General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications:

Pronunciation:
ado tras-too-zoo-mab

Trade Name(s)

• Kadcyla

Ther. Class.

antineoplastics

Pharm. Class.

drug-antibody conjugates

Indications

•   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.

Action

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.

Therapeutic Effect(s):

Decreased spread of metastatic breast cancer, with improved progression-free survival.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism and Excretion: DM1 is metabolized by CYP3A4/5.

Half-life: 4 days.

TIME/ACTION PROFILE (comparative improvement in progression-free survival)

Contraindication/Precautions

Contraindicated in:

• 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 (ILD)/PNEUMONITIS

Misc: chills, fever, HYPERSENSITIVITY REACTIONS, infusion-related reactions

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  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.

Route/Dosage

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.

Availability

Lyophilized powder for injection: 100 mg/vial, 160 mg/vial

Assessment

• Evaluate left ventricular function before and every 3 mo during therapy. For patients with metastatic disease:  If symptomatic HF occurs,  permanently discontinue ado-trastuzumab.  If left ventricular ejection fraction (LVEF) <40%,  hold ado-trastuzumab. Repeat LVEF assessment within 3 wk. If LVEF <40% is confirmed, permanently discontinue ado-trastuzumab.  If LVEF 40–≤45% and ↓ is ≥10% points from baseline,  hold ado-trastuzumab. Repeat LVEF within 3 wk. If LVEF has not recovered to within 10% points from baseline, permanently discontinue ado-trastuzumab.  If LVEF 40–≤45% and ↓ is <10% points from baseline,  continue therapy. Repeat LVEF within 3 wk.  If LVEF >45%,  continue therapy. For patients with early breast cancer:  If LVEF <45%,  hold ado-trastuzumab. Repeat LVEF within 3 wk. If LVEF <45% is confirmed, permanently discontinue ado-trastuzumab.  If LVEF 45–< 50% and ↓ is ≥10% points from baseline,  hold ado-trastuzumab. Repeat LVEF within 3 wk.  If LVEF <50% and not recovered to <10% points from baseline,  permanently discontinue ado-trastuzumab.  If LVEF 45–<50% and ↓ is <10% points from baseline,  continue therapy. Repeat LVEF within 3 wk.  If LVEF ≥50%,  continue therapy.  If symptomatic HF, Grade 3–4 left ventricular systolic dysfunction, Grade 3–4 HF, or Grade 2 HF accompanied by LVEF <45% occurs  permanently discontinue ado-trastuzumab.
• Assess for signs/symptoms of infusion-related/hypersensitivity reactions (fever, chills, flushing, dyspnea, hypotension, wheezing, bronchospasm, tachycardia).  If severe reaction occurs,  slow infusion or interrupt therapy. Observe closely during 1st infusion.  If life-threatening reaction occurs,  permanently discontinue ado-trastuzumab.
• Monitor neurologic status before and during therapy. Assess for paresthesia, loss of deep tendon reflexes (Achilles reflex is usually 1st 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 (↓ level of consciousness, agitation, hallucinations).  If Grade 3 or 4 peripheral neuropathy (severe symptoms; limiting self-care activities of daily living occurs, temporarily discontinue ado-trastuzumab until resolution to Grade ≤2 (moderate symptoms; limiting instrumental activities of daily living) neuropathy.
• Monitor for signs/symptoms of pulmonary toxicity (dyspnea, cough, fatigue, pulmonary infiltrates).  If ILD or pneumonitis occurs, permanently discontinue ado-trastuzumab.
• Monitor for hemorrhage during therapy, especially in patients receiving anticoagulants or antiplatelet therapy or who have thrombocytopenia.

Lab Test Considerations:

Verify negative pregnancy status before starting therapy.

•   HER2-protein overexpression is used to determine whether treatment with ado-trastuzumab is indicated and should be determined by labs with proficiency in specific technology used. Information on approved tests is available at http://www.fda.gov/CompanionDiagnostics.
• Monitor serum AST, ALT, and bilirubin before starting therapy and before each dose. For patients with metastatic disease:  If AST/ALT >2.5–≤5 times upper limit of normal (ULN),  treat at same dose.  If AST/ALT >5–≤20 times ULN,  hold ado-trastuzumab until recovers to Grade ≤2, then resume at ↓ dose.  If AST/ALT >20 times ULN,  permanently discontinue ado-trastuzumab.  If serum bilirubin >1.5–≤3 times ULN,  hold ado-trastuzumab until recovers to Grade ≤1, then resume at same dose.  If bilirubin >3–≤10 times ULN:  hold dose until recovers to Grade ≤1, then resume at ↓ dose.  If bilirubin >10 times ULN,  permanently discontinue ado-trastuzumab.  If AST/ALT >3 times ULN and concurrent total bilirubin >2 times ULN,  permanently discontinue ado-trastuzumab. For patients with early breast cancer:  If ALT >3–≤20 times ULN on day of scheduled treatment,  hold ado-trastuzumab until recovers to Grade ≤1, then resume at ↓ dose.  If ALT >20 times ULN at any time,  permanently discontinue ado-trastuzumab.  If AST >3–≤5 times ULN on day of scheduled treatment,  hold ado-trastuzumab until recovers to Grade ≤1, then resume at same dose.  If AST >5–≤20 times ULN on day of scheduled treatment,  hold ado-trastuzumab until recovers to Grade ≤1, then resume at ↓ dose.  If AST >20 times ULN at any time,  permanently discontinue ado-trastuzumab.  If total bilirubin >1–≤2 times ULN on day of scheduled treatment,  hold ado-trastuzumab until total bilirubin ≤1 times ULN, then resume at ↓ dose.  If total bilirubin >2 times ULN at any time,  permanently discontinue ado-trastuzumab.
• Monitor platelets at baseline 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 platelets 25,000–<50,000/mm³ ,  hold ado-trastuzumab until platelets ≥75,000/mm³ , then resume at same dose.  If platelets <25,000/mm³ ,  hold ado-trastuzumab until platelets ≥75,000/mm³ , then resume at ↓ dose. For patients with early breast cancer:  If platelets 25,000–<75,000/mm³ ,  hold ado-trastuzumab until platelets ≥75,000/mm³ , then resume at same dose. If two delays required due to thrombocytopenia, resume at ↓ dose.  If platelets <25,000/mm³ ,  hold ado-trastuzumab until platelets ≥75,000/mm³ , then resume at ↓ dose.
• May ↓ hemoglobin, neutrophils, and potassium.

Implementation

• High Alert: Do not confuse ado-trastuzumab with trastuzumab. 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 health care provider independently double-check original order, dose calculations, and infusion pump settings.
• Dose reduction schedule:  1st dose reduction:  3 mg/kg 2nd dose reduction:  2.4 mg/kg If need for further dose reduction,  permanently discontinue ado-trastuzumab.
• Discard IV equipment in specially designated containers.

• Y-Site Incompatibility:
  • Do not administer other drugs through same IV line.

Patient/Family Teaching

• Explain purpose and side effects of medication. Advise patient to read  Patient Information  before starting therapy. Administer missed doses as soon as possible; do not wait until next scheduled dose. Adjust schedule to maintain 3-wk interval between doses.
• Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications.
• Advise patient to notify health care provider immediately if signs/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.
• Caution patient to immediately notify health care provider for easy or unusual signs of bleeding.
• Advise patient to notify health care provider if signs/symptoms of peripheral neuropathy (burning, numbness, pain in hands and feet/legs) occur.
• Rep:   May cause fetal harm. Advise women of reproductive potential to use a highly effective method of contraception during therapy and for ≥7 mo after last dose. Advise men with a female partner of reproductive potential to use a highly effective method of contraception during therapy and for ≥4 mo after last dose. Advise women to avoid breastfeeding for ≥7 mo after last dose. Encourage women who have been exposed to ado-trastuzumab during pregnancy, either directly or through seminal fluid, to immediately report exposure to Genentech Adverse Event Line at 1-888-835-2555. May impair fertility in men and women.

Evaluation/Desired Outcomes

↓ spread of metastatic breast cancer.