ado-trastuzumab emtansine (Rx)

Brand and Other Names:Kadcyla
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

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

Breast Cancer

Early breast cancer

  • Indicated as a single agent for adjuvant treatment of patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment
  • 3.6 mg/kg IV q3Weeks
  • Do not administer at doses >3.6 mg/kg
  • Continue treatment for a total of 14 cycles unless there is disease recurrence or unacceptable toxicity

Metastatic breast cancer

  • Indicated as a single agent for treatment of HER2-positive, metastatic breast cancer (MBC) 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
  • 3.6 mg/kg IV q3Weeks
  • Do not administer at doses >3.6 mg/kg
  • Continue until disease recurrence or unacceptable toxicity

Dosage Modifications

Dose reduction for adverse events

  • Do not re-escalate dose after reduction is made
  • First dose reduction: 3 mg/kg
  • Second dose reduction: 2.4 mg/kg
  • Requirement for further dose reduction: Discontinue treatment

Hepatotoxicity

  • MBC
    • Grade 2 (AST/ALT >2.5 to ≤5x ULN): Maintain same dose level
    • Grade 3 (AST/ALT >5 to ≤20x ULN): Do not administer until AST/ALT recovers to Grade ≤2, and then reduce 1 dose level
    • Grade 4 (AST/ALT >20x ULN): Permanently discontinue
  • EBC
    • Grade 2 (AST >3 to ≤5x ULN on day of treatment): Do not administer until AST recovers to Grade ≤1, and then maintain same dose level
    • Grade 2 or 3 (ALT >3 to ≤20x ULN) or Grade 3 (AST >5 to ≤20x ULN) on day of treatment: Do not administer until ALT/AST recovers to Grade ≤1, and then reduce 1 dose level
    • Grade 4 (AST/ALT >20x ULN at any time): Permanently discontinue

Hyperbilirubinemia

  • MBC
    • Grade 2 (total bilirubin >1.5 to ≤10x ULN): Do not administer until total bilirubin recovers to Grade ≤1, and then maintain same dose level
    • Grade 3 (total bilirubin >3 to ≤10x ULN): Do not administer until total bilirubin recovers to Grade≤1, and then reduce 1 dose level
    • Grade 4 (total bilirubin >10x ULN): Permanently discontinue
  • EBC
    • Total bilirubin >1 to ≤2x ULN on day of treatment: Do not administer until total bilirubin ≤1x ULN, and then reduce 1 dose level
    • Total bilirubin >2x ULN at any time: Permanently discontinue

Left ventricular dysfunction

  • MBC
    • 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
  • EBC
    • LVEF <45%: Do not administer drug; repeat LVEF assessment within 3 weeks, if <45% confirmed, discontinue drug
    • LVEF 45% to <50% and decrease is ≥10% points from baseline: Do not administer drug; repeat LVEF assessment within 3 weeks, if LVEF remains <50% and has not recovered to <10% points from baseline, discontinue drug
    • LVEF 45% to <50% and decrease is <10% points from baseline: Continue drug and repeat LVEF assessment within 3 weeks
    • LVEF >50%: Continue treatment

Heart failure

  • MBC
    • Symptomatic CHF: Discontinue drug
  • EBC
    • Symptomatic CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF < 45%: Discontinue treatment

Thrombocytopenia

  • MBC
    • Grade 3 (platelets 25,000/mm³ to ≤50,000/mm³): Do not administer until platelet count recovers to Grade ≤1 (ie, ≥75,000/mm³), and then maintain same dose level
    • Grade 4 (platelets <25,000/mm³): Do not administer until platelet count recovers to Grade ≤1 (ie, ≥75,000/mm³), and then reduce 1 dose level
  • EBC
    • Grade 3 (platelets 25,000/mm³ to ≤75,000/mm³ on day of treatment): Do not administer until platelet count recovers to Grade ≤1 (ie, ≥75,000/mm³), and then maintain same dose level; if patients requires 2 delays, consider reducing dose by 1 level
    • Grade 4 (platelets <25,000/mm³): Do not administer until platelet count recovers to Grade ≤1 (ie, ≥75,000/mm³), and then reduce 1 dose level

Pulmonary toxicity

  • Interstitial lung disease or pneumonitis: Permanently discontinue
  • Radiotherapy-related pneumonitis (EBC only)
    • Grade 2: Discontinue if not resolving with standard treatment
    • Grade 3-4: Discontinue treatment

Peripheral neuropathy

  • Grade 3 or 4: Do not administer until resolution to Grade ≤2

Nodular regenerative hyperplasia

  • All grades: Permanently discontinue

Renal impairment

  • Mild-to-moderate (CrCl ≥30 mL/min): Dose adjustment not necessary (based on population pharmacokinetics)
  • Severe (CrCl <30 mL/min): No dosage adjustment can be recommended owing to limited data

Hepatic impairment

  • Mild or moderate: No adjustment to starting dose required; monitor closely patients with hepatic impairment owing to risk of hepatotoxicity associated with therapy
  • Severe: Not studied

Dosing Considerations

Do not substitute ado-trastuzumab emtansine (Kadcyla) for or with trastuzumab (Herceptin)

Patient Selection

  • Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens
  • Perform assessment of HER2 protein overexpression and/or HER2 gene amplification using FDA-approved tests specific for breast cancers by laboratories with demonstrated proficiency
  • Information on the FDA-approved tests for detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics

Safety and efficacy not established

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Interactions

Interaction Checker

and ado-trastuzumab emtansine

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            Contraindicated (0)

              Serious - Use Alternative (33)

              • abametapir

                abametapir will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

              • apalutamide

                apalutamide will decrease the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

              • atazanavir

                atazanavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • baricitinib

                baricitinib, ado-trastuzumab emtansine. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug. Baricitinib is not recommended in combination with other JAK inhibitors, biologic DMARDs, or potent immunosuppressives.

              • chloramphenicol

                chloramphenicol will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • clarithromycin

                clarithromycin increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • cobicistat

                cobicistat will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • conivaptan

                conivaptan increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • darunavir

                darunavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • deferiprone

                deferiprone, ado-trastuzumab emtansine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis; if an alternative is not possible, monitor absolute neutrophil count more frequently.

              • elvitegravir/cobicistat/emtricitabine/tenofovir DF

                elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • fexinidazole

                fexinidazole will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

              • fosamprenavir

                fosamprenavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • idelalisib

                idelalisib will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

              • imatinib

                imatinib increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • indinavir

                indinavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • isoniazid

                isoniazid increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • itraconazole

                itraconazole increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying ado-trastuzumab until the strong CYP3A4 inhibitors have cleared from the circulation (~3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and ado-trastuzumab cannot be delayed, closely monitor for adverse reactions.

              • ivosidenib

                ivosidenib will decrease the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternate therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

              • ketoconazole

                ketoconazole increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • lonafarnib

                lonafarnib will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with sensitive CYP3A substrates. If coadministration unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.

              • lopinavir

                lopinavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • nefazodone

                nefazodone increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • nelfinavir

                nelfinavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • nicardipine

                nicardipine increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • palifermin

                palifermin increases toxicity of ado-trastuzumab emtansine by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

              • posaconazole

                posaconazole increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • quinidine

                quinidine increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • ritonavir

                ritonavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • saquinavir

                saquinavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • tipranavir

                tipranavir increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • voriconazole

                voriconazole increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. DM1, the cytotoxic component, is metabolized mainly by CYP3A4; strong CYP3A4 inhibitors may increase DM1 exposure and toxicity.

              • voxelotor

                voxelotor will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

              Monitor Closely (25)

              • belzutifan

                belzutifan will decrease the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If unable to avoid coadministration of belzutifan with sensitive CYP3A4 substrates, consider increasing the sensitive CYP3A4 substrate dose in accordance with its prescribing information.

              • cenobamate

                cenobamate will decrease the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

              • cholera vaccine

                ado-trastuzumab emtansine decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.

              • dabrafenib

                dabrafenib will decrease the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

              • dengue vaccine

                ado-trastuzumab emtansine decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.

              • dichlorphenamide

                dichlorphenamide and ado-trastuzumab emtansine both decrease serum potassium. Use Caution/Monitor.

              • duvelisib

                duvelisib will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.

              • elagolix

                elagolix will decrease the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

              • encorafenib

                encorafenib, ado-trastuzumab emtansine. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

              • fedratinib

                fedratinib will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

              • ifosfamide

                ifosfamide, ado-trastuzumab emtansine. Other (see comment). Use Caution/Monitor. Comment: Risk of developing cardiotoxic effects increase in patients with prior or concomitant treatment with other cardiotoxic agents.

              • iloperidone

                iloperidone increases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

              • istradefylline

                istradefylline will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

              • mifepristone

                mifepristone will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration necessary, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions

              • mitotane

                mitotane decreases levels of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.

              • ofatumumab SC

                ofatumumab SC, ado-trastuzumab emtansine. Either increases effects of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with coadministration. When switching from therapies with immune effects, take into account the duration and mechanism of action of these therapies when initiating ofatumumab SC.

              • ponesimod

                ponesimod and ado-trastuzumab emtansine both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

              • ribociclib

                ribociclib will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • rucaparib

                rucaparib will increase the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

              • siponimod

                siponimod and ado-trastuzumab emtansine both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

              • stiripentol

                stiripentol, ado-trastuzumab emtansine. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.

              • tazemetostat

                tazemetostat will decrease the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • tecovirimat

                tecovirimat will decrease the level or effect of ado-trastuzumab emtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

              • trastuzumab

                trastuzumab, ado-trastuzumab emtansine. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Neutropenia or febrile neutropenia incidence were increased when trastuzumab was coadministered with myelosuppressive chemotherapy. .

              • trastuzumab deruxtecan

                trastuzumab deruxtecan, ado-trastuzumab emtansine. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Neutropenia or febrile neutropenia incidence were increased when trastuzumab was coadministered with myelosuppressive chemotherapy. .

              Minor (0)

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                Adverse Effects

                All grades of severity are listed unless otherwise indicated

                >10% (All Grades for MBC)

                Nausea (40%)

                Fatigue (36%)

                Musculoskeletal pain (36%)

                Hemorrhage (32%)

                Thrombocytopenia (31%)

                AST/ALT increased (29%)

                Constipation (27%)

                Headache (28%)

                Diarrhea (24%)

                Epistaxis (23%)

                Peripheral neuropathy (21%)

                Vomiting (19%)

                Abdominal pain (19%)

                Pyrexia (19%)

                Arthralgia (19%)

                Asthenia (18%)

                Cough (18%)

                Dry mouth (17%)

                Myalgia (14%)

                Anemia (14%)

                Stomatitis (14%)

                Insomnia (12%)

                Dyspnea (12%)

                Rash (12%)

                >10% (All Grades for EBC)

                Fatigue (50%)

                Nausea (42%)

                AST/ALT increased (32%)

                Musculoskeletal pain (30%)

                Thrombocytopenia (29%)

                Hemorrhage (29%)

                Headache (28%)

                Peripheral neuropathy (28%)

                Arthralgia (26%)

                Epistaxis (22%)

                Constipation (17%)

                Myalgia (15%)

                Stomatitis (15%)

                Vomiting (15%)

                Dry Mouth (14%)

                Cough (14%)

                Insomnia (14%)

                Diarrhea (12%)

                Abdominal pain (11%)

                >10% (MBC [Grade 3 or 4])

                Thrombocytopenia (15%)

                1-10% (All Grades)

                MBC

                • Hypokalemia (10%)
                • Dizziness (10%)

                EBC

                • Anemia (10%)
                • Pyrexia (10%)
                • Dizziness (10%)
                • Urinary tract infection (10%)

                1-10% (Grade 3 or 4)

                MBC

                • AST/ALT increased (8%)
                • Anemia (4.1%)
                • Hypokalemia (2.7%)
                • Fatigue (2.5%)
                • Peripheral neuropathy (2.2%)
                • Musculoskeletal pain (1.8%)
                • Hemorrhage (1.8%)
                • Diarrhea (1.6%)

                EBC

                • Thrombocytopenia (6%)
                • Peripheral neuropathy (1.6%)
                • AST/ALT increased (1.5%)

                <1% (Grade 3 or 4)

                Nausea/vomiting (0.8%)

                Headache (0.8%)

                Dyspnea (0.8%)

                Arthralgia/myalgia (0.6%)

                Nausea (0.5%)

                Constipation (0.4%)

                Asthenia (0.4%)

                Dizziness (0.4%)

                Insomnia (0.4%)

                Dry mouth (0.4%)

                Stomatitis (0.2%)

                Pyrexia (0.2%)

                Epistaxis (0.2%)

                Cough (0.2%)

                Postmarketing Reports

                Tumor lysis syndrome (TLS) reported; significant tumor burden (eg, bulky metastases) increases risk

                CHF and > 10% reduction in LVEF in patients with baseline LVEF of 40-49%

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                Warnings

                Black Box Warnings

                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 LVEF
                • Evaluate LVEF in all patients before and during treatment
                • Withhold treatment for clinically significant decrease in LVEF (see Dosage Modifications)

                Embryofetal toxicity

                • Can result in embryofetal 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 embryofetal toxicity based on its mechanism of action
                • Advise patient of risk and the need for effective 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 of the liver reported; upon diagnosis of nodular regenerative hyperplasia of the liver, treatment must be permanently discontinued

                CHF and > 10% reduction in LVEF in patients with HER2-positive metastatic breast cancer with a baseline LVEF of 40-49% that received treatment reported (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)

                For patients with radiation pneumonitis in the adjuvant setting, therapy should be permanently discontinued for grade greater than or equal to 3 or for grade 2 not responding to standard treatment

                Patients with dyspnea at rest due to complications of advanced malignancy, co-morbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary toxicity

                Infusion-related reactions (IRRs) 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 (including 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)

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

                Cases of possible tumor lysis syndrome (TLS) reported in patients treated; patients with significant tumor burden (eg, bulky metastases) may be at a higher risk; patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS; providers should consider additional monitoring and/or treatment as clinically indicated

                Drug interactions overview

                • DM1, the cytotoxic component of ado-trastuzumab emtansine, is a CYP3A4 substrate
                • Avoid concomitant use of strong CYP3A4 inhibitors owing to the potential for an increase in DM1 exposure and toxicity; consider an alternative with no or minimal potential to inhibit CYP3A4
                • If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying ado-trastuzumab emtansine until strong CYP3A4 inhibitors have cleared from the circulation (~3 elimination half-lives of the inhibitors) when possible
                • If a strong CYP3A4 inhibitor is coadministered and ado-trastuzumab emtansine cannot be delayed, closely monitor patient for adverse reactions
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                Pregnancy & Lactation

                Pregnancy

                Therapy can cause fetal harm when administered to a pregnant woman

                No data available on use in pregnant women; cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death were observed in postmarketing setting in patients treated with trastuzumab, the antibody component

                Based on mechanism of action, the DM1 component can also cause embryofetal harm when administered to a pregnant woman

                Advise patient of potential risks to a fetus; there are clinical considerations if drug is used in a pregnant woman, or if a patient becomes pregnant within 7 months following last dose

                Pregnancy pharmacovigilance program

                • If administered during pregnancy, or if a patient becomes pregnant while receiving therapy or within 7 months following the last dose, immediately report ado-trastuzumab emtansine exposure to Genentech at 1-888-835-2555

                Reproductive potential

                • Verify pregnancy status of females of reproductive potential prior to initiation of therapy

                Contraception

                • Females: Drug can cause embryofetal harm when administered during pregnancy; advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose
                • Males: Because of potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months following the last dose

                Infertility

                • Based on results from animal toxicity studies, therapy may impair fertility in females and males of reproductive potential; not known if effects are reversible

                Lactation

                There is no information regarding presence of ado-trastuzumab emtansine in human milk, effects on breastfed infant, or on milk production; DM1, the cytotoxic component of the drug, may cause serious adverse reactions in breastfed infants based on its mechanism of action; advise women not to breastfeed during treatment and for 7 months following last dose of the drug

                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.

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                Pharmacology

                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)

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                Administration

                IV Incompatibilities

                Dextrose 5%

                Do not mix or administer as an infusion with other medicinal products

                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 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

                • Withdraw calculated amount from vial and add to a 0.9% NaCl 250-mL infusion bag
                • Gently invert bag to mix solution in order to avoid foaming

                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

                Do not substitute trastuzumab for or with ado-trastuzumab emtansine

                Closely monitor IV infusion site for possible SC infiltration

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

                Subsequent infusions: Administer over 30 minutes if prior infusion well tolerated; observe for IRRs during infusion and for at least 30 minutes afterwards

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

                Missed dose

                • If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle
                • Adjust dosing schedule to maintain a 3-week interval between doses
                • Administer infusion at dose and rate the patient tolerated in the most recent infusion

                Storage

                Unused vials: Refrigerate at 2-8ºC (36-46°F)

                Reconstituted vials or diluted solutions

                • Refrigerate at 2-8ºC (36-46°F)
                • Discard after 24 hr
                • Do NOT freeze
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                Images

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                Patient Handout

                A Patient Handout is not currently available for this monograph.
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                Formulary

                FormularyPatient Discounts

                Adding plans allows you to compare formulary status to other drugs in the same class.

                To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

                Adding plans allows you to:

                • View the formulary and any restrictions for each plan.
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                • Compare formulary status to other drugs in the same class.
                • Access your plan list on any device – mobile or desktop.

                The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                Tier Description
                1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                NC NOT COVERED – Drugs that are not covered by the plan.
                Code Definition
                PA Prior Authorization
                Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                QL Quantity Limits
                Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
                ST Step Therapy
                Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
                OR Other Restrictions
                Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.