Ado-trastuzumab emtansine

Ado-trastuzumab emtansine
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Ado-trastuzumab emtansine is an antineoplastic agent that is FDA approved for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy. Common adverse reactions include fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Recommended Doses and Schedules

• The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Do not administer KADCYLA at doses greater than 3.6 mg/kg. Do not substitute KADCYLA for or with trastuzumab.
• Closely monitor the infusion site for possible subcutaneous infiltration during drug administration.
• Dosing regimen:
  • First infusion: Administer infusion over 90 minutes. Patients should be observed during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions.
  • Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated. Patients should be observed during the infusion and for at least 30 minutes after infusion.

Dose Modifications

• KADCYLA dose should not be re-escalated after a dose reduction is made.
• If a planned dose is delayed or missed, it should be administered as soon as possible; do not wait until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval between doses. The infusion may be administered at the dose and rate the patient tolerated in the most recent infusion.
• The infusion rate of KADCYLA should be slowed or interrupted if the patient develops an infusion-related reaction. Permanently discontinue KADCYLA for life-threatening infusion-related reactions.
• Management of increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require temporary interruption, dose reduction or treatment discontinuation of KADCYLA as per guidelines provided in Tables 1 to 5.

Hepatotoxicity

• A reduction in the dose of KADCYLA is recommended in the case of hepatotoxicity exhibited as increases in serum transaminases and/or hyperbilirubinemia.

• Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN.
• Permanently discontinue KADCYLA in patients diagnosed with nodular regenerative hyperplasia (NRH).

Left Ventricular Dysfunction

Thrombocytopenia

• A reduction in dose is recommended in the case of Grade 4 thrombocytopenia (platelets < 25,000/mm3).

Pulmonary Toxicity

• KADCYLA should be permanently discontinued in patients diagnosed with interstitial lung disease (ILD) or pneumonitis.

Peripheral Neuropathy

• KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ado-trastuzumab emtansine in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ado-trastuzumab emtansine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Ado-trastuzumab emtansine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Ado-trastuzumab emtansine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Ado-trastuzumab emtansine in pediatric patients.

Contraindications

• None

Warnings

Hepatotoxicity

• Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential.
• Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 × ULN or bilirubin > 1.5 × ULN prior to the initiation of treatment.
• In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients, one of which was fatal). Two of these three cases of NRH were observed in the randomized trial (Study 1). NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued.

Left Ventricular Dysfunction

• Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group.
• Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution's normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1.

Embryo-Fetal Toxicity

• KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action.
• If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus.
• Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720.

5.4 Pulmonary Toxicity

• Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) has been reported, with one case of grade 3 pneumonitis. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. These events may or may not occur as sequelae of infusion reactions. In the randomized trial (Study 1), the overall frequency of pneumonitis was 1.2%.
• Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis.
• Patients with dyspnea at rest due to complications of advanced malignancy and co-morbidities may be at increased risk of pulmonary toxicity.

Infusion-Related Reactions, Hypersensitivity Reactions

• Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is not recommended for these patients.
• Infusion-related reactions, characterized by one or more of the following symptoms – flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized trial (Study 1), the overall frequency of IRRs in patients treated with KADCYLA was 1.4%. In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. KADCYLA treatment should be interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR. Patients should be observed closely for IRR reactions, especially during the first infusion.
• One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical trials of single-agent KADCYLA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.

Hemorrhage

• Cases of hemorrhagic events, including central nervous system, respiratory, and gastrointestinal hemorrhage, have been reported in clinical trials with Kadcyla. Some of these bleeding events resulted in fatal outcomes. In the randomized trial (Study 1), the overall frequency of hemorrhage was 32.2% in the KADCYLA-treated group and 16.4% in the lapatinib plus capecitabine-treated group. The incidence of ≥ Grade 3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the lapatinib plus capecitabine-treated group. Although, in some of the observed cases the patients were also receiving anti-coagulation 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.

Thrombocytopenia

• Thrombocytopenia, or decreased platelet count, was reported in clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade 3; 283 of 884 treated patients with any Grade). The majority of these patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of KADCYLA, the incidence and severity of thrombocytopenia were higher in Asian patients.
• In the randomized trial (Study 1), the overall frequency of thrombocytopenia was 31.2% in the KADCYLA-treated group and 3.3% in the lapatinib plus capecitabine-treated group. The incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus capecitabine-treated group. In Asian patients, the incidence of ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated group and 1.3% in the lapatinib plus capecitabine-treated group.
• Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. KADCYLA has not been studied in patients with platelet counts <100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3). Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

Neurotoxicity

• Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any Grade). In the randomized trial (Study 1), the overall frequency of peripheral neuropathy was 21.2% in the KADCYLA-treated group and 13.5% in the lapatinib plus capecitabine-treated group. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group.
• KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity.

HER2 Testing

• Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC.
• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub- optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

Extravasation

• In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis.
• The ADRs described in TABLE 6 were identified in patients with HER2-positive metastatic breast cancer treated in a randomized trial (Study 1). Patients were randomized to receive KADCYLA or lapatinib plus capecitabine. The median duration of study treatment was 7.6 months for patients in the KADCYLA-treated group and 5.5 months and 5.3 months for patients treated with lapatinib and capecitabine, respectively. Two hundred and eleven (43.1%) patients experienced ≥ Grade 3 adverse events in the KADCYLA-treated group compared with 289 (59.2%) patients in the lapatinib plus capecitabine-treated group. Dose adjustments for KADCYLA were permitted. Thirty-two patients (6.5%) discontinued KADCYLA due to an adverse event, compared with 41 patients (8.4%) who discontinued lapatinib, and 51 patients (10.5%) who discontinued capecitabine due to an adverse event. The most common adverse events leading to KADCYLA withdrawal were thrombocytopenia and increased transaminases. Eighty patients (16.3%) treated with KADCYLA had adverse events leading to dose reductions. The most frequent adverse events leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most frequent adverse events leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases and [pyrexia]].
• TABLE 6 reports the ADRs that occurred in patients in the KADCYLA-treated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in TABLE 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

• Hepatic failure has been observed in two patients (0.2%) with HER2-positive metastatic breast cancer in clinical trials (n=884) with KADCYLA as single-agent.

Immunogenicity

• As with all therapeutic proteins, there is the potential for an immune response to KADCYLA. A total of 836 patients from six clinical studies were tested at multiple time points for anti-therapeutic antibody (ATA) responses to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients tested positive for anti-KADCYLA antibodies at one or more post-dose time points. The presence of KADCYLA in patient serum at the time of ATA sampling may interfere with the ability of this assay to detect anti-KADCYLA antibodies. As a result, data may not accurately reflect the true incidence of anti-KADCYLA antibody development. In addition, neutralizing activity of anti-KADCYLA antibodies has not been assessed.
• Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to KADCYLA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-KADCYLA antibodies is not yet known.

Postmarketing Experience

There is limited information regarding Ado-trastuzumab emtansine Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Ado-trastuzumab emtansine Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Ado-trastuzumab emtansine in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ado-trastuzumab emtansine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Ado-trastuzumab emtansine during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Ado-trastuzumab emtansine in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Ado-trastuzumab emtansine in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Ado-trastuzumab emtansine in geriatric settings.

Gender

There is no FDA guidance on the use of Ado-trastuzumab emtansine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Ado-trastuzumab emtansine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Ado-trastuzumab emtansine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Ado-trastuzumab emtansine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Ado-trastuzumab emtansine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Ado-trastuzumab emtansine in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Ado-trastuzumab emtansine Administration in the drug label.

Monitoring

There is limited information regarding Ado-trastuzumab emtansine Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Ado-trastuzumab emtansine and IV administrations.

Overdosage

There is limited information regarding Ado-trastuzumab emtansine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Ado-trastuzumab emtansine Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Ado-trastuzumab emtansine Mechanism of Action in the drug label.

Structure

There is limited information regarding Ado-trastuzumab emtansine Structure in the drug label.

Pharmacodynamics

There is limited information regarding Ado-trastuzumab emtansine Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Ado-trastuzumab emtansine Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Ado-trastuzumab emtansine Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Ado-trastuzumab emtansine Clinical Studies in the drug label.

How Supplied

There is limited information regarding Ado-trastuzumab emtansine How Supplied in the drug label.

Storage

There is limited information regarding Ado-trastuzumab emtansine Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Ado-trastuzumab emtansine Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Ado-trastuzumab emtansine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Ado-trastuzumab emtansine Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Ado-trastuzumab emtansine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.