Ado-trastuzumab emtansine

Name: Ado-trastuzumab emtansine

Uses for Ado-Trastuzumab Emtansine

Breast Cancer

Treatment of metastatic breast cancer in patients whose tumors overexpress the HER2 protein and who have received prior therapy with trastuzumab and a taxane, either separately or in combination.1 2 3 4

Appropriate patients include those who have received prior therapy for metastatic disease or who experienced disease recurrence during or within 6 months of completing adjuvant therapy.1

Efficacy established based on progression-free survival and overall survival.1

Ado-Trastuzumab Emtansine Dosage and Administration

General

  • Do not substitute ado-trastuzumab emtansine (Kadcyla) for or use with trastuzumab (Herceptin).1

  • Because of risk of infusion and/or hypersensitivity reactions, closely observe patients during infusion and for 90 minutes after first infusion and for 30 minutes after subsequent infusions.1 (See Infusion or Hypersensitivity Reactions under Cautions.)

  • Use of ado-trastuzumab emtansine is not recommended in patients for whom prior therapy with trastuzumab was permanently discontinued because of infusion reactions and/or drug hypersensitivity.1

  • Consult specialized references for procedures for proper handling (e.g., use of gloves) and disposal of antineoplastics.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion through a 0.22-μm polyethersulfone filter.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Ado-trastuzumab emtansine powder for injection must be reconstituted and diluted prior to administration.1 Use within 24 hours following reconstitution or dilution.1 (See Storage under Stability.)

Do not mix or administer with any other drug.1

Reconstitution

Reconstitute vial containing 100 or 160 mg of ado-trastuzumab emtansine with 5 or 8 mL of sterile water for injection, respectively, to provide a solution containing 20 mg/mL.1 Gently swirl vial to ensure dissolution.1 Do not shake reconstituted solution.1 Discard any unused solution after 24 hours.1

Reconstituted solution should be clear to slightly opalescent, colorless to pale brown, and free of visible particulates.1

Dilution

Dilute appropriate dose in 250 mL of 0.9% sodium chloride injection.1 Mix the diluted solution by gentle inversion; do not shake.1 Discard any partially used vials.1

Rate of Administration

Initial dose: Administer over 90 minutes.1

Subsequent doses: Administer over 30 minutes (if first infusion well tolerated).1

Dosage

Adults

Breast Cancer IV

3.6 mg/kg every 3 weeks.1 Continue therapy for as long as patient derives clinical benefit or until unacceptable toxicity occurs.1

If a dose is missed or delayed, do not wait until the next scheduled dose.1 Adjust dosage schedule to maintain a 3-week interval between doses.1

Dosage Modification for Toxicity

When dosage modification is required, reduce dosage by 1 dose level in 0.6-mg/kg decrements (e.g., from 3.6 to 3 mg/kg, from 3 to 2.4 mg/kg).1

If a dosage of 2.4 mg/kg requires further reduction, discontinue the drug.1

Do not re-escalate dosage following dosage reduction.1

Hepatotoxicity Recommended Dosage Modifications for Hepatotoxicity

Toxicity

Recommended Dosage Modifications

Grade 2 ALT/AST elevation (>2.5 times ULN but ≤5 times ULN)

Continue therapy at the same dosage1

Grade 2 or 3 total bilirubin elevation (>1.5 times ULN but ≤10 times ULN)

Interrupt therapy; following recovery to grade 1 or less, reduce dosage by one dose level1

Grade 3 ALT/AST elevation (>5 times ULN but ≤20 times ULN)

Interrupt therapy; following recovery to grade 2 or less, reduce dosage by one dose level1

Grade 4 ALT/AST elevation (>20 times ULN) or total bilirubin (>10 times ULN)

Permanently discontinue therapy1

ALT/AST elevation (>3 times ULN) and total bilirubin >2 times ULN

Permanently discontinue therapy1

Nodular regenerative hyperplasia

Permanently discontinue therapy1

Infusion or Hypersensitivity Reactions

If infusion reactions occur, reduce infusion rate or interrupt infusion depending on severity of the reaction.1

If life-threatening infusion reactions occur, permanently discontinue therapy.1

Left Ventricular Dysfunction Recommended Dosage Modifications for Left Ventricular Dysfunction

Left Ventricular Ejection Fraction (LVEF)

Recommended Dosage Modifications

40–45% with decrease from baseline <10%

Continue therapy1

40–45% with decrease from baseline ≥10%

Interrupt therapy for at least 3 weeks.1 Reassess LVEF within 3 weeks; if LVEF has not improved to within 10% of baseline, discontinue therapy1

<40%

Interrupt therapy for at least 3 weeks.1 Reassess LVEF within 3 weeks; if LVEF has not improved to ≥40%, permanently discontinue therapy1

Symptomatic CHF

Discontinue therapy1

Thrombocytopenia

If grade 3 thrombocytopenia (platelet counts ≥25,000/mm3 but <50,000/mm3) occurs, interrupt therapy until thrombocytopenia resolves to grade 1 or less (platelet counts ≥75,000/mm3), and then resume therapy at the same dosage.1

If grade 4 thrombocytopenia (platelet counts <25,000/mm3) occurs, interrupt therapy until thrombocytopenia resolves to grade 1 or less (platelet counts ≥75,000/mm3), and then resume therapy by reducing dosage one dose level.1

Pulmonary Toxicity

If manifestations of interstitial lung disease or pneumonitis develop, permanently discontinue therapy.1

Peripheral Neuropathy

If grade 3 or 4 peripheral neuropathy occurs, interrupt dosing until peripheral neuropathy resolves to grade 2 or less.1

Prescribing Limits

Adults

Breast Cancer IV

Do not exceed dose of 3.6 mg/kg.1

Special Populations

Dosage adjustment not necessary based on baseline albumin concentrations.1 (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Clcr 30-89 mL/minute): No dosage adjustment required.1

Severe renal impairment (Clcr <30 mL/minute): Limited data available; no specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Ado-Trastuzumab Emtansine

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Hepatotoxicity

Hepatotoxicity, mainly manifested by asymptomatic, transient ALT and/or AST elevations, reported.1 Serious, sometimes fatal, hepatobiliary disorders and nodular regenerative hyperplasia also reported.1

Histopathology is necessary to confirm diagnosis of nodular regenerative hyperplasia.1 Consider this diagnosis in patients presenting with manifestations of portal hypertension without elevations in ALT and/or AST concentrations or manifestations of cirrhosis.1 If this condition occurs, permanently discontinue therapy.1

Not evaluated in patients with active HBV or HCV infection, ALT and/or AST concentrations >2.5 times ULN, or total bilirubin >1.5 times ULN.1

Monitor ALT, AST, and bilirubin concentrations prior to each dose of ado-trastuzumab emtansine.1 If ALT, AST, or bilirubin concentrations increase, interrupt therapy, reduce dosage, or permanently discontinue therapy.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Left Ventricular Dysfunction

Decreases in LVEF to <40% reported.1 2

Not evaluated in patients with baseline LVEF <50%, history of symptomatic CHF, serious cardiac arrhythmia, or history of MI or unstable angina within 6 months of initiating therapy.1

Assess LVEF prior to initiation of therapy and at regular intervals (e.g., every 3 months) during treatment.1

If LVEF decreases to ≤45%, temporarily or permanently discontinue therapy.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1

Oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death observed following administration of the anti-HER2 antibody trastuzumab to pregnant women in postmarketing experience.1 Trastuzumab crossed placental barrier during early and late phases of gestation in monkeys.1

DM1 (derivative of maytansine) may cause embryotoxic and fetotoxic effects.1

Verify pregnancy status prior to initiation of ado-trastuzumab emtansine.1 Advise women of childbearing potential to use effective contraception during and for 6 months after discontinuance of drug.1

If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.1 (See Pregnancy under Cautions.)

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescriptions;1 1001 1005 1006 similarity in generic name of Kadcyla (ado-trastuzumab emtansine) and Herceptin (trastuzumab) may result in medication errors.1004 1005 Such errors may be associated with severe toxicity or lack of appropriate therapy.1001 1004 1005 (See Special Alerts.)

Sensitivity Reactions

Infusion or Hypersensitivity Reactions

Infusion reactions (e.g, anaphylactoid-like reaction) reported.1 Infusion reactions characterized by flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and/or tachycardia.1 Symptoms generally resolve within several hours to a day following discontinuance of infusion.1

Not evaluated in patients for whom prior therapy with trastuzumab was permanently discontinued due to infusion reactions and/or hypersensitivity to the drug.1 (See Dosage and Administration.)

Closely observe patients for 90 minutes after first infusion and for 30 minutes after subsequent infusions.1

If severe or life-threatening infusion reactions occur, may need to reduce infusion rate or temporarily or permanently discontinue therapy.1 (See Dosage Modification for Toxicity under Dosage and Administration.) Make appropriate medications and emergency equipment available for immediate use.1

Other Warnings and Precautions

Pulmonary Effects

Severe, sometimes fatal, adverse pulmonary effects (e.g., interstitial lung disease, pneumonitis, ARDS) reported.1

Consider possible pneumonitis in patients presenting with dyspnea, cough, fatigue, and pulmonary infiltrates; symptoms may also occur as sequelae of infusion reactions.1 Patients with dyspnea at rest resulting from advanced disease or other comorbidities may be at greater risk for pulmonary toxicity.1

If interstitial lung disease or pneumonitis occurs, permanently discontinue ado-trastuzumab emtansine.1

Thrombocytopenia

Thrombocytopenia occurs frequently; nadir platelet count occurs at approximately day 8 of each 3-week cycle.1 3 8 11 In clinical trials, incidence and severity of thrombocytopenia higher in Asian patients.1

Not evaluated in patients with baseline platelet counts <100,000/mm3.1

Monitor platelet counts prior to each dose of ado-trastuzumab emtansine.1 Closely monitor patients receiving concomitant anticoagulant therapy or those with platelet counts <100,000/mm3.1

If thrombocytopenia occurs, interrupt therapy until resolution to grade 1 or less.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Peripheral Neuropathy

Peripheral neuropathy (mainly sensory neuropathy) occurs frequently.1

Monitor patients for manifestations of neurotoxicity during therapy.1

If peripheral neuropathy occurs, temporarily discontinue therapy.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Evaluation of HER2

Assess breast tumors for HER2 overexpression prior to initiation of therapy; safety and efficacy of drug established only in patients with HER2-overexpressing tumors.1

Immunohistochemistry (IHC) assays (e.g., Dako Herceptest), which measure overexpression of the HER2 protein, and fluorescent in situ hybridization (FISH) (e.g., Dako HER2 FISH PharmDx), which measures amplification of the HER2 oncogene, are tests most commonly used.5

In clinical study, patients required to have disease demonstrating an IHC score of 3+ or a FISH amplification ratio of ≥2.1 2 Limited data available for patients with FISH-positive tumors that lack HER2 overexpression.1

Select laboratories with demonstrated proficiency in the specific technology being used; improper assay performance can lead to unreliable results.1

Local Effects

Extravasation resulting in erythema, tenderness, skin irritation, pain, or swelling at the infusion site reported; reactions generally are mild and occur within 24 hours following an infusion.1 Specific treatment for extravasation following infusion not established.1

Closely monitor infusion site for subcutaneous infiltration during administration.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If used during pregnancy or if patient becomes pregnant while receiving therapy, apprise of potential fetal hazard.1 Encourage patient to enroll in the MotHER Pregnancy Registry (800-690-6720), and immediately notify Genentech Adverse Event Line (888-835-2555).1

Lactation

Not known whether ado-trastuzumab emtansine is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No substantial differences in pharmacokinetics relative to younger adults; however, survival benefit not observed in patients ≥65 years of age in a subset analysis.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not altered by mild or moderate renal impairment; no dosage adjustment required.1 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Limited data available in patients with severe renal impairment.1

Common Adverse Effects

Stomatitis,1 dry mouth,1 3 abdominal pain,1 diarrhea,1 2 3 4 nausea,1 2 3 4 vomiting,1 2 3 4 constipation,1 3 4 pyrexia,1 3 4 asthenia,1 fatigue,1 2 3 4 myalgia,1 3 arthralgia,1 3 4 musculoskeletal pain,1 dizziness,1 peripheral neuropathy,1 3 headache,1 3 4 insomnia,1 dyspnea,1 3 4 cough,1 3 4 epistaxis,1 3 4 rash,1 pain in extremity,3 4 infusion reaction,3 hypokalemia,1 3 4 liver function test (AST, ALT, alkaline phosphatase) abnormalities,1 2 3 anemia,1 2 3 4 thrombocytopenia.1 2 3

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about ado-trastuzumab emtansine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about ado-trastuzumab emtansine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using ado-trastuzumab emtansine.

Review Date: October 4, 2017

Ado-trastuzumab Emtansine FDA Warning

  • Do not substitute ado-trastuzumab emtansine for or with trastuzumab.
  • Hepatotoxicity, liver failure and death have occurred in patients treated with ado-trastuzumab emtansine. Monitor hepatic function prior to initiation and prior to each dose. Institute dose modifications or permanently discontinue as appropriate.
  • Ado-trastuzumab emtansine may lead to reductions in left ventricular ejection fraction (LVEF). Assess LVEF prior to initiation. Monitor and withhold dosing or discontinue as appropriate.
  • Can cause fetal harm. Advise women of potential risk to the fetus.

Use Labeled Indications

Breast cancer, metastatic: Treatment (single-agent) of HER2-positive, metastatic breast cancer in patients who previously received trastuzumab and a taxane, separately or in combination, and have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.

Monitoring Parameters

Platelet count (at baseline and prior to each dose), transaminases and bilirubin (at baseline and prior to each dose); verify pregnancy status prior to treatment initiation; HER2 expression status. Evaluate left ventricular function (prior to and at least every 3 months during treatment; for LVEF <40% or 40% to 45% with ≥10% absolute decrease below baseline value, reassess within 3 weeks). Monitor infusion site during infusion for possible infiltration; monitor for infusion reactions (during infusion and for 90 minutes after initial infusion and for 30 minutes after subsequent infusions); signs and symptoms of bleeding, neuropathy, and/or pulmonary toxicity

Pregnancy & 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.

Patient Handout

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Dose Adjustments

Mild to moderate renal dysfunction (CrCl 30 - 89 mL/min): No adjustment recommended
Severe renal dysfunction (CrCl less than 30 mL/min): Data not available

Dialysis

Data not available

Ado-trastuzumab emtansine Breastfeeding Warnings

A decision should be made to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Unknown The effects in the nursing infant are unknown.

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