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ADO-TRASTUZUMAB EMTANSINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ado-trastuzumab emtansine is a HER2-targeted antibody and microtubule inhibitor conjugate used as a single agent for previously treated patients with HER2-positive metastatic breast cancer. This agent is NOT indicated as a substitute for trastuzumab.

Specific Substances

    1) CAS 1018448-65-1

Available Forms Sources

    A) FORMS
    1) Ado-trastuzumab emtansine is available in 100 mg and 160 mg vial (single use vial) for intravenous infusion only (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) USES
    1) Ado-trastuzumab emtansine is used as a single agent for the treatment of patients with HER2-positive, metastatic breast cancer who have been previously treated with trastuzumab and a taxane, separately, or in combination. This therapy is intended for patients that have received prior therapy for metastatic disease, or developed disease recurrence during or within 6 months of completing adjuvant therapy (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ado-trastuzumab emtansine, a HER2-targeted antibody and microtubule inhibitor conjugate, is used as a single-agent for the treatment of an individual with HER2-positive, metastatic breast cancer who have previously received trastuzumab and a taxane, separately or in combination. Ado-trastuzumab emtansine should NOT be substituted for trastuzumab.
    B) PHARMACOLOGY: This agent is composed of an antibody component derived from humanized anti-HER2 IgG1, trastuzumab and a small molecule cytotoxin, DM1, a microtubule inhibitor. 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. The binding of DMl to tubulin disrupts microtubule networks in the cell causing cell cycle arrest and apoptotic cell death.
    C) TOXICOLOGY: Theoretically, in overdose the loss of selectivity as a microtubule inhibitor could cause toxicity, especially myelosuppression and GI toxicity (nausea, vomiting, diarrhea, stomatitis).
    D) EPIDEMIOLOGY: Limited data. Overdose is uncommon. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic effects.
    E) WITH THERAPEUTIC USE
    1) SUMMARY: Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation are the most common adverse reactions reported with ado-trastuzumab emtansine. Fever and chills are common during an infusion.
    2) CARDIOVASCULAR: Patients can be at risk to develop left ventricular dysfunction. Hypertension may also occur.
    3) HEMATOLOGIC: Thrombocytopenia is likely to occur. Anemia and neutropenia have also occurred with some frequency in patients treated with ado-trastuzumab emtansine.
    4) RESPIRATORY: Epistaxis, cough, and dyspnea have occurred frequently (greater than 10%) with ado-trastuzumab emtansine. Infrequent cases of interstitial lung disease including pneumonitis (some cases have lead to acute respiratory distress syndrome or fatal outcome) have been observed.
    5) RARE: Infusion reactions and extravasation injuries have developed infrequently with ado-trastuzumab emtansine administration.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, fatigue, muscle pain and headache may develop following overdose. Other adverse events may include thrombocytopenia and increased transaminases.
    2) SEVERE TOXICITY: Cardiotoxicity (ie, left ventricular cardiac dysfunction), hepatotoxicity, and thrombocytopenia (Grade 3 and 4) may develop following a significant exposure. Neurotoxicity may include Grade 3 or 4 peripheral neuropathy. Pulmonary toxicity (interstitial lung disease and pneumonitis) and serious or fatal infusion reactions may occur.
    0.2.20) REPRODUCTIVE
    A) Ado-trastuzumab emtansine is classified as FDA pregnancy category D. There are no adequate or well controlled studies of ado-trastuzumab emtansine use in pregnant women, however two components of ado-trastuzumab emtansine (trastuzumab and DM1) are known or suspected to cause fetal harm or death when administered to a pregnant woman. Ado-trastuzumab emtansine use during pregnancy can result in fetal harm. Lactation studies with ado-trastuzumab emtansine have not been conducted.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for ado-trastuzumab emtansine in humans.

Laboratory Monitoring

    A) Monitor vital signs and neuro status.
    B) Monitor serum electrolytes and liver enzymes following exposure. Serial CBCs are indicated to evaluate for myelosuppression.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Obtain a chest radiograph and monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms or evidence of dyspnea or pneumonitis.
    E) Obtain an echocardiogram following a significant exposure to assess left ventricular ejection fraction.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Ado-trastuzumab emtansine is available only for intravenous use.
    B) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes and IV fluids as needed. Treat significant diarrhea with antidiarrheal agents. Obtain a CBC and monitor for thrombocytopenia; during therapeutic use patients reached nadir by day 8. Monitor respiratory function; dyspnea, cough or epistaxis have developed with therapy. Monitor liver enzymes (ie, transaminases); repeat as indicated.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Cardiac dysfunction (left ventricular dysfunction), neurotoxicity (peripheral neurotoxicity) and myelosuppression (ie, thrombocytopenia) are likely the most significant toxicity that can occur with ado-trastuzumab emtansine therapy. A decrease in left ventricular ejection fraction can occur. Obtain an echocardiogram to assess left ventricular ejection fraction. Monitor for myelosuppression.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not necessary as ado-trastuzumab emtansine is administered intravenously. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.
    D) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway or if unstable due to cardiac toxicity, an infusion reaction, severe respiratory distress syndrome, or CNS depression.
    E) INTRATHECAL INJECTION
    1) Intrathecal injection has not been reported with ado-trastuzumab emtansine, but this agent has caused neurotoxicity following IV infusion. Severe neurotoxicity may develop with an inadvertent intrathecal infusion. Based on other agents the following therapy is suggested. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Add fresh frozen plasma (25 mL FFP to 1 L NS or LR) or 5% albumin to the perfusate to enhance removal as ado-trastuzumab emtansine is highly protein bound. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    F) ANTIDOTE
    1) None.
    G) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    H) MYELOSUPPRESSION
    1) Monitor serial CBCs for thrombocytopenia, neutropenia and/or anemia which have been reported with ado-trastuzumab emtansine therapy; most cases were mild. Consider further therapy as indicated. Administer colony stimulating factors if severe neutropenia develops. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    I) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    J) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    K) EXTRAVASATION
    1) Reactions have been mild with therapeutic use and usually occur within 24 hours of an infusion. If extravasation occurs, withdraw as much solution as possible from the catheter before it is removed. Monitor site.
    L) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be useful given the increased protein binding (93%) of ado-trastuzumab emtansine.
    M) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac monitoring, and daily monitoring of CBC.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    N) PITFALLS
    1) Symptoms of overdose are likely to be similar to reported side effects of ado-trastuzumab emtansine. Early symptoms of overdose may be delayed or not evident (ie, congestive heart failure), so reliable follow-up is imperative. Patients receiving ado-trastuzumab emtansine may have severe comorbidities and may be receiving other drugs that may produce synergistic effects (ie, cardiotoxicity, myelosuppression). Ado-trastuzumab emtansine should NOT be substituted for trastuzumab.
    O) PHARMACOKINETICS
    1) Ado-trastuzumab emtansine is a HER2-targeted antibody drug conjugate. This agent is composed of an antibody component that is derived from humanized anti-HER2 IgG1, trastuzumab and a small molecule cytotoxin, DM1, a microtubule inhibitor. 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. The binding of DMl to tubulin disrupts microtubule networks in the cell causing cell cycle arrest and apoptotic cell death. Protein binding is 93%; the volume of distribution is 3.13 L. The elimination half-life is 4 days.
    P) DIFFERENTIAL DIAGNOSIS
    1) Clinical events may be related to underlying disease or previous use of chemotherapeutic agents (ie, trastuzumab or taxane therapy). A history of preexisting heart disease or a borderline or low left ventricular ejection fraction.

Range Of Toxicity

    A) TOXICITY: A lethal human dose has not been established. In clinical trials, overdose of ado-trastuzumab emtansine has been reported at approximately 2 times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal case, a patient received 6 mg/kg and died approximately 3 weeks later; the cause of death and a casual relationship to ado-trastuzumab emtansine were not determined.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 3.6 mg/kg via IV infusion. Administer over 90 minutes for the first infusion and 30 minutes for each subsequent infusion, every 3 weeks (21 days) until disease progression or unacceptable toxicity occurs. PEDIATRIC: The safety and effectiveness of ado-trastuzumab emtansine has not been established in pediatric patients.

Clinical Effects

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Pyrexia was reported in 18.6% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 8.4% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLURRED VISION
    a) Blurred vision was reported in 4.5% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 0.8% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    2) CONJUNCTIVITIS
    a) Conjunctivitis was reported in 3.9% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 2.3% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) LEFT VENTRICULAR CARDIAC DYSFUNCTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Patients receiving ado-trastuzumab emtansine are at increased risk to develop left ventricular dysfunction with therapy. During clinical trials, some patients treated with ado-trastuzumab emtansine had a decrease of left ventricular ejection fraction (LVEF) of less than 40% (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    b) Left ventricular dysfunction was reported in 1.8% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 3.3% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension was reported in 5.1% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 2.3% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INTERSTITIAL PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Cases of interstitial lung disease (ILD), including pneumonitis, have been reported in clinical trials of ado-trastuzumab emtansine. Some of these cases have led to acute respiratory distress syndrome or fatal outcomes (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) EPISTAXIS
    1) WITH THERAPEUTIC USE
    a) Epistaxis was reported in 22.5% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 8.4% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough was reported in 18.2% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 13.1% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    D) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea was reported in 12% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 8% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache is one of the most common adverse events (greater than 25%) reported with ado-trastuzumab emtansine therapy (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    b) Headache was reported in 28.2% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 14.5% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) PERIPHERAL NERVE DISEASE
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy, all grades, was reported in 21.2% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 13.5% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer. In addition, Grade 3 or 4 peripheral neuropathy was reported in 2.2% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 0.2% of patients who received oral lapatinib 1250 mg daily plus capecitabine (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia was reported in 17.8% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 17.6% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    D) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported in 12% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 8.6% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea is one of the most common adverse events (greater than 25%) reported with ado-trastuzumab emtansine therapy. Vomiting is also likely to occur with therapy (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    b) Nausea was reported in 39.8% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 45.1% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    c) Vomiting was reported in 19.2% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 29.9% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation is one of the most common adverse events (greater than 25%) reported with ado-trastuzumab emtansine therapy (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    b) Constipation was reported in 26.5% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 11.1% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain was reported in 18.6% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 17.6% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 24.1% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 79.7% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Hepatotoxicity, mainly in the form of asymptomatic, transient elevations in serum transaminases, has been reported with ado-trastuzumab emtansine treatment in clinical studies. However, serious hepatobiliary disorders (eg, at least 2 fatal cases of severe drug-induced liver injury with associated hepatic encephalopathy) have also been reported. Comorbidities and/or concomitant medications may have been partially responsible for some of these cases (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) Increased transaminase concentration (greater than 25%) is one of the most common adverse reactions reported with ado-trastuzumab emtansine therapy (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    2) Grade 3 and 4 increased transaminases were reported in 8% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 2.5% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    b) INCREASED BILIRUBIN LEVEL
    1) Increased bilirubin was reported in 17% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 57% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    c) SERUM ALKALINE PHOSPHATASE
    1) Increased blood alkaline phosphatase was reported in 4.7% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 3.7% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) UTI was reported in 9.4% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 3.9% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia is one of the most common adverse events (greater than 25%) reported with ado-trastuzumab emtansine therapy. In most cases, patients had Grade 1 or 2 thrombocytopenia and nadir usually occurred by day 8 (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    b) Grade 3 and 4 thrombocytopenia was reported in 14.5% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 0.4% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer. Grade 3 or higher thrombocytopenia was reported in 103 of 884 patients treated with ado-trastuzumab emtansine in clinical trials overall (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia (all grades) was reported in 6.7% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 9% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer. Grade 3 and 4 neutropenia was reported in 2% of patients who received ado-trastuzumab emtansine compared with 4.3% who received oral lapatinib (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia (all grades) was reported in 14.3% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 10.5% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer. In addition, Grade 3 and 4 anemia was reported in 4.1% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 2.5% of patients who received oral lapatinib 1250 mg daily plus capecitabine (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE EXTRAVASATION
    1) WITH THERAPEUTIC USE
    a) Reactions secondary to extravasation, including erythema, tenderness, skin irritation, pain, and swelling at the infusion site, have been reported in clinical trials of ado-trastuzumab emtansine. These reactions generally occurred within 24 hours of the infusion and were usually mild (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) Musculoskeletal pain is one of the most common adverse events (greater than 25%) reported with ado-trastuzumab emtansine therapy (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    b) Musculoskeletal pain was reported in 36.1% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 30.5% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia was reported in 14.1% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 3.7% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Drug hypersensitivity was reported in 2.2% of patients who received ado-trastuzumab emtansine 3.6 mg/kg IV on day 1 of a 21-day cycle (n=490) compared with 0.8% of patients who received oral lapatinib 1250 mg daily on a 21-day cycle plus oral capecitabine 1000 mg/m(2) twice daily on days 1 to 14 of a 21-day cycle (n=488) in a randomized, open-label clinical trial of patients with human epidermal growth factor receptor-2-positive (HER2-positive), unresectable locally advanced or metastatic breast cancer (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    B) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) One patient experienced a serious, allergic/anaphylactic-like reaction in clinical trials of ado-trastuzumab emtansine administered as a single agent. Emergency equipment and medications to treat such reactions should be available for immediate use during infusions (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Ado-trastuzumab emtansine is classified as FDA pregnancy category D. There are no adequate or well controlled studies of ado-trastuzumab emtansine use in pregnant women, however two components of ado-trastuzumab emtansine (trastuzumab and DM1) are known or suspected to cause fetal harm or death when administered to a pregnant woman. Ado-trastuzumab emtansine use during pregnancy can result in fetal harm. Lactation studies with ado-trastuzumab emtansine have not been conducted.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ABNORMALITIES
    1) Use of trastuzumab, either alone or in combination with chemotherapy, during pregnancy has resulted in oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death (Prod Info KADCYLA(R) intravenous injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified ado-trastuzumab emtansine FDA pregnancy category D (Prod Info KADCYLA(R) intravenous injection, 2015).
    B) PREGNANCY REGISTRY
    1) The MotHER Registry has been established, and prescribers can enroll patients exposed to ado-trastuzumab emtansine during pregnancy or within 7 months prior to conception by calling 1-800-690-6720 (Prod Info KADCYLA(R) intravenous injection, 2015).
    C) CONTRACEPTION
    1) Ado-trastuzumab emtansine can cause fetal harm when administered during pregnancy. Women of reproductive potential should use effective contraception during and for at least 7 months after treatment. Verify pregnancy status prior to initiation (Prod Info KADCYLA(R) intravenous injection, 2015).
    D) ANIMAL STUDIES
    1) LACK OF DATA
    a) Animal studies with ado-trastuzumab emtansine have not yet been conducted (Prod Info KADCYLA(R) intravenous injection, 2015).
    b) DM1, a component of ado-trastuzumab emtansine, disrupts microtubule function and is toxic to rapidly dividing animal cells. DM1 is genotoxic and has the potential to be embryotoxic and teratogenic (Prod Info KADCYLA(R) intravenous injection, 2015).
    c) During animal studies, administration of trastuzumab crossed the placental barrier at doses approximately 7 times the human clinical dose. The concentrations of fetal blood and amniotic fluid were 33% and 25%, respectively. There was no association with adverse effects (Prod Info KADCYLA(R) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether ado-trastuzumab emtansine is excreted in human milk. Because of the potential for adverse effects in the nursing infant from ado-trastuzumab emtansine exposure, either discontinue nursing or discontinue ado-trastuzumab emtansine taking into account the washout period of trastuzumab and the importance of the drug to the mother (Prod Info KADCYLA(R) intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) Small amounts of ado-trastuzumab emtansine were excreted in the milk of lactating animals following postpartum administration of ado-trastuzumab emtansine in doses approximately 7 times the recommended human dose(Prod Info KADCYLA(R) intravenous injection, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for ado-trastuzumab emtansine in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential for ado-trastuzumab emtansine in humans (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Summary Of Exposure

    A) USES: Ado-trastuzumab emtansine, a HER2-targeted antibody and microtubule inhibitor conjugate, is used as a single-agent for the treatment of an individual with HER2-positive, metastatic breast cancer who have previously received trastuzumab and a taxane, separately or in combination. Ado-trastuzumab emtansine should NOT be substituted for trastuzumab.
    B) PHARMACOLOGY: This agent is composed of an antibody component derived from humanized anti-HER2 IgG1, trastuzumab and a small molecule cytotoxin, DM1, a microtubule inhibitor. 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. The binding of DMl to tubulin disrupts microtubule networks in the cell causing cell cycle arrest and apoptotic cell death.
    C) TOXICOLOGY: Theoretically, in overdose the loss of selectivity as a microtubule inhibitor could cause toxicity, especially myelosuppression and GI toxicity (nausea, vomiting, diarrhea, stomatitis).
    D) EPIDEMIOLOGY: Limited data. Overdose is uncommon. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic effects.
    E) WITH THERAPEUTIC USE
    1) SUMMARY: Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation are the most common adverse reactions reported with ado-trastuzumab emtansine. Fever and chills are common during an infusion.
    2) CARDIOVASCULAR: Patients can be at risk to develop left ventricular dysfunction. Hypertension may also occur.
    3) HEMATOLOGIC: Thrombocytopenia is likely to occur. Anemia and neutropenia have also occurred with some frequency in patients treated with ado-trastuzumab emtansine.
    4) RESPIRATORY: Epistaxis, cough, and dyspnea have occurred frequently (greater than 10%) with ado-trastuzumab emtansine. Infrequent cases of interstitial lung disease including pneumonitis (some cases have lead to acute respiratory distress syndrome or fatal outcome) have been observed.
    5) RARE: Infusion reactions and extravasation injuries have developed infrequently with ado-trastuzumab emtansine administration.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, fatigue, muscle pain and headache may develop following overdose. Other adverse events may include thrombocytopenia and increased transaminases.
    2) SEVERE TOXICITY: Cardiotoxicity (ie, left ventricular cardiac dysfunction), hepatotoxicity, and thrombocytopenia (Grade 3 and 4) may develop following a significant exposure. Neurotoxicity may include Grade 3 or 4 peripheral neuropathy. Pulmonary toxicity (interstitial lung disease and pneumonitis) and serious or fatal infusion reactions may occur.

Genotoxicity

    A) DM1, the carcinogenic component of trastuzumab emtansine, was aneugenic/clastogenic during an in vivo single-dose rat bone marrow micronucleus assay at exposures comparable to the maximum human concentration. There was also no evidence of mutagenicity in an in vitro bacterial reverse mutation (Ames) assay (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and neuro status.
    B) Monitor serum electrolytes and liver enzymes following exposure. Serial CBCs are indicated to evaluate for myelosuppression.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Obtain a chest radiograph and monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms or evidence of dyspnea or pneumonitis.
    E) Obtain an echocardiogram following a significant exposure to assess left ventricular ejection fraction.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac monitoring, and daily monitoring of CBC.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor vital signs and neuro status.
    B) Monitor serum electrolytes and liver enzymes following exposure. Serial CBCs are indicated to evaluate for myelosuppression.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Obtain a chest radiograph and monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms or evidence of dyspnea or pneumonitis.
    E) Obtain an echocardiogram following a significant exposure to assess left ventricular ejection fraction.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not necessary as trastuzumab is administered IV.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) TOXICITY: A lethal human dose has not been established. In clinical trials, overdose of ado-trastuzumab emtansine has been reported at approximately 2 times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal case, a patient received 6 mg/kg and died approximately 3 weeks later; the cause of death and a casual relationship to ado-trastuzumab emtansine were not determined.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 3.6 mg/kg via IV infusion. Administer over 90 minutes for the first infusion and 30 minutes for each subsequent infusion, every 3 weeks (21 days) until disease progression or unacceptable toxicity occurs. PEDIATRIC: The safety and effectiveness of ado-trastuzumab emtansine has not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRAVENOUS INFUSION
    1) The recommended dose is 3.6 mg/kg via IV infusion. Administer over 90 minutes for the first infusion and 30 minutes for each subsequent infusion, every 3 weeks (21 days) until disease progression or unacceptable toxicity occurs (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    2) CAUTION: This agent is NOT indicated as a substitute for trastuzumab (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    7.2.2) PEDIATRIC
    A) SUMMARY
    1) The safety and effectiveness of ado-trastuzumab emtansine has not been established in pediatric patients (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Minimum Lethal Exposure

    A) A lethal human dose has not been established. During clinical trials, a patient received 6 mg/kg and died approximately 3 weeks later; the cause of death and a casual relationship to ado-trastuzumab emtansine were not determined (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Maximum Tolerated Exposure

    A) In clinical trials, overdose of ado-trastuzumab emtansine has been reported at approximately 2 times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) In a phase 1 pharmacokinetic study, the mean cycle 1 Cmax of the ado-trastuzumab emtansine conjugate (ADC) and DM1, the cytotoxic small molecule component of ado-trastuzumab emtansine, were 83.4 +/- 16.5 mcg/mL and 4.61 +/- 1.61 ng/mL, respectively (Prod Info KADCYLA(TM) intravenous injection solution, 2013).
    2) Cmax of the ado-trastuzumab emtansine conjugate (ADC) and DM1, the cytotoxic small molecule component of ado-trastuzumab emtansine, were observed close to the end of the infusion (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ado-trastuzumab emtansine is a human epidermal growth factor receptor 2 protein (HER2)-targeted antibody-drug conjugate (ADC) which contains the monoclonal antibody, trastuzumab, covalently linked to a small molecule cytotoxin (DM1). Emtansine refers to the complex of DM1 and stable thioether link attached to trastuzumab. DM1 is a microtubule inhibitor. Ado-trastuzumab emtansine binds to the extracellular domain of the HER2 protein, which inhibits the growth of tumor cells and mediates antibody-dependent cellular cytotoxicity in breast cancer cells that overexpress the HER2 protein, similar to trastuzumab. Upon binding to the HER2 protein, receptor-mediated internalization of ado-trastuzumab emtansine occurs, with subsequent lysosomal degradation, and intracellular release of DM1-containing cytotoxic catabolites. DM1 binds to tubulin, disrupting intracellular microtubule networks, interrupting the cell cycle and causing apoptosis (Prod Info KADCYLA(TM) intravenous injection solution, 2013).

References

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