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trastuzumab

( trass-TOO-zoo-mab )
Funding:
Evidence Building Program
  • Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer Supplemental
  • Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer
New Drug Funding Program
  • Trastuzumab - Gastric Cancer
  • Trastuzumab in Combination with Paclitaxel - Metastatic Breast Cancer
  • Trastuzumab - Second Line - Metastatic Breast Cancer
  • Trastuzumab - Single Agent - Metastatic Breast Cancer
  • Trastuzumab - Adjuvant Treatment for HER2_neu-Overexpressing Primary Breast Cancer
  • Trastuzumab in Combination with Vinorelbine - Metastatic Breast Cancer
  • Trastuzumab in Combination with Docetaxel - Metastatic Breast Cancer
Other Name(s): Herceptin® (Hoffmann-La Roche)
Appearance: Clear, colourless solution mixed into larger bags of fluids
A - Drug Name

trastuzumab

SYNONYM(S):   anti-ERB-2; anti-HER2/c-erbB2 monoclonal antibody; Anti-p185-HER2; rhuMAb HER2

COMMON TRADE NAME(S):   Herceptin® (Hoffmann-La Roche)

 
B - Mechanism of Action and Pharmacokinetics

Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively targets the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). Trastuzumab inhibits the proliferation of tumour cells that overexpress HER2 and mediates antibody dependent cell mediated cytotoxicity (ADCC) on HER2 overexpressing cells. The HER2 antigen is overexpressed in about 30% of patients with breast cancer. Significant clinical effects of trastuzumab appear limited to patients with tumours which strongly overexpress HER2 (3+ positive with Herceptest, 2/3+ positive with immunohistochemical tests).

 
Absorption
Not orally bioavailable.  Steady state levels reached approximately 20 weeks (weekly breast dosing) and 52 weeks (q3w breast dosing).
Distribution

Trastuzumab follows a non-linear but dose dependent pharmacokinetic profile. Clearance decreases and T1/2 increases with increasing dose. Patients with high circulating levels of the external domain of HER2 may have lower trastuzumab levels or take longer to achieve steady state levels.

Cross blood brain barrier?Minimal
PPBNo information found
Metabolism

Likely clearance of IgG through the reticuloendothelial system.

Active metabolitesno
Inactive metabolitesno
Elimination

Higher clearance observed in metastatic gastric cancer patients, leading to lower exposure at steady state than metastatic breast cancer patients.

Urineno
Half-life28.5 days (weekly breast regimen); 12.2 days (q3w gastric regimen); may persist in circulation for approximately 24 weeks
 
C - Indications and Status
Health Canada Approvals:
 
  • Treatment in patients with metastatic breast cancer whose tumours substantially overexpress HER2
    • Can be used in combination with pertuzumab and docetaxel for patients with HER2 positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
  • For the treatment of patients with early stage breast cancer whose tumours overexpress HER2:
    • Following surgery, and after chemotherapy
    • Following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel
    • In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin
  • In combination with capecitabine or intravenous 5-fluorouracil and cisplatin for the treatment of patients with HER2-positive (IHC 3+ or IHC2+ confirmed by FISH) metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

 
 
D - Adverse Effects

Emetogenic Potential:  

Minimal

 

Extravasation Potential:   None

 

The following table contains adverse effects mainly reported after 1 year of adjuvant trastuzumab monotherapy (sequential), where the incidence is greater (≥1%) than the observation arm.

 

ORGAN SITESIDE EFFECT* (%)ONSET**
CardiovascularArrhythmia (<1%)E
 Arterial thromboembolism (rare)D
 Cardiotoxicity (6%)D
 Hypertension (6%)E
 Venous thromboembolism (4%)E
DermatologicalDermatomyositis (rare)E
 Nail disorder (3%)E
 Radiation dermatitis (3%) (with chemotherapy)E
 Rash (6%)E
GastrointestinalAbdominal pain (4%)E
 Constipation (3%)E
 Diarrhea (9%)E
 Dyspepsia (2%)E
 Mucositis (2%)E
 Nausea, vomiting (8%)I
 Weight changes (2%)E
GeneralEdema (7%)E
 Fatigue (12%)E
 Pain (4%)E
HematologicalMyelosuppression ± infection, bleeding (combined with chemotherapy; infrequent as a single agent)E
Hepatobiliary↑ LFTs (rare)D
 Pancreatitis (rare)E
HypersensitivityHypersensitivity (2%)I
Metabolic / EndocrineAbnormal electrolyte(s) (4%)E
MusculoskeletalMusculoskeletal pain (13%)D
NeoplasticLeukemia (secondary) (rare)D
Nervous SystemDepression (5%)E  D
 Dizziness (5%)E
 Dysgeusia (2%)E
 Headache (12%)E
 Sleep disorder (6%)E
 Vertigo (2%)E
RenalRenal failure (rare)E  D
RespiratoryCough, dyspnea (7%)E
 Pneumonitis (rare)E
VascularHot flashes (10%)E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

Serious adverse effects associated with trastuzumab include infusion-related reactions (with acute respiratory distress syndrome) and cardiotoxicity.  When given in combination with chemotherapy, the incidence of most adverse effects increases over those expected for either agent alone.

Cardiotoxicity (CHF) of any grade occurs in 4% of metastatic, 3% of adjuvant patients and occurs predominately during treatment. The incidence is increased dramatically in combination therapy with an anthracycline.  The risk of cardiac dysfunction associated with trastuzumab therapy may be increased in older patients, patients with high BMI, patients with low LVEF, prior or concurrent use of anti-hypertensive medications, patients with pre-existing cardiac disease and patients who have had prior cardiotoxic therapy (e.g. anthracycline therapy or radiation therapy to the chest area).  A higher incidence of cardiac events was observed when trastuzumab was given after anthacycline-containing chemotherapy than with non-anthracycline regimens, and also when trastuzumab was given concurrently with a taxane than when administered sequentially to a taxane.  Rates with non-anthracycline containing regimens such as TCH appear to be lower.  Cardiotoxicity associated with trastuzumab typically responds to appropriate medical therapy (diuretic,  beta-blockers, ACE inhibitors or digoxin, etc) but may be severe and lead to cardiac failure with mural thrombi and stroke.  Refer to the Canadian consensus guidelines for management options (Mackey et al, 2008).

Infusion-associated symptoms are common with trastuzumab. During the first infusion with trastuzumab, chills and/or fever (up to 40%) have been observed. The symptoms are usually mild to moderate in severity, and occur infrequently with subsequent trastuzumab infusions. The symptoms can be treated with an analgesic/antipyretic such as meperidine or acetaminophen, or an antihistamine such as diphenhydramine. Interruption of trastuzumab infusion was infrequent.

Severe, including fatal hypersensitivity reactions usually occur during or immediately after the infusion, but the onset may be delayed. Rarely symptoms may initially improve and then worsen up to one week after the infusion. Dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress and allergic-like reactions have been described. The trastuzumab infusion should be discontinued and the patients must be carefully monitored until resolution of their symptoms. Supportive therapy such as oxygen, beta-agonists and corticosteroids may be used. Patients who are experiencing dyspnea at rest (due to pulmonary metastases) may be at increased risk of a fatal infusion reaction – these patients should be treated with extreme caution and risk versus benefit be considered.

Pulmonary events, which may be life-threatening, have been reported to occur from within 24 hours to over 30 days after treatment initiation. Dyspnea, pulmonary infiltrates, pneumonitis, pleural effusions, non-cardiogenic pulmonary edema, and ARDS may occur. Patients with dyspnea at rest (due to intrinsic lung disease or tumour involvement with the lungs) and patients who have had prior radiation or chemotherapy may be at greater risk of pulmonary toxicity. Pneumonitis and pulmonary fibrosis have also been described.   In early and metastatic breast cancer clinical trials, the incidence of pulmonary toxicities was increased in patients treated with chemotherapy and trastuzumab versus chemotherapy alone.

Although gastrointestinal effects (e.g diarrhea) are generally mild to moderate and hematologic effects occur infrequently, increased incidences of these effects are observed in patients receiving combination therapy with trastuzumab and cytotoxic chemotherapy.

 
E - Dosing
 

Do not administer as an IV push or bolus. Patient should be observed for fever and chills or other infusion-related symptoms for up to 24 hours.  Delayed reactions have also occurred.  Interruption of the infusion helps to control such symptoms. The infusion may be resumed when the symptoms abate, if the symptoms are not severe. If a dose is missed or delayed by more than 1 week, then the loading dose should be repeated.

NOTE:  Herceptin® (trastuzumab) and Kadcyla® (trastuzumab emtansine) are NON-INTERCHANAGEABLE. There have been fatal reports where the incorrect trastuzumab product was administered to patients with breast cancer in the clinical trials setting.

 
Adults:
 

*3 weekly -
loading dose:            8mg/kg administered as a 90-minute infusion
maintenance dose:    6mg/kg administered as a 30-minute infusion† every 3 weeks.

**Weekly -
loading dose:            4mg/kg administered as a 90-minute infusion.                   
maintenance dose:    2mg/kg administered as a 30-minute infusion† weekly

* Health Canada approved dosing for early breast cancer and gastric cancer; dosing has been used in clinical trials for metastatic breast cancer
** Health Canada approved dosing for metastatic and early breast cancer.
†Infuse maintenance dose over 30 minutes if the loading dose is well-tolerated.

Dosage with Toxicity:
 

Dosage with myelosuppression: No adjustment required

Dosage with cardiotoxicity:

Product Monograph Recommendations

  • Trastuzumab should be held with a fall in LVEF (if LVEF falls ≥10 points from baseline and/or if LVEF falls to < 50%). Repeat LVEF in 3 weeks and consider discontinuing. Discontinue if clinically significant cardiac dysfunction or cardiac failure develops.

Canadian Consensus Guidelines:  Discontinue if symptomatic.

Management of trastuzumab therapy in adjuvant breast cancer patients with asymptomatic decreases in LVEF (Mackey et al 2008):

Relationship of LVEF to Lower Limit of Normal (LLN)

Trastuzumab dose modification

based on asymptomatic LVEF decrease from baseline

≤ 10 percentage points

10-15 percentage points

≥ 15 percentage points

Within facility’s normal limits

Continue

Continue

Hold and repeat MUGA/ECHO after 4 weeks

1-5% below LLN

Continue 1

Hold and repeat MUGA/ECHO after 4 weeks 1, 2

Hold and repeat MUGA/ECHO after 4 weeks 2, 3

≥ 6% below LLN

Continue and repeat MUGA/ECHO after 4 weeks 3

Hold and repeat MUGA/ECHO after 4 weeks 2, 3

Hold and repeat MUGA/ECHO after 4 weeks 2, 3

1 Consider cardiac assessment and starting ACEI therapy
2 After 2 holds, consider permanent trastuzumab discontinuation
3 Start ACEI therapy and refer to cardiologist

(Continued on next page)

 

 

 

Dosage with other toxicity:

 

Toxicity
Action
Mild hypersensitivity reaction

↓ infusion rate (and/ or hold)  and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate. Consider premedication for next infusion.

Moderate hypersensitivity reaction

Hold and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate; complete infusion at ↓ rate if possible. Use premedication for next infusion.

Severe hypersensitivity reaction or Pulmonary Toxicity

Hold and manage symptoms aggressively with beta-agonists, antihistamines, antipyretics, and/or corticosteroids.  Discontinue permanently and do not rechallenge


 
Dosage with Hepatic Impairment:
 

No adjustment required.


 
Dosage with Renal Impairment:
 

No adjustment required. The disposition of trastuzumab is not altered based on serum creatinine.


 
Dosage in the elderly:
 

No adjustment required; the risk of cardiac dysfunction and myelosuppression may be increased in elderly patients.  The reported trials did not determine differences in efficacy between patients > 65 years versus younger patients.


 
Children:
 

Safety and effectiveness in children have not been established.


 
 
F - Administration Guidelines
 
  • NOTE:  Herceptin® (trastuzumab) and Kadcyla® (trastuzumab emtansine) are NON-INTERCHANAGEABLE. There have been fatal reports where the incorrect trastuzumab product was administered to patients with breast cancer in the clinical trials setting.
  • Mix in 250 mL bag NS. Do not use D5W as it causes protein aggregation. Do not shake.
  • Infuse loading dose IV over 90 minutes; subsequent infusions may be given over 30 minutes if the initial loading dose is well-tolerated.
  • DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.
  • Should not be mixed or diluted with other drugs.
  • Diluent supplied - Bacteriostatic Water for Injection (BWFI) - contains benzyl alcohol 1.1%; if patient is hypersensitive to benzyl alcohol, may reconstitute with Sterile Water for Injection, but must be used immediately and discard unused portion.
  • Solution reconstituted with the supplied BWFI is stable up to 28 days refrigerated.
  • Do not freeze the reconstituted solution.

 
 
G - Special Precautions
Contraindications:

 

  • Patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any components of this product.
  • Trastuzumab should only be used in patients whose tumours overexpress HER2

 

Other Warnings/Precautions:

 

  • The risk of cardiotoxicity must be weighed against the potential benefits of treatment, especially in older patients, patients with pre-existing cardiac disease (including LVEF < 55%) and patients who have had prior cardiotoxic therapy. Note: in the adjuvant trials, patients with cardiac risk factors were excluded from the trials.
  • Exercise caution in patients with pre-existing pulmonary disease or patients with extensive pulmonary tumour involvement, as they may experience more severe lung toxicities. 
  • Use with caution before or after anthracyclines (for up to 24 weeks after trastuzumab discontinuation due to long half-life).
  • Life-threatening infusion-related reactions associated with the administration of trastuzumab may occur. See Adverse Effects for recommended precautions, monitoring, and treatment.

 


Other Drug Properties:

 

  • Carcinogenicity: Unknown

 

Pregnancy and Lactation:
  • Fetotoxicity: Yes
  • Embryotoxicity: Yes

    Trastuzumab is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 7 months after the last dose.

  • Excretion into breast milk: Yes

    Breastfeeding is not recommended.

  • Fertility effects: Unlikely
 
H - Interactions

 

AGENTEFFECTMECHANISMMANAGEMENT
Paclitaxel↑ Trastuzumab level↓ Trastuzumab clearanceCaution
Anthracyclines and other cardiotoxic drugs↑ cardiotoxicityAdditive effectsAvoid concomitant use; exercise extreme caution with anthracycline-based therapy for up to 27 weeks after stopping trastuzumab
 
I - Recommended Clinical Monitoring

 

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

 

Recommended Clinical Monitoring
 
Monitor TypeMonitor Frequency

Toxicity ratings of infusion-associated symptoms (especially first infusion)

Close monitoring at each visit

Clinical exam for symptoms of cardiac failure, pulmonary toxicity, diarrhea, infusion reactions.

At each visit

Cardiac assessment, including evaluation of left ventricular function (Echocardiogram or MUGA scan);

more frequent with asymptomatic reductions in LVEF; baseline, q3 months during treatment, then q6 months after trastuzumab discontinuation x2 years (and annually up to 5 years after last trastuzumab dose in adjuvant breast cancer patients who received anthracyclines), also as clinically indicated
 

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

 
Suggested Clinical Monitoring
 
Monitor TypeMonitor Frequency
Liver function testsperiodic
CBCperiodic
 
J - Supplementary Public Funding

Evidence Building Program (

EBP Website

)
  • Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer Supplemental
  • Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer
New Drug Funding Program (NDFP Website )
  • Trastuzumab - Gastric Cancer
  • Trastuzumab in Combination with Paclitaxel - Metastatic Breast Cancer
  • Trastuzumab - Second Line - Metastatic Breast Cancer
  • Trastuzumab - Single Agent - Metastatic Breast Cancer
  • Trastuzumab - Adjuvant Treatment for HER2_neu-Overexpressing Primary Breast Cancer
  • Trastuzumab in Combination with Vinorelbine - Metastatic Breast Cancer
  • Trastuzumab in Combination with Docetaxel - Metastatic Breast Cancer

 

 
K - References

 

Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003 Nov 1; 21(21):3965-71.

Mackey JR, Clemons M, Cote, MA, et al. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian trastuzumab working group. Current Oncology 2008; 15: 24-35.

McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 1252-8.

Petalozzi B, Brignoli S. (Letter to the editor) Trastuzumab in CSF. J Clin Oncol 2000;18(11):2350-1.

Product monograph:  Adriamycin® (doxorubicin).  Pfizer Canada Inc., July 9, 2014.

Product monograph: Herceptin® (trastuzumab). Genetech Inc, (USA), August 4, 2010.

Product monograph:  Herceptin® (trastuzumab). Hoffmann-La Roche Ltd., December, 2015.

 

 

November 2017 updated public funding form titles

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.