- HER2-positive metastatic breast cancer in patients previously treated with trastuzumab and a taxane who have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 mo of completing adjuvant therapy.
- Adjuvant treatment of HER2–positive early breast cancer in patients who have residual invasive disease after neoadjuvant taxane and trastuzumab-based therapy.
A HER2-targeted antibody and microtubule inhibitor conjugate. Trastuzumab, the antibody, attaches to receptors and is taken into the cell, where the microtubule inhibitor, DM1, causes cell cycle arrest and death.
Decreased spread of metastatic breast cancer, with improved progression-free survival.
Absorption: IV administration results in complete bioavailability.
Metabolism and Excretion: DM1 is metabolized by CYP3A4/5.
Half-life: 4 days.
TIME/ACTION PROFILE (comparative improvement in progression-free survival)
|IV||4–6 mo||10–12 mo||2 yr|
- Interstitial lung disease or pneumonitis;
- OB: Pregnancy;
- Lactation: Lactation.
Use Cautiously in:
- Underlying cardiovascular or pulmonary disease, including dyspnea at rest;
- Rep: Women of reproductive potential and men with female partners of reproductive potential should use effective contraception;
- Pedi: Safety and effectiveness not established in children.
Adverse Reactions/Side Effects
CV: HF, hypertension, peripheral edema
Derm: pruritus, rash
EENT: ↑ lacrimation, blurred vision, conjunctivitis, dry eyes
F and E: hypokalemia
GI: ↑ liver enzymes, constipation, nausea, altered taste, diarrhea, dry mouth, dyspepsia, HEPATOTOXICITY, stomatitis, vomiting
GU: ↓ fertility
Hemat: anemia, HEMORRHAGE, neutropenia, THROMBOCYTOPENIA
MS: musculoskeletal pain, arthralgia, myalgia
Neuro: fatigue, headache, peripheral neuropathy, dizziness, insomnia, weakness
Resp: cough, INTERSTITIAL LUNG DISEASE
Misc: chills, fever, HYPERSENSITIVITY REACTIONS, infusion-related reactions
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Strong CYP3A4 inhibitors, including atazanavir, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, and voriconazole may ↑ levels and risk of toxicity; avoid concurrent use.
- Concurrent use of anticoagulants, or antiplatelet agents, especially during the first cycle, may ↑ risk of bleeding.
Should not be used interchangeably with trastuzumab.
Metastatic Breast Cancer
IV (Adults): 3.6 mg/kg every 3 wk until disease progression or unacceptable toxicity.
Early Breast Cancer
IV (Adults): 3.6 mg/kg every 3 wk (21–day cycle) for a total of 14 cycles unless there is disease progression or unacceptable toxicity.
Lyophilized powder for injection: 100 mg/vial, 160 mg/vial
Evaluate left ventricular function in all patients prior to and every 3 mo during therapy. For patients with metastatic disease: If symptomatic HF: discontinue ado-trastuzumab. If left ventricular ejection fraction (LVEF) <40%: Hold dose. Repeat LVEF assessment within 3 wk. If LVEF <40% is confirmed, discontinue therapy. If LVEF 40% to ≤45% and decrease is ≥10% points from baseline: Hold dose. Repeat LVEF within 3 wk. If LVEF has not recovered to within 10% points from baseline, discontinue therapy. If LVEF 40% to ≤45% and decrease is <10% points from baseline: Continue therapy with ado-trastuzumab. Repeat LVEF within 3 wk. If LVEF >45%: Continue therapy. Discontinue therapy if symptomatic heart failure occurs. For patients with early breast cancer: If LVEF <45%: Hold dose. Repeat LVEF within 3 wk. If LVEF < 45% confirmed, discontinue therapy. If LVEF 45% to < 50% and decrease is ≥ 10% points from baseline: Hold dose. Repeat LVEF within 3 wk. If the LVEF < 50% and not recovered to < 10% points from baseline, discontinue therapy. If LVEF 45% to < 50% and decrease is < 10% points from baseline: Continue therapy. Repeat LVEF within 3 wk. If LVEF ≥ 50%: Continue therapy. If symptomatic heart failure, Grade 3-4 left ventricular systolic dysfunction or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF < 45%: Discontinue therapy.
- Monitor infusion site closely for infiltration and extravasation closely. Within 24 hrs erythema, tenderness, skin irritation, pain, or swelling at infusion site is seen if extravasation occurs.
- Assess for signs and symptoms of infusion reactions (fever, chills, flushing, dyspnea, hypotension, wheezing, bronchospasm, tachycardia). Slow or interrupt therapy if symptoms are severe. Observe closely during first infusion. Permanently discontinue for life-threatening reactions.
- Monitor neurologic status before and during treatment. Assess for paresthesia (numbness, tingling, pain, burning sensation), loss of deep tendon reflexes (Achilles reflex is usually first involved), weakness (wrist drop or footdrop, gait disturbances), cranial nerve palsies (jaw pain, hoarseness, ptosis, visual changes), arthralgia, myalgia, muscle spasm, autonomic dysfunction (ileus, difficulty voiding, orthostatic hypotension, impaired sweating), and CNS dysfunction (decreased level of consciousness, agitation, hallucinations). Temporarily discontinue therapy in patients with Grade 3 or 4 peripheral neuropathy (severe symptoms; limiting self-care activities of daily living [ADL]) until resolution to ≤ Grade 2 (moderate symptoms; limiting instrumental ADL) neuropathy.
- Monitor for signs and symptoms of pulmonary toxicity (dyspnea, cough, fatigue, pulmonary infiltrates). Permanently discontinue therapy if interstitial lung disease or pneumonitis develops.
Monitor for hemorrhage (central nervous system, respiratory, gastrointestinal hemorrhage) during therapy, especially in patients receiving anticoagulants, antiplatelet therapy, or who have thrombocytopenia.
Lab Test Considerations:
HER2 protein overexpression is used to determine whether treatment with ado-trastuzumab is indicated. HER2 protein overexpression should be determined by labs with proficiency in specific technology used. Information on approved tests is available at http://www.fda.gov/CompanionDiagnostics.
- Verify negative pregnancy status before starting therapy.
- Monitor serum transaminases and bilirubin prior to starting therapy and before each dose. For patients with metastatic disease: If AST/ALT is Grade 2 (>2.5 to ≤5× upper limit of normal [ULN]): Treat at same dose. If AST/ALT is Grade 3 (>5 to ≤20× ULN): Do not administer ado-trastuzumab until AST/ALT recovers to Grade ≤2, and then reduce 1 dose level. If AST/ALT is Grade 4 (>20× ULN): Permanently discontinue ado-trastuzumab. If serum bilirubin is Grade 2 (>1.5 to ≤3× ULN) : Hold dose until bilirubin recovers to Grade ≤1, then treat at same dose level. If bilirubin is Grade 3 (>3 to ≤10× ULN): Hold dose until bilirubin recovers to Grade ≤1, then reduce 1 dose level. If bilirubin is Grade 4 (>10× ULN): Permanently discontinue ado-trastuzumab. Permanently discontinue ado-trastuzumab in patients with AST/ALT >3× ULN and concomitant total bilirubin >2× ULN. For patients with early breast cancer: If ALT Grade 2-3 (> 3.0 to ≤ 20 × ULN on day of scheduled treatment): Hold dose until ALT recovers to Grade ≤1, then reduce one dose level. If ALT Grade 4 (> 20 × ULN at any time): Permanently discontinue therapy. If AST Grade 2 (> 3.0 to ≤ 5 × ULN on day of scheduled treatment): Hold dose until AST recovers to Grade ≤1, then treat with same dose. If AST Grade 3 (> 5 to ≤ 20 × ULN on day of scheduled treatment): Hold dose until AST recovers to Grade ≤1, then reduce one dose level. If AST Grade 4 (> 20 × ULN at any time): Permanently discontinue therapy. If total bilirubin >1.0 to ≤ 2.0 × ULN on day of scheduled treatment: Hold dose until total bilirubin ≤ 1.0× ULN, then reduce one dose level. If total bilirubin >2 × ULN at any time: Permanently discontinue therapy.
- Monitor platelet count prior to starting therapy and before each dose. Nadir of thrombocytopenia occurs by Day 8 and generally improves to Grade 0 or 1 by next scheduled dose. For patients with metastatic disease: If thrombocytopenia is Grade 3 (platelets 25,000/mm3 to <50,000/mm3 : Hold dose until platelet count recovers to ≤Grade 1 (≥75,000/mm3 ), then treat at same dose level. If thrombocytopenia is Grade 4 (platelets <25,000/mm3 ): Hold dose until platelet count recovers to ≤Grade 1, then reduce 1 dose level. For patients with early breast cancer: If Grade 2-3 on day of scheduled treatment (25,000 to < 75,000/mm3 ): Hold dose until platelet count recovers to Grade ≤1 (≥ 75,000/mm3 ), then treat at the same dose level. If 2 delays required due to thrombocytopenia, reduce dose by one level. If Grade 4 at any time < 25,000/mm3 : Hold dose until platelet count recovers to Grade ≤1 (≥ 75,000/mm3 ), then reduce one dose level.
- May cause ↓ hemoglobin, neutrophils, and serum potassium.
- High Alert: Do not confuse ado-trastuzumab with trastuzumab. Double-check names. Trade name of administered product should be clearly recorded in patient file to improve traceability.
- High Alert: Fatalities have occurred with chemotherapeutic agents. Before administering, clarify all ambiguous orders; double check single, daily, and course-of-therapy dose limits; have second practitioner independently double check original order, dose calculations and infusion pump settings.
- Dose reduction schedule is: Starting dose: 3.6 mg/kg First dose reduction: 3 mg/kg Second dose reduction: 2.4 mg/kg Requirement for further dose reduction: discontinue therapy.
- Solution should be prepared in a biologic cabinet. Wear gloves, gown, and mask while handling medication. Discard IV equipment in specially designated containers.
- Y-Site Incompatibility:
- Do not mix or administer with other medications.
- Intermittent Infusion: Reconstitution: Reconstitute by slowly injecting 5 or 8 mL of sterile water for injection into 100 or 160 mg vial of ado-trastuzumab respectively, for a solution of 20 mg/mL. Swirl gently until dissolved; do not shake. Solution is clear, colorless to pale brown, and slightly opalescent; do not administer solutions that are discolored or contain particulate matter. Use reconstituted vials immediately or store in refrigerator up to 4 hr; then discard. Do not freeze. Calculate amount of solution needed. Dilution: Withdraw from vial and add to infusion bag containing 250 mL of 0.9% NaCl; do not use dextrose solutions. Gently invert bag to mix without foaming. Use diluted solution immediately; may be stored in refrigerator up to 24 hrs prior to use, then discard; do not freeze or shake. Administer every 3 wk (21-day cycle); if cycle is delayed, administer as soon as possible. Do not wait until next planned cycle; maintain 3-wk interval between doses.
- Rate: Infuse through a 0.2 or 0.22 micron in-line non-protein adsorptive polyethersulfone filter. Do not administer as IV push or bolus. First infusion: Infuse over 90 min; observe for infusion related reaction. Subsequent infusions: Infuse over 30 min if prior infusions were well tolerated. Observe patient during infusion and for at least 90 min after infusion.
- Management of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy may require temporary interruption, dose reduction, or discontinuation.
- Explain purpose of medication to patient. If a dose is missed administer as soon as possible; do not wait until next scheduled dose. Adjust schedule to maintain 3 wk interval between doses.
Inform patient of potential liver injury and HF. Advise patient to notify health care professional immediately if signs and symptoms of liver injury (nausea, vomiting, abdominal pain, jaundice, dark urine, pruritus, anorexia) or HF (new onset or worsening shortness of breath, cough, swelling of ankles/legs, palpitations, weight gain of >5 lbs in 24 hr, dizziness, loss of consciousness) occur.
- Advise patient to notify health care professional if signs of peripheral neuropathy (burning, numbness, pain in hands and feet/legs) occur.
- Rep: May cause fetal harm. Advise females of reproductive potential to use a highly effective method (IUD, hormonal contraceptive, tubal ligation, partner's vasectomy) of contraception during and for at least 7 mo after last dose. Advise males with a female partner of reproductive potential to use highly effective contraception during and for at least 4 mo after last dose. Instruct patient to notify health care professional promptly if pregnancy is suspected and to avoid breastfeeding for at least 7 mo after last dose. Encourage women who have been exposed to ado-trastuzumab either directly or through seminal fluid, to immediately report exposure to Genentech Adverse Event Line at 1-888-835-2555. May impair fertility in male and female patients.
Decreased spread of metastatic breast cancer.