Ado-trastuzumab emtansine

Name: Ado-trastuzumab emtansine

How should this medicine be used?

Ado-trastuzumab emtansine injection comes as a powder to be mixed with liquid and injected slowly into a vein by a doctor or nurse in a hospital or medical facility. It is usually injected once every 3 weeks. The length of your treatment depends on how well your body responds to the medication and the side effects that you experience.

It should take 90 minutes for you to receive your first dose of ado-trastuzumab emtansine. A doctor or nurse will watch you closely to see how your body reacts to ado-trastuzumab emtansine. If you do not have any serious problems when you receive your first dose of ado-trastuzumab emtansine, it will usually take 30 minutes for you to receive each of your remaining doses of the medication.

Ado-trastuzumab emtansine injection may cause serious infusion-related reactions, which may occur during the infusion of the medication. If you experience any of the following symptoms, tell your doctor immediately: flushing; fever; chills; dizziness; lightheadedness; fainting; shortness of breath; difficulty breathing; or fast, irregular, or pounding heartbeat.

Your doctor may need to delay your treatment, adjust your dose, or stop your treatment if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with ado-trastuzumab emtansine.

Brand names

  • Kadcyla®

Ado-trastuzumab emtansine dosing information

Usual Adult Dose for Breast Cancer:

Usual dose: 3.6 mg/kg IV every 3 weeks

Maximum dose: 3.6 mg/kg IV every 3 weeks

Duration of therapy: Until disease progression or unacceptable toxicity

Comments: Administer the first infusion over 90 minutes. Subsequent infusions may be administered over 30 minutes as tolerated.

Do not substitute ado-trastuzumab emtansine for or with trastuzumab.

What other drugs will affect ado-trastuzumab emtansine?

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • imatinib;

  • isoniazid;

  • nefazodone;

  • an antibiotic--clarithromycin, telithromycin;

  • a blood thinner--warfarin, Coumadin, Jantoven;

  • antifungal medication--itraconazole, ketoconazole, posaconazole, voriconazole;

  • heart medication--nicardipine, quinidine;

  • hepatitis C medications--boceprevir, telaprevir;

  • HIV/AIDS medication--atazanavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir; or

  • medicine used to prevent blood clots--alteplase, clopidogrel, dipyridamole, ticlopidine, urokinase.

This list is not complete. Other drugs may interact with ado-trastuzumab emtansine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Ado-Trastuzumab Emtansine Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations of the antibody-drug conjugate and DM1 are observed near the end of IV infusion.1

Steady-state concentrations achieved after the second cycle of therapy.13

Systemic accumulation of the antibody-drug conjugate not observed following repeated doses administered by IV infusion every 3 weeks.1 13

Distribution

Extent

Not known whether ado-trastuzumab emtansine distributes into human milk.1 (See Lactation under Cautions.)

Trastuzumab (the antibody component of the antibody-drug conjugate) distributes into milk in monkeys.1

Plasma Protein Binding

93%.1

Elimination

Metabolism

DM1 metabolized by CYP3A4/5 in vitro.1

Half-life

Antibody-drug conjugate: approximately 4 days.1

Special Populations

Age, race, and serum albumin concentrations do not have clinically important effects on pharmacokinetics of ado-trastuzumab emtansine.1 (See Special Populations under Dosage and Administration.)

Mild (Clcr of 60–89 mL/minute) or moderate (Clcr of 30–59 mL/minute) renal impairment: Pharmacokinetics similar to that in patients with normal renal function.1 (See Renal Impairment under Dosage and Administration.)

Severe renal impairment (Clcr <30 mL/minute): Limited data available.1

Effect of hepatic impairment on pharmacokinetics not determined.1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ado-Trastuzumab Emtansine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion only

100 mg

Kadcyla

Genentech

160 mg

Kadcyla

Genentech

What are some things I need to know or do while I take Ado-Trastuzumab Emtansine?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • Very bad and sometimes deadly bleeding problems have happened with ado-trastuzumab emtansine. Talk with the doctor.
  • Some people have side effects during the infusion. These include chills, fast heartbeat, fever, flushing, shortness of breath, very bad dizziness or passing out, and wheezing. You will be watched closely during the infusion and for some time after. Tell your doctor if you have any of these side effects or any other effects during the infusion.
  • This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
  • If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for at least 4 months after stopping this medicine. Use birth control that you can trust.
  • If you are a man and your sex partner gets pregnant while you take ado-trastuzumab emtansine or within 4 months after your last dose, call your doctor right away.

What are some other side effects of Ado-Trastuzumab Emtansine?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Dry mouth.
  • Change in taste.
  • Belly pain.
  • Upset stomach or throwing up.
  • Loose stools (diarrhea).
  • Hard stools (constipation).
  • Feeling tired or weak.
  • Muscle or joint pain.
  • Headache.
  • Nosebleed.
  • Not able to sleep.
  • Rash.
  • Dizziness.
  • Mouth irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Ado-trastuzumab Emtansine Brand Names

Ado-trastuzumab Emtansine may be found in some form under the following brand names:

  • Kadcyla

Inform MD

Before receiving ado-trastuzumab emtansine,

  • tell your doctor and pharmacist if you are allergic to ado-trastuzumab emtansine, trastuzumab, any other medications, or any of the ingredients in ado-trastuzumab emtansine injection. Ask your doctor or pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • tell your doctor if you have or have ever had any of the conditions mentioned in the "Ado-trastuzumab Emtansine Precautions" section.
  • tell your doctor if you have or have ever had trouble breathing, even when resting, or any other medical condition.
  • tell your doctor if you are breast-feeding. You should not breast-feed while receiving ado-trastuzumab emtansine.

 

Dosing Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Drug Interactions

Antineoplastic Agents (Anthracycline, Systemic): Ado-Trastuzumab Emtansine may enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline, Systemic). Management: When possible, patients treated with ado-trastuzumab emtansine should avoid anthracycline-based therapy for up to 7 months after stopping ado-trastuzumab emtansine. Monitor closely for cardiac dysfunction in patients receiving this combination. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Dosing & Uses

Dosage Forms & 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

Safety and efficacy not established

(web3)