Herceptin

Name: Herceptin

What side effects can this medication cause?

Trastuzumab injection may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • diarrhea
  • constipation
  • stomach pain
  • heartburn
  • loss of appetite
  • back, bone, joint, or muscle pain
  • difficulty falling asleep or staying asleep
  • hot flushes
  • numbness, burning, or tingling in the arms, hands, feet, or legs
  • changes in the appearance of nails
  • acne
  • depression

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:

  • sore throat, fever, chills, difficulty urinating, pain when urinating, and other signs of infection
  • nosebleeds and other unusual bruising or bleeding
  • excessive tiredness
  • pale skin

Trastuzumab injection may cause other side effects. Call your doctor if you have any unusual problems while you are taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

What are the side effects of Herceptin (trastuzumab)?

BLACK BOX WARNING

  • Trastuzumab can cause heart failure, especially when it is combined with cyclophosphamide and anthracycline-containing chemotherapy regimens. Left ventricular function should be monitored prior to and during treatment.
  • It should be stopped in patients receiving adjuvant therapy, and withheld in patients with metastatic cancer if the function of the heart decreases significantly.

Herceptin (trasuzumab) side effects

Common side effects include:

  • Diarrhea (25% of patients)
  • A prickling or burning sensation in the skin (9% of patients)
  • Either an upper respiratory or a catheter-related infection (26% of patients)
  • Increased cough (26% of patients)
  • Nausea and vomiting (23%-33% of patients)
  • Rash (18% of patients)
  • infusion-related side effects including mild to moderate chills and/or fever (40% of patients)
  • Insomnia
  • Weight loss
  • Stomatitis
  • Shortness of breath
  • Distortion of taste
  • Fatigue
  • Pain
  • Cough
  • Dizziness

Other side effects include:

  • Bone pain
  • Joint pain
  • Muscle pain
  • Increased heart rate
  • Body swelling (edema)
  • Acne
  • Headache

What else should I know about Herceptin (trastuzumab)?

What preparations of trastuzumab are available?
  • Trastuzumab is available as a powder in a vial containing 440 mg of the drug. It must be mixed with a liquid before intravenous injection.
How should I keep it stored?
  • Trastuzumab should be stored at 2 C to 8 C (36F to 46 F), and should not be frozen.
When was XYZ approved by the FDA?
  • Trastuzumab was approved by the FDA in 1998.

Description

Herceptin (trastuzumab) is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.

Herceptin (trastuzumab) is a sterile, white to pale yellow, preservative-free lyophilized powder for Injection, for intravenous administration.

Each multiple-dose vial of Herceptin delivers 420 mg trastuzumab, 381.8 mg α,α-trehalose dihydrate, 9.5 mg L-histidine HCl monohydrate, 6.1 mg L-histidine, and 1.7 mg polysorbate 20. Reconstitution with 20 mL of the appropriate diluent (BWFI or SWFI) yields a solution containing 21 mg/mL trastuzumab at a pH of approximately 6. If Herceptin is reconstituted with SWFI without preservative, the reconstituted solution is considered single-dose.

Each single-dose vial of Herceptin delivers 150 mg trastuzumab, 136.2 mg α,α-trehalose dihydrate, 3.4 mg L-histidine HCl monohydrate, 2.2 mg L-histidine, and 0.6 mg polysorbate 20. Reconstitution with 7.4 mL of sterile water for injection (SWFI) yields a solution containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab), at a pH of approximately 6.

Indications

Adjuvant Breast Cancer

Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies]) breast cancer

  • as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
  • as part of a treatment regimen with docetaxel and carboplatin
  • as a single agent following multi-modality anthracycline based therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see DOSAGE AND ADMINISTRATION].

Metastatic Breast Cancer

Herceptin is indicated:

  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
  • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see DOSAGE AND ADMINISTRATION].

Metastatic Gastric Cancer

Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin [see DOSAGE AND ADMINISTRATION].

Herceptin Drug Class

Herceptin is part of the drug class:

  • Monoclonal antibodies

Side Effects of Herceptin

Herceptin may cause serious side effects (see "Drug Precautions").

The most common side effects associated with Herceptin in patients with metastatic stomach cancer are:

  • Low white blood cell counts
  • Diarrhea
  • Fatigue
  • Low red blood cell counts
  • Swelling of the mouth lining
  • Weight loss
  • Upper respiratory tract infections
  • Fever
  • Low platelet counts
  • Swelling of the mucous membranes
  • Swelling of the nose and throat
  • Change in taste

The most common side effects associated with Herceptin in patients with breast cancer are:

  • Fever
  • Nausea
  • Vomiting
  • Infusion reactions
  • Diarrhea
  • Infections
  • Increased cough
  • Headache
  • Fatigue
  • Shortness of breath
  • Rash
  • Low white and red blood cell counts
  • Muscle pain

What is trastuzumab (herceptin)?

Trastuzumab is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Trastuzumab is used to treat certain types of breast cancer or stomach cancer. Other cancer medicines are sometimes used in combination with trastuzumab.

Trastuzumab may also be used for other purposes not listed in this medication guide.

What should i discuss with my health care provider before receiving trastuzumab (herceptin)?

Before using trastuzumab, tell your doctor if you are allergic to any drugs, or if you have:

  • heart disease;
  • congestive heart failure;
  • a history of heart attack; or
  • any allergies or breathing problems.

If you have any of these conditions, you may not be able to receive trastuzumab, or you may need a dosage adjustment or special tests during treatment.

FDA pregnancy category D. Trastuzumab can cause harm to an unborn baby. Do not use trastuzumab without telling your doctor if you are pregnant. Use effective birth control, and tell your doctor if you become pregnant during treatment.

If you are pregnant, your name may need to be listed on a Cancer and Childbirth registry when you start using this medication.

It is not known whether trastuzumab passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Herceptin Dosage and Administration

General

  • Observe patients for fever and chills or other infusion-associated symptoms during infusion.1 (See Infusion-related Effects under Cautions.)

  • Infusion should be interrupted in patients experiencing dyspnea or clinically important hypotension.1 Discontinuance of therapy should be considered strongly in patients who develop ARDS, anaphylaxis, or angioedema.1 Immediately discontinue infusion and initiate appropriate medical treatment if severe trastuzumab-induced reactions occur.1 24 Patients should be monitored carefully until signs and symptoms have resolved completely.1

Administration

IV Administration

Administer by IV infusion.1

Do not administer by rapid IV injection (e.g., IV push or bolus).1

Reconstitution

Reconstitute prior to administration.1

Reconstitute vial containing 440 mg of lyophilized drug with 20 mL of the supplied bacteriostatic water for injection, containing 1.1% benzyl alcohol to provide a solution containing 21 mg of trastuzumab per mL.1 22

Alternatively, for patients sensitive to benzyl alcohol, reconstitute using 20 mL of sterile water for injection.1

Handle with care during reconstitution; shaking the reconstituted solution or causing excessive foaming during the addition of diluent may cause problems with dissolution and the amount of the drug that can be withdrawn from the vial.1 22

Slowly inject 20 mL of diluent into the vial with the stream of diluent directed into the lyophilized cake of trastuzumab.1 22 Swirl vial gently to aid reconstitution; do not shake reconstituted solution because trastuzumab may be sensitive to shear-induced stress (e.g., agitation, rapid expulsion from a syringe).1 22

Allow vial to stand undisturbed for 5 minutes following reconstitution; slight foaming of the reconstituted solution is not unusual.1 22 Reconstituted solution should be clear to slightly opalescent, colorless to pale yellow, and free of visible particulate matter.1 22

Vials reconstituted with bacteriostatic water for injection should be immediately labeled in the area marked “Do not use after:” with the future date that is 28 days from the date of reconstitution; discard unused portions after 28 days.1

Vials reconstituted with sterile water for injection should be used immediately; discard any unused solution.1

Dilution

Dilute reconstituted solutions prior to administration by adding an appropriate volume of trastuzumab 21 mg/mL solution to a polyvinyl chloride or polyethylene infusion bag containing 250 mL of 0.9% sodium chloride injection; gently invert bag to mix the solution.1

Do not dilute infusion solutions in or administer with 5% dextrose injection; do not mix or dilute trastuzumab with other drugs.1

Rate of Administration

Administer initial loading dose over 90 minutes; if initial dose is well tolerated, administer maintenance doses over 30 minutes.1

Dosage

Adults

Breast Cancer Metastatic Breast Cancer IV

Initially, 4 mg/kg as a loading dose followed by once-weekly maintenance doses of 2 mg/kg.1 4 Continue once-weekly administration until disease progression or intolerable toxicity is observed.4 6 7 18 19

Adjuvant Treatment of Early Breast Cancer† IV

Loading dose of 4 mg/kg followed by maintenance doses of 2 mg/kg once weekly for 51 weeks has been used in clinical studies.28 Trastuzumab was initiated concurrently with paclitaxel after doxorubicin and cyclophosphamide in these studies.28 Other regimens also have been investigated.29 30

Cautions for Herceptin

Warnings/Precautions

Warnings

Cardiovascular Toxicity

Risk of cardiotoxicity (e.g., dyspnea [including paroxysmal nocturnal], increased cough, peripheral edema, S3 gallop, cardiomyopathy, CHF, and reduced ejection fraction [decrease of >10%]).1 4 CHF1 may be severe and may result in disabling heart failure, mural thrombosis and stroke, and/or death.1

Discontinue therapy if a clinically important decrease in left ventricular function or CHF occurs.1 18 19 If trastuzumab is used in early breast cancer, therapy interruption may be needed in patients experiencing asymptomatic decreases in left ventricular function.31 Institute appropriate medical therapy if cardiac dysfunction occurs.1 21

Monitor patients closely for signs of cardiotoxicity.1 Perform baseline cardiac evaluation including history, physical examination, and cardiac function tests (i.e., ECG, echocardiogram and/or MUGA scan) prior to initiating therapy.1 Monitor cardiac function frequently.1 14 Closely monitor patients who develop asymptomatic decreases in ejection fraction for signs and symptoms of heart failure.1

Increased risk of cardiac dysfunction in geriatric patients, patients with preexisting cardiac disease, and patients who have had prior cardiotoxic therapy (e.g., anthracycline therapy or radiation therapy to the chest area).1

Extreme caution is advised during trastuzumab therapy for metastatic breast cancer in patients with preexisting cardiac dysfunction.1

Infusion-related Effects

Risk of severe and rarely fatal infusion-related reactions (e.g., bronchospasm, dyspnea, hypoxia, severe hypotension) generally with the first dose (possibly during or immediately following the infusion).1 24

Risk of symptoms worsening progressively and leading to further pulmonary complications.1

Risk of marked clinical deterioration following initial improvement in those with acute signs and symptoms.1

Risk of delayed adverse events with rapid clinical deterioration occurring following completion of trastuzumab infusion.1

Severe infusion-related reactions may result in death within hours of the infusion or up to 1 week after the infusion.1

Interrupt infusion and administer supportive therapy (e.g., oxygen, IV fluids, β-adrenergic agonists, corticosteroids) if severe infusion-related reactions occur.1

Subsequent infusions may be tolerated following complete recovery, typically accompanied by prophylactic treatment (e.g., antihistamines and/or corticosteroids); severe reactions may recur despite the use of premedication.1

Preexisting pulmonary compromise may increase risk of serious infusion-related adverse effects.24

Risk of mild to moderate infusion-related symptoms1 (e.g., chills,1 2 fever,1 2 nausea,1 vomiting,1 pain [including at tumor sites],1 rigors,1 headache,1 dizziness,1 dyspnea,1 hypotension,1 rash,1 asthenia)1 occurring during the first infusion or possibly with subsequent infusions.1 4 Administer acetaminophen, diphenhydramine, and/or meperidine, and reduce infusion rate if such infusion-related symptoms occur.1 4 Discontinuance of therapy is required infrequently.1

Respiratory Effects

Risk of severe and rarely fatal adverse respiratory effects (e.g., dyspnea, wheezing, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency, hypoxia); may require supplemental oxygen or ventilatory support.1 24 ARDS also may occur.1 (See Boxed Warning.)

Possible increased risk of serious or fatal adverse pulmonary reactions in patients with clinically important preexisting pulmonary compromise secondary to intrinsic lung disease (e.g., asthma, COPD) and/or malignant pulmonary involvement (e.g., lymphangitic spread of tumor, pleural effusions, parenchymal masses) resulting in dyspnea at rest.1 24 Administer with extreme caution in such patients; carefully weigh the risks and benefits of therapy.24

Hematologic Effects

Possible exacerbation of chemotherapy-induced neutropenia (including fatal sepsis associated with neutropenia) in patients receiving trastuzumab in combination with myelosuppressive chemotherapy.1

Risk of leukopenia and anemia especially in those receiving trastuzumab in combination with paclitaxel.1 These reactions occur frequently with combination chemotherapy, but rarely in those receiving monotherapy;1 they are mild to moderate in severity, reversible, and do not require discontinuance of therapy.1

Sensitivity Reactions

Hypersensitivity Reactions

Risk of severe hypersensitivity reactions (e.g., fatal anaphylaxis).1 24 Signs and symptoms of hypersensitivity reactions include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension.1 Onset usually during initial infusion, but may occur following completion of an infusion.1

If a severe hypersensitivity reaction occurs, interrupt infusion and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, oxygen).1 Monitor patients carefully until signs and symptoms have resolved completely.1 Discontinuance of therapy should be considered strongly in patients who develop anaphylaxis or angioedema.1 Additional infusions may be tolerated following complete recovery, typically accompanied by prophylactic treatment (e.g., antihistamines, corticosteroids); severe reactions may occur despite the use of premedication.1

Administer with caution in patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation.1

General Precautions

Evaluation of HER2

Assess breast tumors for HER2 overexpression prior to initiating therapy.1 Fluorescent in situ hybridization (FISH) (e.g., PathVysion), which measures amplification of the HER2 oncogene, and immunohistochemistry (IHC) assays (e.g., HercepTest), which measure overexpression of the HER2 protein are tests most commonly used.9

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescriptions;1001 1002 1005 1006 similarity in generic name of Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine) may result in medication errors.1001 1004 1005 1006 Such errors may be associated with severe toxicity or lack of appropriate therapy.1001 1004 1005 (See Special Alerts.)

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in monkeys; not known whether distributed into human milk.1 Discontinue nursing during trastuzumab therapy and for 6 months following the last dose of the drug because of potential risk to nursing infants.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 18

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 18 19 Possible increased frequency of cardiotoxicity and cardiac dysfunction compared with younger adults.1 Pharmacokinetics not affected by age.1

Renal Impairment

Pharmacokinetics are not affected by increased Scr concentrations up to 2 mg/dL.1

Common Adverse Effects

Fever, diarrhea, infections, chills, increased cough, headache, rash, insomnia.1

Herceptin Dosage and Administration

Patient Selection

Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.

Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.

Improper assay performance, including use of suboptimally 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.

Recommended Doses and Schedules

  • Do not administer as an intravenous push or bolus. Do not mix Herceptin with other drugs.
  • Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine.

Adjuvant Treatment, Breast Cancer

Administer according to one of the following doses and schedules for a total of 52 weeks of Herceptin therapy:

During and following paclitaxel, docetaxel, or docetaxel/carboplatin:

  • Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
  • One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.

As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens:

  • Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes
  • Subsequent doses at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks [see Dosage and Administration (2.3)].
  • Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)].

Metastatic Treatment, Breast Cancer

  • Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression.

Metastatic Gastric Cancer

  • Administer Herceptin at an initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks until disease progression [see Dosage and Administration (2.3)].

Important Dosing Considerations

If the patient has missed a dose of Herceptin by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; three-weekly schedule: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent Herceptin maintenance doses should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

If the patient has missed a dose of Herceptin by more than one week, a re-loading dose of Herceptin should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; three-weekly schedule: 8 mg/kg) as soon as possible. Subsequent Herceptin maintenance doses (weekly schedule: 2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

Infusion Reactions

[See Boxed Warning, Warnings and Precautions (5.2)]

  • Decrease the rate of infusion for mild or moderate infusion reactions
  • Interrupt the infusion in patients with dyspnea or clinically significant hypotension
  • Discontinue Herceptin for severe or life-threatening infusion reactions.

Cardiomyopathy

[See Boxed Warning, Warnings and Precautions (5.1)]

Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin and at regular intervals during treatment. Withhold Herceptin dosing for at least 4 weeks for either of the following:

  • ≥ 16% absolute decrease in LVEF from pre-treatment values
  • LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values.

Herceptin may be resumed if, within 4–8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.

Permanently discontinue Herceptin for a persistent (> 8 weeks) LVEF decline or for suspension of Herceptin dosing on more than 3 occasions for cardiomyopathy.

Preparation for Administration

To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not ado-trastuzumab emtansine.

420 mg Multiple-dose vial

Reconstitution

Reconstitute each 420 mg vial of Herceptin with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution containing 21 mg/mL trastuzumab that delivers 20 mL (420 mg trastuzumab). In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single use solution.

Use appropriate aseptic technique when performing the following reconstitution steps:

  • Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized cake of Herceptin. The stream of diluent should be directed into the lyophilized cake. The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL trastuzumab.
  • Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
  • Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow.
  • Store reconstituted Herceptin in the refrigerator at 2°C to 8° C (36°F to 46°F); discard unused Herceptin after 28 days. If Herceptin is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Do not freeze.

Dilution

  • Determine the dose (mg) of Herceptin [see Dosage and Administration (2.2)]. Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed, withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.
    DO NOT USE DEXTROSE (5%) SOLUTION.
  • Gently invert the bag to mix the solution.
  • The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Do not freeze.

150 mg Single-dose vial

Reconstitution

Reconstitute each 150 mg vial of Herceptin with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab).

Use appropriate aseptic technique when performing the following reconstitution steps:

  • Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing the lyophilized 150 mg Herceptin, directing the diluent stream into the lyophilized cake. The reconstituted vial yields a solution for single-dose use, containing 21 mg/mL trastuzumab.
  • Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
  • Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow.
  • Use the Herceptin solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for single-dose only. If not used immediately, store the reconstituted Herceptin solution for up to 24 hours at 2°C to 8°C (36°F to 46°F); discard any unused Herceptin after 24 hours. Do not freeze.

Dilution

  • Determine the dose (mg) of Herceptin [see Dosage and Administration (2.1)].
  • Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed.
  • Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION.
  • Gently invert the bag to mix the solution.
  • The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze.

Herceptin - Clinical Pharmacology

Mechanism of Action

The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Herceptin has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2.

Herceptin is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, Herceptin-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

Pharmacodynamics

Cardiac Electrophysiology

The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors.

Pharmacokinetics

The pharmacokinetics of trastuzumab was evaluated in a pooled population pharmacokinetic (PK) model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receiving intravenous Herceptin. Total trastuzumab clearance increases with decreasing concentrations due to parallel linear and non-linear elimination pathways.

Although the average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the three-weekly schedule compared to the weekly schedule of Herceptin, the average steady-state exposure was essentially the same at both dosages. The average trastuzumab exposure following the first cycle and at steady state as well as the time to steady state was higher in breast cancer patients compared to MGC patients at the same dosage; however, the reason for this exposure difference is unknown. Additional predicted trastuzumab exposure and PK parameters following the first Herceptin cycle and at steady state exposure are described in Tables 7 and 8, respectively.

Population PK based simulations indicate that following discontinuation of Herceptin, concentrations in at least 95% of breast cancer and MGC patients will decrease to approximately 3% of the population predicted steady-state trough serum concentration (approximately 97% washout) by 7 months [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].

Table 7: Population Predicted Cycle 1 PK Exposures (Median with 5th – 95th Percentiles) in Breast Cancer and MGC Patients
Schedule Primary tumor type N Cmin
(µg/mL)
Cmax
(µg/mL)
AUC0-21days
(µg.day/mL)
8 mg/kg + 6 mg/kg q3w Breast cancer 1195 29.4
(5.8 - 59.5)
178
(117 - 291)
1373
(736 - 2245)
MGC 274 23.1
(6.1 - 50.3)
132
(84.2 - 225)
1109
(588 - 1938)
4 mg/kg + 2 mg/kg qw Breast cancer 1195 37.7
(12.3 - 70.9)
88.3
(58 - 144)
1066
(586 - 1754)
Table 8: Population Predicted Steady State PK Exposures (Median with 5th - 95th Percentiles) in Breast Cancer and MGC Patients
Schedule Primary tumor type N Cmin,ss*
(µg/mL)
Cmax,ss†
(µg/mL)
AUCss, 0-21 days
(µg.day/mL)
Time to steady-state (week) Total CL range at steady-state (L/day)
* Steady-state trough serum concentration of trastuzumab † Maximum steady-state serum concentration of trastuzumab
8 mg/kg + 6 mg/kg q3w Breast cancer 1195 47.4
(5 - 115)
179
(107 - 309)
1794
(673 - 3618)
12 0.173 - 0.283
MGC 274 32.9
(6.1 - 88.9)
131
(72.5 - 251)
1338
(557 - 2875)
9 0.189 - 0.337
4 mg/kg + 2 mg/kg qw Breast cancer 1195 66.1
(14.9 - 142)
109
(51.0 - 209)
1765
(647 - 3578)
12 0.201 - 0.244

Specific Populations

Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on age (< 65 (n = 1294); ≥ 65 (n = 288)), race (Asian (n = 264); non-Asian (n = 1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n = 636) or moderate (CLcr 30 to 60 mL/min) (n = 133)). The pharmacokinetics of trastuzumab in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment is unknown.

Drug Interaction Studies

There have been no formal drug interaction studies performed with Herceptin in humans. Clinically significant interactions between Herceptin and concomitant medications used in clinical trials have not been observed.

Paclitaxel and doxorubicin: Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combination therapy.

Docetaxel and carboplatin: When Herceptin was administered in combination with docetaxel or carboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma concentrations of trastuzumab were altered.

Cisplatin and capecitabine: In a drug interaction substudy conducted in patients in Study 7, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with Herceptin.

Patient Counseling Information

Cardiomyopathy

  • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy].

Embryo-Fetal Toxicity

  • Advise pregnant women and females of reproductive potential that Herceptin exposure during pregnancy or within 7 months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)].
  • Advise women who are exposed to Herceptin during pregnancy or who become pregnant within 7 months following the last dose of Herceptin that there is a pregnancy exposure registry and a pregnancy pharmacovigilance program that monitor pregnancy outcomes. Encourage these patients to enroll in the MotHER Pregnancy Registry and report their pregnancy to Genentech [see Use in Specific Populations (8.1)].
  • Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Herceptin [see Use in Specific Populations (8.3)].

Herceptin® [trastuzumab]

Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
US License No.1048

Herceptin® is a registered trademark of Genentech, Inc.
©2017 Genentech, Inc.

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