ado-trastuzumab

ado tras-TOO-zoo-mab

Therapeutic Classification: antineoplastics

Pharmacologic Classification: drug-antibody conjugates

High Alert

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.

Therapeutic effects:

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

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

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

Half-Life: 4 days.

(comparative improvement in progression-free survival)

ROUTE	ONSET	PEAK	DURATION
IV	4–6 mo	10–12 mo	2 yr

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.

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

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.

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: Permanently discontinue ado-trastuzumab. If left ventricular ejection fraction (LVEF) <40%: Hold dose. 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 dose. 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 dose. 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 dose. 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%: Permanently discontinue ado-trastuzumab.
Monitor infusion site closely for infiltration and extravasation. Within 24 hr, 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, 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 (↓ level of consciousness, agitation, hallucinations). If Grade 3 or 4 peripheral neuropathy (severe symptoms; limiting self-care activities of daily living [ADL]) occurs: Temporarily discontinue therapy 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 ado-trastuzumab if ILD or pneumonitis develops.
Monitor for hemorrhage during therapy, especially in patients receiving anticoagulants or antiplatelet therapy or who have thrombocytopenia.

Lab Test Considerations:

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.
- Verify negative pregnancy status before starting therapy.
- Monitor serum AST, ALT, and bilirubin prior to 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 dose until AST/ALT recovers to Grade ≤2; then ↓ by one dose level. If AST/ALT >20 times ULN: Permanently discontinue ado-trastuzumab. If serum bilirubin >1.5–≤3 times ULN: Hold dose until bilirubin recovers to Grade ≤1; then treat at same dose level. If bilirubin >3–≤10 times ULN: Hold dose until bilirubin recovers to Grade ≤1; then ↓ by one dose level. If bilirubin >10 times ULN: Permanently discontinue ado-trastuzumab. If AST/ALT >3 times ULN and concomitant 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 dose until ALT recovers to Grade ≤1; then ↓ by one dose level. If ALT >20 times ULN at any time: Permanently discontinue ado-trastuzumab. If AST >3–≤5 times ULN on day of scheduled treatment: Hold dose until AST recovers to Grade ≤1; then treat with same dose. If AST >5–≤20 times ULN on day of scheduled treatment: Hold dose until AST recovers to Grade ≤1; then ↓ by one dose level. 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 dose until total bilirubin ≤1 times ULN; then ↓ by one dose level. If total bilirubin >2 times ULN at any time: Permanently discontinue ado-trastuzumab.
- 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 platelets 25,000–<50,000/mm³: Hold dose until platelet count recovers to ≥75,000/mm³; then treat at same dose level. If platelets <25,000/mm³: Hold dose until platelet count recovers to ≥75,000/mm³; then ↓ by one dose level. For patients with early breast cancer: If platelets 25,000–<75,000/mm³: Hold dose until platelet count recovers to ≥75,000/mm³); then treat at same dose level. If two delays required due to thrombocytopenia, ↓ by one dose level. If platelets <25,000/mm³: Hold dose until platelet count recovers to ≥75,000/mm³; then ↓ by one dose level.
- May ↓ hemoglobin, neutrophils, and serum potassium.

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 practitioner 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; Need for further dose reduction: Permanently discontinue ado-trastuzumab.
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 administer other drugs through same IV line.

IV Administration:

Intermittent Infusion: Reconstitution: Slowly inject 5 or 8 mL of sterile water for injection into 100 or 160 mg vial of ado-trastuzumab respectively. 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 particulates. Use reconstituted vials immediately or store in refrigerator up to 4 hr; then discard. Do not freeze. Concentration: 20 mg/mL. Diluent: Withdraw required dose 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 hr prior to use; then discard; do not freeze or shake.
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. 1st 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 and for ≥90 min after infusion.

Explain purpose of medication to patient. If dose is missed, administer 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 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 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. Notify health care professional promptly if pregnancy is suspected and 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 all patients.

Decreased spread of metastatic breast cancer.

Kadcyla

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Action ⬆ ⬇

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Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

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Assessment ⬆ ⬇

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US Brand Names ⬆