheezing {02}(difficulty in breathing or troubled breathing)
Note: Anemia and leukopenia occur less frequently (14%) and more frequently (24%), respectively, in patients receiving trastuzumab and chemotherapy. Symptoms were mild to moderate in severity, with < 1% Grade III toxicity and no Grade IV toxicity reported {01}.
Allergic reactions usually occur during the first dose but may be delayed for 24 hours or more after the infusion. Patients should be informed of the possibility of delayed severe reactions.{02}
Pulmonary events may be fatal, however, most patients with fatal reactions had significant pre-existing pulmonary compromise secondary to intrinsic lung disease and/or malignant pulmonary involvement. These patients should be treated with extreme caution. Severe reactions may be delayed for 24 hours or more after infusion. Patients should be informed of the possibility of delayed reaction.{02}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (³ 20%)
Asthenia {01} (unusual weakness)
diarrhea {01} — usually mild to moderate in severity
infection {01} (fever or chills; cough or hoarseness )—usually mild with little clinical significance
nausea {01}
pain {01}
vomiting {01}
Note: Incidence of diarrhea and infection is more frequent in patients receiving trastuzumab in combination with chemotherapy {01}.
Incidence less frequent (5 to 19%)
Insomnia {01} (trouble in sleeping)
loss of appetite {01}
paresthesia {01} (numbness or tingling of hands or feet)
rhinitis {01} ( runny nose)
skin rash {01}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Trastuzumab (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to trastuzumab, Chinese hamster ovary cell proteins, or other components of the product formulation
Pregnancy—Trastuzumab crosses the placenta in monkeys
Breast-feeding—Use is not recommended (while taking this medication and for 6 months after the last dose)
Other medications, especially cyclophosphamide, doxorubicin, or epirubicin
Other medical problems, especially cardiac disease and pre-existing pulmonary compromise
Proper use of this medication
» Proper dosing
Precautions while using this medication
» Importance of regular monitoring by physician. Serious adverse events may occur during infusion or 24 hours or more after infusion.
Side/adverse effects
Signs of potential side effects, especially infusion reactions (including some with fatal outcomes), cardiotoxicity, allergic reactions (including fatal anaphylaxis), angioedema, urticaria, adult respiratory distress syndrome, bronchospasm, anemia, dyspnea, hypotension, leukopenia, noncardiogenic pulmonary edema, pleural effusions, pulmonary infiltrates, pulmonary insufficiency and hypoxia requiring supplemental oxygen or ventilatory support, and wheezing
General Dosing Information
Trastuzumab is recommended for administration by intravenous infusion only. Rapid intravenous (push or bolus) administration is not recommended {01}.
Trastuzumab is recommended for use only in patients whose tumors overexpress the HER2 protein {01}.
If clinically significant congestive heart failure occurs, it is recommended that discontinuation of trastuzumab therapy be seriously considered {01}.
Infusion-related reactions can occur with the first dose, but usually do not reappear with subsequent doses. It is recommended that patients be observed for symptoms of an infusion-related reaction, which can be treated with acetaminophen, diphenhydramine, and meperidine, with or without reducing the rate of the infusion. If the initial infusion is well-tolerated, subsequent doses may be administered over 30 minutes {01}.
Parenteral Dosage Forms
TRASTUZUMAB FOR INJECTION
Usual adult dose
Carcinoma, breast
Loading dose: Intravenous infusion (over ninety minutes), 4 mg per kg of body weight.
Maintenance: Intravenous infusion (over thirty minutes), 2 mg per kg of body weight administered every seven days.
Usual adult prescribing limits
Single doses greater than 500 mg have not been tested in clinical trials.
Usual pediatric dose
Safety and efficacy have not been established.
Strength(s) usually available
U.S.—
440 mg (Rx) [Herceptin ( L-histidine HCL) ( L-histidine) (alpha,alpha-trehalose dihydrate ) (polysorbate 20)]
Packaging and storage:
Store between 2 and 8 ºC (36 and 46 ºF).
Preparation of dosage form:
Trastuzumab is reconstituted for intravenous use by adding to the vial, using asceptic technique, 20 mL of bacteriostatic water for injection (with benzyl alcohol), provided by the manufacturer. This produces a multidose solution containing 21 mg of trastuzumab per mL. Sterile water for injection should be used for initial dilution if the patient is hypersensitive to benzyl alcohol {01}.
Trastuzumab for injection is prepared for intravenous infusion by withdrawing the necessary amount of drug and diluting it, in an infusion bag, with 250 mL 0.9% sodium chloride injection. The bag should be inverted gently to mix the solution, producing a colorless to pale yellow transparent solution. The prepared solution should be inspected visually for particulate matter and discoloration prior to administration {01}.
Stability:
After reconstitution, solutions stored in bacteriostatic water for injection at a concentration of 21 mg per mL retain their potency for 28 days if refrigerated at 2 to 8 °C (36 to 46 °F). Solutions stored in sterile water for injection should be used immediately {01}.
Infusion solutions prepared in 0.9% sodium chloride injection are stable for up to 24 hours prior to use if refrigerated at 2 to 8 °C (36 to 46 °F) and for 24 hours at room temperature (between 15 and 30 °C [59 and 86 °F]). However, because diluted trastuzumab effectively contains no preservative, the manufacturer recommends that diluted solutions be stored in a refrigerator at 2 to 8 °C (36 to 46 °F) {01}.
Incompatibilities:
Trastuzumab should not be mixed or diluted in any dextrose solution or with any other drugs. Incompatibilities between trastuzumab and polyvinyl chloride or polyethylene infusion bags have not been observed {01}.
Revised: 07/24/2000
References
- Herceptin package insert (Genentech, Inc—US), Rev 10/2/98, Rec 10/5/98).
- Technical Information: Herceptin®, trastuzumab. Genentech, Inc., South San Francisco, CA, USA, 5/2000.
