ado-trastuzumab emtansine (Kadcyla)

Dosing and uses of Kadcyla (ado-trastuzumab emtansine)

• Adult
• Pediatric

 

Adult dosage forms and strengths

lyophilized powder for reconstitution

• 100mg/vial
• 160mg/vial
• 20mg/mL following reconstitution

 

Metastatic Breast Cancer

Indicated as a single agent for treatment of HER2-positive, metastatic breast cancer in patients who previously received trastuzumab and a taxane, separately or in combination

Patient should have either 1) received prior therapy for metastatic disease, or 2) developed disease recurrence during or within 6 months of completing adjuvant therapy

3.6 mg/kg IV infusion q3weeks until disease progression or unacceptable toxicity

Do not exceed 3.6 mg/kg/dose

 

Renal Impairment

CrCl <30 mL/min: Dose adjustment not necessary

CrCl ≥ 30 mL/min: Not studied

 

Hepatic Impairment

Mild or moderate hepatic impairment : No adjustment to starting dose required; monitor closely patients with hepatic impairment due to risk of hepatotoxicity associated with therapy

Severe hepatic impairment: Not studied

 

Dosage modifications

Do not re-escalate dose after reduction is made

Dose reduction for adverse events

• First dose reduction: 3 mg/kg
• Second dose reduction: 2.4 mg/kg
• Requirement for further dose reduction: Discontinue treatment

Hepatotoxicity

• AST/ALT >2.5 to ≤5x ULN (Grade 2): Maintain same dose level
• AST/ALT >5 to ≤20x ULN (Grade 3): Do not administer until AST/ALT recovers to Grade ≤2, and then reduce one dose level
• AST/ALT >20x ULN (Grade 4): Permanently discontinue

Hyperbilirubinemia

• >1.5 to ≤3x ULN (Grade 2): Do not administer until total bilirubin recovers to Grade ≤1, and then reduce one dose level
• >3 to ≤10x ULN (Grade 3): Do not administer until total bilirubin recovers to Grade ≤1, and then reduce one dose level
• >10x ULN (Grade 4): Permanently discontinue

Left ventricular dysfunction

• Symptomatic CHF: Discontinue drug
• LVEF <40%: Do not administer drug; repeat LVEF assessment within 3 weeks, if <40% confirmed, discontinue drug
• LVEF 40% to ≤45% and decrease is ≥10% points from baseline: Do not administer drug; repeat LVEF assessment within 3 weeks, if LVEF has not recovered to within 10% points from baseline, discontinue drug
• LVEF 40% to ≤45% and decrease is <10% points from baseline: Continue drug and repeat LVEF assessment within 3 weeks
• LVEF >45%: Continue drug

Thrombocytopenia

• Platelets 25,000/mm3 to ≤50,000/mm³: Do not administer until platelet count recovers to ≤Grade 1 (ie, ≥75,000/mm³), and then treat at same dose level
• Platelets <25,000/mm³: Do not administer until platelet count recovers to ≤Grade 1 (ie, ≥75,000/mm³), and then reduce one dose level

Pulmonary toxicity

• Permanently discontinue with interstitial lung disease or pneumonitis

Peripheral neuropathy

• Temporarily discontinue for Grade 3 or 4 peripheral neuropathy until resolution to ≤Grade 2

 

Dosing Considerations

Do not substitute ado-trastuzumab emtansine (Kadcyla) for or with trastuzumab (Herceptin); see Black box warnings

If planned dose is delayed or missed, administer as soon as possible; do not wait for next planned cycle; adjust administration schedule to maintain a 3-week interval between doses

 

Administration

Administer as IV infusion only with a 0.22 micron in-line nonprotein adsorptive polyethersulfone (PES) filter

Do NOT give as IV push or bolus

Do not mix or infuse with other medicinal products

Closely monitor IV infusion site for possible SC infiltration

First infusion: Administer over 90 minutes; observe for fever, chills, or other infusion-related reactions during infusion and for at least 90 minutes afterwards

Subsequent infusion: Administer over 90 minutes if prior infusion well tolerated; observe for infusion-related reactions during infusion and for at least 30 minutes afterwards

Slow or interrupt dose if infusion-related reaction occurs; permanently discontinue for life-threatening related reactions

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Kadcyla (ado-trastuzumab emtansine) adverse (side) effects

Percentage based on all grades

 

>10%

Nausea (39.8%)

Fatigue (36.3%)

Musculoskeletal pain (36.1%)

Thrombocytopenia (31.2%)

Transaminases increased (28.8%)

Headache (28.2%)

Constipation (26.5%)

Diarrhea (24.1%)

Epistaxis (22.5%)

Peripheral neuropathy (21.2%)

Vomiting (19.2%)

Arthralgia (19.2%)

Abdominal pain (18.6%)

Pyrexia (18.6%)

Cough (18.2%)

Asthenia (17.8%)

Dry mouth (16.7%)

Anemia (14.3%)

Stomatitis (14.1%)

Myalgia (14.1%)

Insomnia (12%)

Dyspnea (12%)

Rash (11.6%)

Hypokalemia (10.2%)

Dizziness (10.2%)

 

1-10%

Urinary tract infections (9.4%)

Dyspepsia (9.2%)

Dysgeusia (8%)

Chills (7.6%)

Peripheral edema (7.1%)

Neutropenia (6.7%)

Pruritus (5.5%)

Immunogenicity (5.3%)

Hypertension (5.1%)

Blood alkaline phosphatase increased (4.7%)

Blurred vision (4.5%)

Dry eyes (3.9%)

Conjunctivitis (3.9%)

Lacrimation increased (3.3%)

Drug hypersensitivity (2.2%)

Left ventricular dysfunction (1.8%)

Infusion-related reactions (1.4%)

Pneumonitis (1.2%)

 

<1%

Hepatobiliary nodular regenerative hyperplasia (0.4%)

Portal hypertension (0.4%)

 

Warnings

Black box warnings

Do not substitute ado-trastuzumab emtansine (Kadcyla) for or with trastuzumab (Herceptin); dosing and treatment schedules for Kadcyla and Herceptin are quite different, so confusion between these products could lead to dosing errors and potential harm to patients

Hepatotoxicity

• Serious hepatoxicity reported including liver failure and death
• Monitor serum transaminases and bilirubin before initiating and prior to each dose
• Reduce dose or discontinue as appropriate with elevated transaminases or total bilirubin (see Dosage modifications)

Cardiac toxicity

• May decrease left ventricular ejection fraction (LVEF) Evaluate LVEF in all patients before and during treatment
• Withhold treatment for clinically significant decrease in LVEF (see Dosage modifications)

Embryo-fetal toxicity

• Can result in embryo-fetal death or birth defects
• Postmarketing reports of oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death DM1, the cytotoxic component, can be expected to cause embryo-fetal toxicity based on its mechanism of action
• Advise patient of risk and the need for effect contraception
• Verify pregnancy status prior to initiation

 

Contraindications

None

 

Cautions

Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, reported (see Black box warnings and Dosage modifications)

Cases of nodular regenerative hyperplasia (NRH) of the liver reported; upon diagnosis of nodular regenerative hyperplasia of the liver, treatment must be permanently discontinued

Increased risk of left ventricular dysfunction (see Black box warnings and Dosage modifications)

Discontinue treatment permanently if patient diagnosed with nodular regenerative hyperplasia

Known to cause fetal harm and death (see Black box warnings)

Pulmonary toxicity may occur; cases of interstitial lung disease, including pneumonitis reported; permanently discontinue drug (see Dosage modifications)

Infusion related reactions (IRR) and/or hypersensitivity may occur; temporarily interrupt infusion for severe IRRs and permanently discontinue if life-threatening IRR occurs

Thrombocytopenia or decreased platelet counts reported (see Dosage modifications)

Hemorrhagic events reported and include CNS, respiratory, and GI hemorrhage, have been reported; although, in some cases patients were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, in others there were no known additional risk factors; use caution with these agents and consider additional monitoring when concomitant use is medically necessary

Peripheral neuropathy may occur (see Dosage modifications)

HER2 testing: Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for ado-trastuzumab emtansine therapy because these are the only patients studied for whom benefit has been shown

Extravasation observed during clinical trials; carefully monitor infusion site during infusion and inform patient to report any tenderness/redness

DM1, the cytotoxic component of ado-trastuzumab emtansine is a CYP3A4 substrate; avoid concomitant strong CYP3A4 inhibitors because of potential for increased DM1 exposure and toxicity

 

Pregnancy and lactation

Pregnancy category: D; Can result in embryo-fetal death or birth defects

Postmarketing reports of oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Black box warnings); if patient becomes pregnant while receiving therapy or within 7 months following the last dose, apprise patient of potential hazard to fetus

Lactation: Unknown whether distributed in human breast milk; a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Kadcyla (ado-trastuzumab emtansine)

Mechanism of action

HER2-targeted antibody-drug conjugate (ADC) which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative)

Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites

Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death

In addition, in vitro studies have shown that similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2

 

Absorption

Peak plasma time: Near end of infusion

Peak plasma concentration: 83.4 mcg/mL (ADC); 4.61 ng/mL (DM1)

 

Distribution

Protein bound: 93% (DM1)

Vd: 3.13 L (ADC)

DM1 is a P-gp substrate (in vitro)

 

Metabolism

DM1 metabolized by mainly by CYP3A4 and to a lesser degree by CYP3A5

 

Elimination

Half-life: 4 days (ADC)

Total body clearance: 0.68 L/day (ADC)

 

Administration

IV Incompatibilities

Dextrose 5%

 

IV Compatibilities

0.9% NaCL

 

IV Preparation

Use aseptic technique and procedures for antineoplastic drug preparation

Reconstitution

• Reconstitute vial by slowly injecting with sterile water for injection (SWI)
• Gently swirl vial until completely dissolved; do not shake
• Inspect reconstituted solution for particulates and discoloration (colorless to pale brown); do not use if particulates are visible or the solution is cloudy or discolored
• 100 mg vial: Reconstitute with 5 mL SWI
• 160 mg vial: Reconstitute with 8 mL SWI
• Resulting concentration is 20mg/mL

Dilution

• Calculate volume of the 20 mg/mL reconstituted solution required for individual dose
• Withdraw this amount from the vial and add to 250 mL infusion bag of 0.9% NaCl
• Gently invert the bag to mix the solution in order to avoid foaming
• Do NOT dilute in dextrose 5% solution

 

IV Administration

Administer as IV infusion only with a 0.22 micron in-line nonprotein adsorptive polyethersulfone (PES) filter

Do NOT give as IV push or bolus

Do not mix or infuse with other medicinal products

Closely monitor IV infusion site for possible SC infiltration

First infusion: Administer over 90 minutes; observe for fever, chills, or other infusion-related reactions during infusion and for at least 90 minutes afterwards

Subsequent infusion: Administer over 90 minutes if prior infusion well tolerated; observe for infusion-related reactions during infusion and for at least 30 minutes afterwards

Slow or interrupt dose if infusion-related reaction occurs; permanently discontinue for life-threatening related reactions

 

Storage

If not used immediately, reconstituted vial or diluted solution may be stored refrigerated at 2-8ºC (36-46°F)

Discard after 4 hr

Do NOT freeze