Active ingredients: Trastuzumab
Herceptin 150 mg powder for concentrate for solution for infusion
Herceptin package inserts are available for pack sizes:- Herceptin 150 mg powder for concentrate for solution for infusion
- Herceptin 600 mg solution for injection in vial
- Herceptin 600 mg solution for injection via administration device
Why is Herceptin used? What is it for?
Herceptin contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal antibodies bind to specific proteins or antigens. Trastuzumab is designed to selectively bind to an antigen called human epidermal growth factor receptor 2 (HER2). HER2 is present in large quantities on the surface of some cancer cells, stimulating their growth. When Herceptin binds to HER2, it stops the growth of these cells and causes them to die.
Your doctor may prescribe Herceptin for the treatment of breast and stomach cancer if:
- You have early breast cancer with high levels of a protein called HER2.
- You have metastatic breast cancer (breast cancer that has spread far from the primary tumor) with high levels of HER2. Herceptin could be prescribed in combination with the chemotherapy medicines paclitaxel or docetaxel as the first treatment for metastatic breast cancer or it could be prescribed on its own where other treatments have proved ineffective. It is also used in combination with medicines called aromatase inhibitors to treat patients with high levels of HER2 and hormone receptor positive metastatic breast cancer (cancer that is sensitive to the presence of female sex hormones).
- You have metastatic gastric cancer with high levels of HER2, in combination with the other anticancer drugs capecitabine or 5-fluorouracil and cisplatin.
Contraindications When Herceptin should not be used
Do not use Herceptin if:
- you are allergic to trastuzumab, to murine (mouse) proteins, or to any of the other ingredients.
- have severe breathing problems at rest due to cancer or if you need oxygen treatment.
Precautions for use What you need to know before taking Herceptin
Your doctor will closely supervise your therapy.
Cardiac checks
Treatment with Herceptin given alone or with a taxane can affect your heart, especially if you have already taken an "anthracycline (taxanes and anthracyclines are two other types of medicines used to treat cancer). Your heart function will therefore be checked first. , during (every three months) and after (up to two to five years) treatment with Herceptin If you experience signs of heart failure (ie the heart does not pump your blood properly), you may need to stop taking Herceptin.
Talk to your doctor, pharmacist or nurse before taking Herceptin if:
- have had heart failure, coronary artery disease, heart valve disease (heart murmurs), high blood pressure, have taken or are currently taking any medicines to treat high blood pressure.
- have taken or are currently taking a medicine called doxorubicin or epirubicin (medicines used to treat cancer). These drugs (or any other anthracycline) can damage the heart muscle and increase the risk of heart problems when taking Herceptin.
- suffer from shortness of breath, particularly if you are currently taking a taxane. Herceptin can cause difficulty in breathing, especially the first time it is given. This may be more serious if you are already suffering from shortness of breath. Very rarely, patients with severe breathing difficulties before treatment have died when they received Herceptin.
- have ever received other cancer treatments.
If you are receiving Herceptin treatment in combination with any other medicines used to treat cancer, such as paclitaxel, docetaxel, an aromatase inhibitor, capecitabine, 5-fluorouracil, or cisplatin, you should also read the package leaflet for these medicines.
Children and adolescents
Herceptin is not recommended under 18 years of age.
Interactions Which drugs or foods may change the effect of Herceptin
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
It can take up to 7 months for Herceptin to be cleared from the body. Therefore, you should tell your doctor, pharmacist or nurse that you have taken Herceptin if you start any new medicines within 7 months of stopping therapy.
Warnings It is important to know that:
Pregnancy
- If you are pregnant, think you may be pregnant or are planning to become pregnant, please tell your doctor, pharmacist or nurse before taking this medicine.
- You must use effective contraception during treatment with Herceptin and for at least 7 months after stopping treatment.
- Your doctor will discuss with you the risks and benefits of taking Herceptin during pregnancy. In rare cases, a decrease in the (amniotic) fluid surrounding the developing baby in the womb has been observed in pregnant women treated with Herceptin. This condition could be harmful to the baby in utero and has been associated with incomplete lung maturation, which resulted in fetal death.
Feeding time
Do not breastfeed while taking Herceptin and for 7 months following the last dose of Herceptin as Herceptin may pass to the baby via breast milk. Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
It is not known whether Herceptin will affect your ability to drive or use machines. However, if you experience symptoms such as chills or fever, you should not drive or operate machinery until these symptoms disappear.
Dosage and method of use How to use Herceptin: Dosage
Before starting treatment, your doctor will determine the amount of HER2 in your tumor. Only patients with elevated HER2 levels will be treated with Herceptin. Herceptin should only be given by a doctor or nurse. Your doctor will prescribe the dose and treatment schedule that is right for you. The dose of Herceptin depends on your body weight.
There are two different types (formulations) of Herceptin:
- one is given by infusion into a vein (intravenous infusion)
- the other is given by injection under the skin (subcutaneous injection).
It is important to check the product label to ensure that the correct formulation prescribed by your doctor is being administered. Herceptin intravenous formulation is not intended for subcutaneous administration and should only be administered by intravenous injection.
Herceptin intravenous formulation is administered as an "intravenous infusion (" drip ") directly into your veins. The first dose of your treatment is given over a 90-minute period and you will be observed by a healthcare professional during administration in case you develop any side effect. If the first dose is well tolerated, subsequent doses may be given over a period of 30 minutes (see section 2 "Warnings and precautions"). The number of infusions you receive will depend on your response to treatment. Your doctor will discuss this. with her.
In patients with early breast cancer, metastatic breast cancer and metastatic gastric cancer, Herceptin is administered every 3 weeks. Herceptin can also be given once a week for the treatment of metastatic breast cancer.
In order to avoid medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not trastuzumab emtansine.
Overdose What to do if you have taken too much Herceptin
There are no known effects to be attributed to Herceptin overdose.
If you stop using Herceptin
Do not stop taking this drug without first talking to your doctor. All doses should be taken at the right time every week or every three weeks (depending on your dosing schedule). This helps the drug work at its best.
It can take up to 7 months for Herceptin to be cleared from the body. Therefore, your doctor may decide to continue to monitor your heart function even after finishing the treatment.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse
Side Effects What are the side effects of Herceptin
Like all medicines, Herceptin can cause side effects, although not everybody gets them. Some of these side effects can be serious and may require hospitalization.
Reactions such as chills, fever and other flu-like symptoms may occur during the Herceptin infusion. These effects are very common (may affect more than 1 in 10 people). Other infusion-related symptoms are: nausea, vomiting , pain, increased muscle tension and tremors, headache, dizziness, difficulty breathing, wheezing, high or low blood pressure, heart rhythm disturbances (palpitations, fast or irregular heartbeat), swelling of the face or lips, skin rash and sensation of tiredness. Some of these symptoms can be severe and some patients have died (see section 2 "Warnings and precautions").
These effects mainly occur with the first intravenous infusion ('drip' into the vein) and during the first few hours after the start of the infusion. They are generally temporary. You will be monitored by a healthcare professional during the infusion and for at least six hours after starting the first infusion and for two hours after starting the other infusions. If you experience a reaction, the infusion will be slowed or stopped and you may be given a treatment to counteract the unwanted effects. The infusion can be continued after symptoms have improved.
Occasionally, symptoms begin more than six hours after starting the infusion. If this happens to you, contact your doctor immediately. Sometimes, symptoms can improve and then get worse later.
Other side effects can occur at any time during treatment with Herceptin, not just in connection with an infusion. Heart problems can sometimes occur during treatment and occasionally after treatment has ended and can be serious. They include weakening of the blood. heart muscle which can lead to heart failure, inflammation (swelling, redness, heat and pain) of the lining of the heart and heart rhythm disturbances. This can lead to symptoms such as:
- breathlessness (even at night),
- cough,
- fluid retention (swelling) in the legs or arms,
- palpitations (fast or irregular heartbeat).
Your doctor will monitor your heart regularly during treatment, but you should tell your doctor immediately if you notice any of the above symptoms.
If you experience any of the above symptoms when you have finished Herceptin treatment, you should see your doctor and inform him / her about your previous Herceptin treatment.
Very common side effects of Herceptin (may affect more than 1 in 10 people):
- infections
- diarrhea
- constipation
- burning in the chest (dyspepsia)
- weakness
- skin rash
- chest pain
- abdominal pain
- joint pain
- low counts of red blood cells and white blood cells (which help fight infections) sometimes associated with fever
- muscular pain
- conjunctivitis
- excessive tearing
- nosebleed
- a runny nose
- hair loss
- tremor
- hot flashes
- dizziness
- nail problems
- weight loss
- loss of appetite
- inability to sleep (insomnia)
- Altered taste
- Low platelet count
- Numbness or tingling of the fingers and toes
- Redness, swelling or blisters in the mouth and / or throat
- Pain, swelling, redness or numbness of the hands and / or feet
Common side effects of Herceptin (may affect up to 1 in 10 people):
- allergic reactions
- dry mouth and skin
- throat infections
- dry eyes
- bladder and skin infections
- sweating
- Shingles
- fatigue and malaise
- sinus inflammation
- been anxious
- inflammation of the pancreas or liver
- depression
- kidney disorders
- changes in thinking
- increased muscle tone or tension (hypertonia)
- asthma
- pain in the arms and / or legs
- lung disorders
- itchy rash
- backache
- drowsiness
- neck pain
- bruises
- bone pain
- hemorrhoids
- acne
- itch
- leg cramps
Uncommon side effects of Herceptin may affect up to 1 in 100 people:
- deafness
- rash with wheals
Rare side effects of Herceptin: may affect up to 1 in 1000 people:
- weakness
- jaundice
- inflammation / scarring of the lungs
Other side effects that have been reported with the use of Herceptin: frequency cannot be estimated from the available data:
- abnormalities or changes in blood clotting
- anaphylactic reactions
- high levels of potassium
- swelling of the brain
- swelling or bleeding behind the eyes
- swelling of the heart membrane
- slow heart rate
- shock
- abnormal heart rhythm
- respiratory distress
- respiratory failure
- acute accumulation of fluid in the lungs
- acute narrowing of the airways
- abnormal lowering of oxygen levels in the blood
- swelling of the throat
- difficulty breathing when lying down
- liver damage / failure
- swelling of the face, lips and throat
- kidney failure abnormal lowering of fluid levels around the baby in the uterus
- failure of lung development in the uterus
- abnormal kidney development in the uterus
Some of the side effects that occur may be due to breast cancer. If you receive Herceptin in combination with chemotherapy, some of these side effects may also be due to the chemotherapy.
If you get any of the side effects, please tell your doctor, pharmacist or nurse.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2 ° C - 8 ° C).
Infusion solutions should be used immediately after dilution. Do not use Herceptin if you notice any particles or color changes prior to administration.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Herceptin contains
- The active substance is trastuzumab. Each vial contains 150 mg of trastuzumab which must be dissolved in 7.2 ml of water for injections. The resulting solution contains approximately 21 mg / ml of trastuzumab.
- The other ingredients are L-histidine hydrochloride, L-histidine, α dihydrate, α-trehalose, polysorbate 20.
What Herceptin looks like and contents of the pack
Herceptin is a powder for concentrate for solution for infusion that is supplied in a glass vial sealed with a rubber stopper that contains 150 mg of trastuzumab. The powder is a white to light yellow lyophilized pellet. Each pack contains 1 vial of powder.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
HERCEPTIN 150 MG POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains 150 mg of trastuzumab, humanized IgG1 monoclonal antibody, produced by mammalian cell culture (Chinese hamster ovary cells) in suspension, purified by affinity chromatography and ion exchange, with specific viral inactivation and removal procedures.
Herceptin reconstituted solution contains 21 mg / ml of trastuzumab.
For the full list of excipients (see section 6.1).
03.0 PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
White to light yellow lyophilized powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Breast cancer
Metastatic breast cancer
Herceptin is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer (MBC):
• as monotherapy for the treatment of patients who have received at least two chemotherapy regimens for metastatic disease. Previously administered chemotherapy must have contained at least one anthracycline and one taxane, unless the patient is unsuitable for such treatments. Hormone receptor positive patients must also have failed to respond to hormone therapy, unless the patient is unsuitable for such treatments.
• in combination with paclitaxel for the treatment of patients who have not received chemotherapy for their metastatic disease and for whom treatment with anthracyclines is not indicated.
• in combination with docetaxel for the treatment of patients who have not received chemotherapy for their metastatic disease.
• in combination with an aromatase inhibitor in the treatment of postmenopausal patients with hormone receptor positive MBC not previously treated with trastuzumab.
Early stage breast cancer
Herceptin is indicated for the treatment of adult patients with HER2 positive early breast cancer (EBC):
• after surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see section 5.1)
• after adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel.
• in combination with adjuvant chemotherapy with docetaxel and carboplatin.
• in combination with neoadjuvant chemotherapy, followed by adjuvant Herceptin therapy, in locally advanced disease (including inflammatory form) or in tumors> 2 cm in diameter (see sections 4.4 and 5.1).
Herceptin should only be used in patients with metastatic or early stage breast cancer whose tumors exhibit HER2 overexpression or amplification of the HER2 gene as determined by an accurate and validated test (see sections 4.4 and 5.1).
Metastatic gastric cancer
Herceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of adult patients with metastatic adenocarcinoma of the stomach or gastroesophageal junction HER2 positive who have not previously received anticancer treatment for metastatic disease.
Herceptin should only be given to patients with metastatic gastric cancer (MGC) whose tumors have HER2 overexpression, defined as an IHC2 + result and confirmed by a SISH or FISH result, or defined as an IHC3 + result. Accurate and validated methods of determination must be used (see sections 4.4 and 5.1).
04.2 Posology and method of administration
Measurement of HER2 expression is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Herceptin treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy (see section 4.4) and should only be administered by a health care worker.
It is important to check the labeling of the medicine to ensure that the correct formulation (intravenous or subcutaneous fixed dose) is being administered to the patient as prescribed. Herceptin intravenous formulation is not intended for subcutaneous administration and should only be administered by intravenous infusion.
Switching from treatment with Herceptin intravenous formulation to treatment with Herceptin subcutaneous formulation and back, given every three weeks (q3w), was investigated in study MO22982 (see section 4.8).
In order to avoid medication errors it is important to check the vial labels to make sure that the medicine you are preparing and giving is Herceptin (trastuzumab) and not Kadcyla (trastuzumab emtansine).
Dosage
Metastatic breast cancer
Administration every three weeks
The recommended starting loading dose is 8 mg / kg body weight. The recommended maintenance dose at three-week intervals is 6 mg / kg body weight, starting three weeks after the loading dose.
Weekly administration
The recommended starting loading dose of Herceptin is 4 mg / kg body weight. The recommended weekly maintenance dose of Herceptin is 2 mg / kg body weight, starting one week after the loading dose.
Administration in combination with paclitaxel or docetaxel
In the pivotal studies (H0648g, M77001), paclitaxel or docetaxel were administered the day after the first dose of Herceptin (for dose, see the Summary of Product Characteristics (SmPC) of paclitaxel or docetaxel) and immediately after subsequent Herceptin doses if the previous Herceptin dose was well tolerated.
Administration in combination with an aromatase inhibitor
In the pivotal study (BO16216) Herceptin and anastrozole were administered from day 1. There were no restrictions on the timing of administration of Herceptin and anastrozole (for dose, see the SmPC for anastrozole or other aromatase inhibitors. ).
Early stage breast cancer
Administration every three weeks and weekly
When administered three times a week, the recommended initial loading dose of Herceptin is 8 mg / kg body weight. The recommended maintenance dose of Herceptin at three-week intervals is 6 mg / kg body weight, starting three weeks after the loading dose.
In weekly administration (initial loading dose of 4 mg / kg followed by 2 mg / kg once weekly) concomitantly with paclitaxel after chemotherapy with doxorubicin and cyclophosphamide.
See section 5.1 for dose of combination chemotherapy.
Metastatic gastric cancer
Administration every three weeks
The recommended starting loading dose is 8 mg / kg body weight. The recommended maintenance dose at three-week intervals is 6 mg / kg body weight, starting three weeks after the loading dose.
Metastatic and early stage breast cancer and metastatic gastric cancer
Duration of treatment
Patients with metastatic breast cancer or metastatic gastric cancer should be treated with Herceptin until disease progression. Patients with early breast cancer should be treated with Herceptin for 1 year or until recurrence occurs, whichever comes first. Prolonging treatment in EBC for more than one year is not recommended (see section 5.1).
Dosage reduction
No dose reductions of Herceptin were made in clinical trials. Patients may continue Herceptin therapy during periods of reversible chemotherapy-induced myelosuppression, but should be closely monitored during this period for complications related to neutropenia. Refer to the SmPC of paclitaxel, docetaxel or the aromatase inhibitor to reduce or delay the dosage.
If the percentage of left ventricular ejection fraction (LVEF) decreases ≥ 10 points from baseline and falls below 50%, dosing should be suspended and the LVEF assessment repeated within approximately 3 weeks. If LVEF does not improve or declines further, or if symptomatic congestive heart failure (CHF) develops, discontinuation of Herceptin should be seriously considered, unless the benefits for the individual patient outweigh the risks. All these patients will have to be evaluated by a cardiologist and followed up over time.
Missed doses
If the patient has missed a dose of Herceptin for a week or less, the usual maintenance dose of Herceptin (weekly: 2 mg / kg, every 3 weeks: 6 mg / kg) should be given as soon as possible. Do not wait for the next scheduled cycle. Subsequent maintenance doses of Herceptin should be administered 7 or 21 days later depending on the respective dosing regimen: weekly or every three weeks.
If the patient has missed a dose of Herceptin for more than a week, a new Herceptin loading dose should be given in approximately 90 minutes (weekly administration: 4 mg / kg, administration every 3 weeks: 8 mg / kg) as soon as possible. Subsequent maintenance doses of Herceptin (weekly administration: 2 mg / kg, administration every 3 weeks: 6 mg / kg, respectively) should be administered 7 or 21 days later depending on the respective dosing regimen: weekly or every three weeks.
Particular populations
Pharmacokinetic studies have not been conducted in the elderly population and in subjects with renal or hepatic dysfunction. In a population pharmacokinetic analysis, age and renal impairment were not found to change the availability of trastuzumab.
Pediatric population
There is no indication for a specific use of Herceptin in the pediatric population.
Method of administration
The Herceptin loading dose should be administered as a 90 minute intravenous infusion. Do not administer as an intravenous injection or intravenous bolus. Herceptin intravenous infusion should be administered by healthcare professionals trained to manage anaphylaxis and in the presence of emergency equipment. Patients should be observed for at least six hours after the start of the first infusion and for two hours after the start of subsequent infusions for symptoms, such as fever and chills or other infusion-related symptoms (see sections 4.4 and 4.8. These symptoms can be controlled by stopping the infusion or slowing the rate. The infusion can be resumed once symptoms have relieved.
If the initial loading dose is well tolerated, subsequent doses can be administered as a 30 minute infusion.
For instructions on reconstitution of Herceptin intravenous formulation before administration, see section 6.6.
04.3 Contraindications
• Known hypersensitivity to trastuzumab, to mouse proteins or to any of the excipients listed in section 6.1.
• Patients with severe dyspnoea at rest, due to complications of advanced malignancies, or patients requiring supplemental oxygen therapy.
04.4 Special warnings and appropriate precautions for use
In order to improve the traceability of biological drugs, the commercial name and batch number of the administered product must be clearly recorded (or declared) in the patient's medical record.
The test for HER2 must be performed in a specialized laboratory that can guarantee adequate validation of the analytical procedures (see section 5.1).
There are currently no data from clinical trials on re-treatment of patients previously exposed to Herceptin for adjuvant treatment.
Cardiac dysfunction
General consideration
Patients treated with Herceptin are at increased risk of developing CHF (Class II-IV according to New York Heart Association [NYHA]) or asymptomatic cardiac dysfunction. These events have been observed in patients treated with Herceptin alone or in combination therapy with paclitaxel or docetaxel, particularly after chemotherapy with anthracyclines (doxorubicin or epirubicin) .They are moderate to severe in intensity and have been associated with death (see paragraph 4.8). In addition, particular caution should be observed when treating patients with increased cardiac risk, e.g. hypertension, confirmed coronary artery disease, CHF, left ventricular ejection fraction (LVEF) old age.
All candidates for Herceptin treatment, but particularly patients previously exposed to anthracycline and cyclophosphamide (AC) treatment, should undergo baseline cardiac status assessment, including history and physical examination, electrocardiogram (ECG), echocardiogram, and / or multiple gate acquisition (MUGA) scan or magnetic resonance imaging. Monitoring can help identify patients who develop cardiac dysfunction. The evaluation of cardiac function, conducted in the manner of the initial one, should be repeated every 3 months during treatment and every 6 months after discontinuation of treatment up to 24 months after the last administration of Herceptin.
Based on a population pharmacokinetic analysis of all available data (see section 5.2), trastuzumab may remain in the circulation for up to 7 months after stopping Herceptin. Patients receiving anthracyclines after ending Herceptin treatment may be at increased risk for cardiac dysfunction. If possible, physicians should avoid anthracyclines for up to 7 months after stopping Herceptin. If anthracyclines are used, the patient's heart function should be monitored closely.
Formal cardiology evaluation should be considered in patients who have experienced cardiologic problems following the initial screening. Cardiac function should be monitored during treatment in all patients (e.g. every 12 weeks). Monitoring can aid in the identification of patients who develop cardiac dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6-8 weeks). In the case of patients who report continued decrease in left ventricular function but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been observed.
The safety of continuing or restarting Herceptin in patients experiencing cardiac dysfunction has not been investigated in prospective studies. If LVEF decreases ≥ 10 points from baseline and falls below 50% , dosing should be suspended and LVEF assessed again within approximately 3 weeks. If LVEF does not improve or declines further, or symptomatic CHF develops, discontinuation of Herceptin should be seriously considered, unless the benefits for the individual patient are considered to outweigh the risks These patients should be evaluated by a cardiologist and followed up over time.
If symptomatic heart failure occurs during therapy with Herceptin, it should be treated with standard drug therapies for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction in the pivotal studies improved with standard treatment with an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta blocker Most patients with cardiac symptoms and evidence of clinical benefit associated with Herceptin treatment continued therapy without further cardiac clinical events.
Metastatic breast cancer
Herceptin should not be administered concomitantly with anthracyclines in the context of the MBC.
MBC patients who have previously received anthracyclines are also at risk of cardiac dysfunction with Herceptin treatment, although this risk is lower than with concomitant use of Herceptin and anthracyclines.
Early stage breast cancer
For patients with EBC, the cardiologic assessment, conducted in the manner of the initial one, should be repeated every 3 months during treatment and every 6 months after stopping treatment, up to 24 months after the last Herceptin administration. Additional monitoring is recommended in patients receiving anthracycline-based chemotherapy and should be done annually for up to 5 years after the last Herceptin administration, or longer if a continued decrease in LVEF is observed.
Patients with a history of myocardial infarction (MI), angina pectoris requiring medical treatment, previous or current CHF (NYHA Class II-IV), LVEF cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically relevant valvular heart disease, poor hypertension controlled (hypertension controlled by appropriate standard medical treatment) and haemodynamically significant pericardial effusion were excluded from the adjuvant and neoadjuvant EBC treatment pivotal studies with Herceptin. Therefore, treatment cannot be recommended in these patients.
Adjuvant treatment
Herceptin should not be administered concomitantly with anthracyclines in the context of adjuvant treatment.
An increased incidence of symptomatic and asymptomatic cardiac events was observed in patients with early breast cancer when Herceptin was administered after anthracycline-based chemotherapy compared to administration with a docetaxel and non-anthracycline carboplatin regimen and was more pronounced when Herceptin was administered concomitantly with the taxanes than when administered sequentially to the taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months. In one of 3 pivotal studies in which a follow up median of 5.5 years (BCIRG006) a sustained increase in the cumulative rate of symptomatic cardiac events or LVEF was observed in patients administered Herceptin concomitantly with a taxane following anthracyclines therapy of up to 2.37% compared to approximately 1. " 1% in the two comparison arms (anthracycline plus cyclophosphamide followed by a taxane and taxane, carboplatin and Herceptin).
Four large studies conducted in the adjuvant setting have identified cardiac risk factors including: older age (> 50 years), low LVEF (antihypertensive drugs. In patients treated with Herceptin after completion of adjuvant chemotherapy, the risk of cardiac dysfunction is been associated with a higher cumulative dose of anthracyclines given prior to initiation of Herceptin therapy and a body mass index (BMI)> 25 kg / m2.
Neoadjuvant-adjuvant treatment
In EBC patients who are candidates for neoadjuvant-adjuvant treatment, Herceptin should be administered concomitantly with anthracyclines only in chemotherapy-naive patients and only with low-dose anthracycline regimens i.e. maximum cumulative doses of doxorubicin 180 mg / m2 or epirubicin 360 mg / m2.
If patients were treated concomitantly with a full course of low dose anthracyclines and Herceptin in the neoadjuvant setting, no further cytotoxic chemotherapy should be given after surgery. In other situations the decision about the need for additional cytotoxic chemotherapy must be made according to individual factors.
To date, experience of concomitant administration of trastuzumab with low dose anthracycline regimens is limited to two studies (MO16432 and BO22227).
In pivotal study MO16432, Herceptin was administered concomitantly with neoadjuvant chemotherapy, containing three courses of doxorubicin (cumulative dose of 180 mg / m2).
The incidence of symptomatic cardiac dysfunction was 1.7% in the Herceptin-containing arm.
The pivotal study BO22227 was designed to demonstrate non-inferiority of treatment with Herceptin subcutaneous formulation compared to Herceptin intravenous formulation based on co-primary endpoints of PK and efficacy (Ctrough of pre-dose Cycle 8 trastuzumab, and pCR rate at definitive surgery, respectively) (see Section 5.1 of the SmPC of Herceptin subcutaneous formulation). In the pivotal study BO22227, Herceptin was administered concomitantly with neoadjuvant chemotherapy containing four courses of epirubicin (cumulative dose of 300 mg / m2); at a median follow-up of 40 months, the incidence of congestive heart failure was 0.0% in the IV Herceptin arm.
Clinical experience in patients over the age of 65 is limited.
Infusion related reactions, and hypersensitivity
Serious adverse reactions related to the Herceptin infusion have been reported including dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, decreased oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema (see section 4.8). Premedication can be used to reduce the risk of such events. Most of these events occur during or within 2.5 hours of starting the first infusion. If there is an infusion reaction, the Herceptin infusion should be stopped or the infusion rate slowed and the patient should be monitored until resolution of all observed symptoms (see section 4.2). These symptoms can be treated with an analgesic / antipyretic such as meperidine or paracetamol, or with an antihistamine such as diphenhydramine. Most patients have experienced resolution of the symptoms. symptoms and subsequently received further Herceptin infusions. Serious reactions have been successfully treated with supportive care, such as oxygen, beta agonists and corticosteroids. In rare cases these reactions have been associated with a clinical course culminating in a fatal outcome Patients who experience dyspnoea at rest, due to complications of advanced tumors and comorbidities, may be at greater risk higher to experience a fatal reaction to the infusion. These patients should therefore not be treated with Herceptin (see section 4.3).
Initial improvements followed by clinical worsening and delayed reactions with rapid clinical deterioration have also been reported. Deaths have occurred within hours and up to one week after the infusion. On very rare occasions, patients have experienced the onset of infusion reactions and pulmonary symptoms more than six hours after starting the Herceptin infusion. Patients they should be warned of the possibility of such a delayed onset and should be instructed to contact their physician if this happens.
Pulmonary events
Severe pulmonary events have been reported with Herceptin use in the post-marketing setting (see section 4.8). These events have occasionally been fatal. Cases of interstitial lung disease including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia have also been reported. , lung inflammation, pleural effusion, respiratory distress, acute pulmonary edema and respiratory failure. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic treatments such as taxanes, gemcitabine, vinorelbine and radiotherapy, for which such association is already known. These events may occur in the context of an infusion reaction or have a delayed onset. Patients who experience dyspnoea at rest, due to complications of advanced cancers and comorbidities, may be at a higher risk of experiencing events. These patients nti should therefore not be treated with Herceptin (see section 4.3). In the presence of lung inflammation, caution should be observed, especially in patients concomitantly treated with taxanes.
04.5 Interactions with other medicinal products and other forms of interaction
No formal drug interaction studies have been performed. No clinically significant interactions were observed between Herceptin and co-administered medicinal products in clinical studies.
Effect of trastuzumab on the pharmacokinetics of other antineoplastics
Pharmacokinetic data from studies BO15935 and M77004 in women with HER2 positive metastatic breast cancer suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) did not was altered by the presence of trastuzumab (IV loading dose 8 mg / kg or 4 m / kg followed by 6 mg / kg q3w or 2 mg / kg q1w IV, respectively).
However, trastuzumab may increase the total exposure of a metabolite of doxorubicin (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical effect of the increase in this metabolite were unclear.
Data from study JP16003, single-arm with Herceptin (IV loading dose 4 mg / kg and IV 2 mg / kg weekly) and docetaxel (60 mg / m2 IV), performed in Japanese women with HER2 positive metastatic breast cancer , suggested that concomitant administration of Herceptin had no effect on the single dose pharmacokinetics of docetaxel. JP19959 is a substudy of study BO18255 (ToGA) performed in Japanese male and female patients with advanced gastric cancer to study the pharmacokinetic profile of capecitabine and cisplatin administered with or without Herceptin. The results of this substudy suggest that exposure to the bioactive metabolites (eg 5-FU) of capecitabine was not altered by the concomitant use of cisplatin monotherapy or cisplatin with Herceptin. However, capecitabine itself showed higher concentrations and a longer half-life when combined with Herceptin. The data also suggest that the pharmacokinetics of cisplatin were not altered by the concomitant use of capecitabine or capecitabine in combination with Herceptin.
Pharmacokinetic data from study H4613g / GO01305 in patients with metastatic or locally advanced inoperable HER2-positive breast cancer suggested that trastuzumab did not impact carboplatin pharmacokinetics.
Effects of antineoplastics on trastuzumab pharmacokinetics
Comparing simulated serum concentrations of trastuzumab following Herceptin monotherapy (4 mg / kg loading dose / 2 mg / kg q1w IV) and serum concentrations observed in Japanese women with HER2 positive metastatic breast cancer (study JP16003) showed that concomitant administration of docetaxel had no effect on the pharmacokinetics of trastuzumab.
A comparison of pharmacokinetic data from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g), in which patients received concomitant treatment with Herceptin and paclitaxel, and two Phase II studies in which Herceptin was administered as monotherapy (W016229 and MO16982), in women with HER2 positive metastatic breast cancer, indicates that the individual and mean serum trough concentrations of trastuzumab vary within and between studies, but it is unclear the effect of concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab. A comparison of trastuzumab pharmacokinetic data from study M77004 in which women with HER2-positive metastatic breast cancer received concomitant treatment with Herceptin, paclitaxel and doxorubicin, and trastuzumab pharmacokinetic data in the studies where Herceptin was administered alone (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested that doxorubicin and paclitaxel have no effect on the pharmacokinetics of trastuzumab.
Pharmacokinetic data from study H4613g / GO01305 suggested that carboplatin had no effect on trastuzumab pharmacokinetics.
Co-administration of anastrozole does not appear to have affected the pharmacokinetics of trastuzumab.
04.6 Pregnancy and lactation
Women of childbearing age
Women of childbearing potential should be advised of the need to use effective contraception during treatment with Herceptin and for 7 months after the end of treatment (see section 5.2).
Pregnancy
Reproduction studies were conducted in monkeys cynomolgus at doses up to 25 times the weekly human maintenance dose of 2 mg / kg Herceptin intravenous formulation and revealed no evidence of impaired fertility or fetal harm. Placental transfer of trastuzumab was observed during the developmental period. early fetal (days 20-50 of gestation) and late (days 120-150 of gestation). It is not known whether Herceptin can affect reproductive capacity. Since animal reproduction studies are not always predictive of effects in reproduction. male, Herceptin should be avoided in pregnancy unless the potential benefits to the mother outweigh the potential risks to the fetus.
There have been post-marketing reports of impaired renal development and / or function in association with oligohydramnios, some associated with fatal fetal pulmonary hypoplasia, in pregnant women treated with Herceptin. In the event of pregnancy, the woman should be informed of the possibility of harm to the fetus. Close monitoring by a multidisciplinary team is desirable if a pregnant woman is treated with Herceptin or if pregnancy occurs during treatment with Herceptin or within 7 months following the last dose of the medicine.
Feeding time
A study in monkeys Cynomolgus during lactation, at doses 25 times higher than the weekly human maintenance dose of 2 mg / kg Herceptin intravenous formulation, has shown that trastuzumab is secreted in milk. The presence of trastuzumab in neonatal monkey serum was not associated with any adverse effects on growth or development from birth to 1 month of age. It is not known whether trastuzumab is secreted in human breast milk. Because human IgG1 is secreted in human breast milk and the potential risk of harm to the newborn is unknown, women should not breastfeed during Herceptin therapy and for 7 months following the last dose.
Fertility
No fertility data are available.
04.7 Effects on ability to drive and use machines
Herceptin has no or negligible influence on the ability to drive and use machines. However, patients who develop infusion-related symptoms (see section 4.4) should be advised not to drive and operate machinery until symptoms resolve.
04.8 Undesirable effects
Summary of the safety profile
Among the most serious and / or common adverse reactions reported to date with the use of Herceptin (intravenous formulation and subcutaneous formulation) are: cardiac dysfunction, infusion reactions, haematotoxicity (particularly neutropenia), infections and pulmonary adverse reactions.
Tabulated list of adverse reactions
In this section, the following frequency categories have been used: very common (≥1 / 10), common (≥1 / 100,
Table 1 presents adverse reactions that have been reported with the use of intravenous Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting.
All terms included refer to the highest percentage observed in pivotal clinical trials.
Table 1: Undesirable effects reported with intravenous Herceptin alone or in combination with chemotherapy in pivotal clinical trials (N = 8386) and in the post-marketing period
+ Indicates adverse reactions reported in association with a fatal outcome.
1 Indicates adverse reactions reported largely in association with Infusion Related Reactions. No specific percentages are available for these.
* Observed with combination therapy following treatment with anthracyclines, in combination with taxanes.
Description of specific adverse reactions
Cardiac dysfunction
Congestive heart failure (NYHA Class II-IV) is a common adverse reaction associated with the use of Herceptin and has been associated with a fatal outcome (see section 4.4). Signs and symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary edema, s3 gallop, decreased ventricular ejection fraction have been observed in patients treated with Herceptin (see section 4.4).
In 3 pivotal clinical trials with Herceptin as adjuvant given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic congestive heart failure) was similar in patients receiving chemotherapy alone (e.g. those who had not received Herceptin) and in patients receiving Herceptin sequentially after a taxane (0.3-0.4%) .The highest percentage was observed in patients receiving Herceptin concomitantly with a taxane (2.0 %). Experience with concomitant administration of Herceptin and low dose anthracyclines in the neoadjuvant setting is limited (see section 4.4).
When Herceptin was given after completion of adjuvant chemotherapy, NYHA Class III-IV heart failure was observed in 0.6% of patients in the treated arm for one year after a median follow-up of 12 months. In study BO16348 after a median follow-up of 8 years, the incidence of severe CHF (NYHA Class III and IV) in the Herceptin 1-year arm was 0.8% and the rate of left ventricular dysfunction was mildly symptomatic and asymptomatic was 4.6%.
Severe CHF reversibility (defined as a sequence of at least two consecutive LVEF ≥50% post-event) was observed in 71.4% of patients treated with Herceptin. Reversibility was demonstrated in 79.5% of patients. of mildly symptomatic and asymptomatic left ventricular dysfunction Approximately 17% of cardiac dysfunction related events occurred after completion of Herceptin treatment.
In the pivotal studies on the treatment of metastatic disease with the Herceptin intravenous formulation, the incidence of cardiac dysfunction varied between 9% and 12% when the drug was administered in combination with paclitaxel compared to 1% - 4% for paclitaxel alone. In monotherapy, the rate was 6% - 9%. The highest rate of cardiac dysfunction occurred in patients receiving Herceptin concomitantly with anthracyclines / cyclophosphamide (27%), and was significantly higher than with anthracyclines / cyclophosphamide alone (7% - 10%). In a subsequent clinical study with prospective monitoring of cardiac function, the incidence of symptomatic congestive heart failure was 2.2% in patients receiving Herceptin and docetaxel compared to 0% in patients receiving docetaxel monotherapy. Part of the patients (79%) who developed cardiac dysfunction in these clinical trials improved after receiving standard medical treatment for congestive heart failure.
Infusion reactions, allergic-type reactions and hypersensitivity
It is estimated that approximately 40% of patients treated with Herceptin will experience some form of infusion reaction. However, most infusion reactions are mild to moderate in intensity (NCI-CTC scoring system) and tend to occur early in treatment, i.e. during infusions one, two and three, with less frequency in subsequent infusions. Such reactions include chills, fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, rash, nausea, vomiting and headache (see section 4.4). The rate of infusion-related reactions of all degrees varies across studies depending on indication, method of data acquisition and administration of trastuzumab concomitantly with chemotherapy or monotherapy.
Severe anaphylactic reactions requiring immediate additional interventions can usually occur during both the first and second infusion of Herceptin (see section 4.4) and have been associated with a fatal outcome.
Anaphylactoid reactions have been observed in isolated cases.
Hematotoxicity
Febrile neutropenia and leukopenia are very commonly observed events. Commonly developing adverse reactions have included: anemia, thrombocytopenia and neutropenia. The frequency of episodes of hypoprothrombinemia is unknown. The risk of neutropenia may be slightly increased when trastuzumab is administered with docetaxel following anthracyclines therapy.
Pulmonary events
Severe pulmonary adverse reactions occur in association with the use of Herceptin and have been associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, lung inflammation, pleural effusion, respiratory distress, acute pulmonary edema and respiratory failure (see section 4.4).
Details about the risk minimization measures that are in accordance with the European Risk Management Plan are presented in the Special warnings and precautions for use (section 4.4).
Immunogenicity
In the setting of neoadjuvant-adjuvant EBC treatment, 8.1% (24/296) of patients treated with intravenous Herceptin developed antibodies against trastuzumab (regardless of the presence of antibodies at baseline). Neutralizing antibodies to trastuzumab were detected in post-baseline specimens in 2 of 24 patients treated with intravenous Herceptin.
The clinical relevance of these antibodies is unknown; however, the pharmacokinetics, efficacy (determined by pathological complete response [pCR]) and safety of intravenous Herceptin determined by the occurrence of administration related reactions (ARRs) did not appear to be compromised by these antibodies.
There are no immunogenicity data available for Herceptin in gastric cancer.
Switching from treatment with Herceptin intravenous formulation to treatment with Herceptin subcutaneous form and vice versa
Study MO22982 examined the transition from treatment with Herceptin intravenous formulation to treatment with Herceptin subcutaneous formulation with the primary objective of evaluating patient preference for intravenous or subcutaneous administration of trastuzumab. The trial analyzed 2 cohorts (one treated with the subcutaneous formulation in vial and the other with the subcutaneous formulation via delivery device) using a 2-arm cross-over design, whereby 488 patients were randomized to a of two different Herceptin treatment sequences given every three weeks (iv [Cycles 1-4] → sc [Cycles 5-8] or sc [Cycles 1-4] → iv [Cycles 5-8]). Herceptin IV treatment naïve subjects (20.3%) or previously exposed IV Herceptin (79.7%). For IV → sc sequence (combined cohorts of subcutaneous vial formulation and subcutaneous administration device formulation) the rates related to adverse events (of all grades) were respectively described before the switch (cycles 1-4) and after the switch (cycles 5-8) as 53.8% vs. 56.4%; for the sequence sc → ev (combined cohorts of scin vial and s.c. via delivery device), the rates of adverse events (all grades) were described before switch and after switch as 65.4% vs. 48.7%.
Prior to switch (cycles 1-4), rates of onset of serious adverse events, grade 3 adverse events and discontinuation of treatment due to adverse events were low (
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
No cases of overdose have been reported in human clinical trials. Single doses of Herceptin, used alone, above 10 mg / kg were not administered in clinical trials. Up to this level, dosages were well tolerated.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03
Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against human epithelial growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20% -30% of primary breast cancers. Studies on HER2 positivity rates in gastric cancer (GC) detected by immunohistochemistry (IHC) and hybridization in situ fluorescent (FISH) or hybridization in situ chromogenic (CISH) have shown that there is a "wide variability in HER2 positivity in a range from 6.8% to 34.0% for IHC and from 7.1% to 42.6% for FISH." Studies have shown that breast cancer patients with HER2 overexpression have a shorter disease-free survival than cancer patients without HER2 overexpression. The extracellular domain of the receptor (ECD, p105) can be released into the bloodstream and measured in serum samples.
Mechanism of action
Trastuzumab binds with "high affinity and specificity to subdomain IV, a perimembranous region of the extracellular domain of HER2. Binding of trastuzumab to HER2 inhibits the ligand-independent signaling of HER2 and prevents proteolytic cleavage of its extracellular domain, a mechanism of activation of HER2 Consequently, trastuzumab has demonstrated, both in vitro that in animals, to be able to inhibit the proliferation of human tumor cells that overexpress HER2. Furthermore, trastuzumab is a potent mediator of cell-mediated antibody dependent cytotoxicity (ADCC). In vitro trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing tumor cells over HER2 non-overexpressing tumor cells.
Detection of HER2 overexpression or HER2 gene amplification
Detection of HER2 overexpression or HER2 gene amplification in breast cancer
Herceptin should only be used in cancer patients with HER2 overexpression or amplification of the HER2 gene as determined by an accurate and validated test. HER2 overexpression should be detected by immunohistochemical (IHC) examination of fixed tumor sections (see section 4.4). Amplification of the HER2 gene should be detected by hybridization in situ by fluorescence (FISH) or hybridization in situ chromogenic (CISH) of fixed tumor sections. Patients showing marked overexpression of HER2 with an indication of an IHC score of 3+ or a positive FISH or CISH result are candidates for treatment with Herceptin.
To ensure accurate and reproducible results, the tests must be carried out in specialized laboratories able to guarantee the validation of the analytical procedures.
The recommended system for scoring IHC tagging models is that shown in Table 2:
Table 2 Recommended system for scoring IHC tagging patterns in breast cancer
In general, the FISH test is considered positive if the ratio of the number of copies of the HER2 gene per tumor cell to the number of copies of chromosome 17 is greater than or equal to 2, or if there are more than 4 copies of the HER2 gene for tumor cell if chromosome 17 is not used as a reference.
In general, the CISH test is considered positive if there are more than 5 copies of the HER2 gene per nucleus in more than 50% of cancer cells.
For complete instructions on performing and interpreting the tests, refer to the leaflets attached to the validated FISH and CISH test packs. Official recommendations on HER2 testing may also apply.
For any other method that can be used to evaluate the expression of the HER2 protein or gene, the analyzes should only be performed by laboratories that ensure optimal performance of validated methods. Such methods must be clear, precise and accurate enough to demonstrate HER2 overexpression, and must be able to distinguish moderate (level 2+) from high (level 3+) HER2 overexpression.
Detection of HER2 overexpression or HER2 gene amplification in gastric cancer
Only an accurate and validated test should be used to determine HER2 overexpression or amplification of the HER2 gene. IHC is recommended as a first test and, in cases where evaluation of HER2 gene amplification is also required, a silver ion in situ hybridization (SISH) or FISH technique should be used. However, SISH technology is recommended to allow for parallel evaluation of tumor histology and morphology. To ensure the validation of the assessment procedures and the production of accurate and reproducible results, the HER2 test must be performed in a laboratory with trained personnel. Full instructions on performing the test and interpreting the results should be found in the product information sheet provided with the tests used for HER2 evaluation.
In the ToGA study (BO18255), patients whose tumors were IHC3 + or FISH positive were defined as HER2-positive and therefore included in the study. Based on the clinical study results, the positive effects were limited to patients with a higher level of HER2 protein overexpression, defined as 3+ with IHC or 2+ with IHC and a positive FISH result. .
In a methodology comparison study (study D008548) a high degree of agreement (> 95%) was observed between SISH and FISH techniques for the determination of HER2 gene amplification in patients with gastric cancer.
HER2 overexpression must be determined by immunohistochemical (IHC) examination of fixed tumor sections. Amplification of the HER2 gene must be detected by hybridization in situ, using SISH or FISH, on fixed tumor sections.
The recommended system for scoring IHC tagging models is that shown in Table 3:
Table 3 Recommended System for Scoring IHC Marking Patterns in Gastric Cancer
In general, SISH or FISH tests are considered positive if the ratio of the number of copies of the HER2 gene per tumor cell to the number of copies of chromosome 17 is greater than or equal to 2.
Clinical efficacy and safety
Metastatic breast cancer
Herceptin was used in monotherapy clinical trials in MBC patients with tumors characterized by HER2 overexpression and failure of one or more prior chemotherapy regimens for metastatic disease (Herceptin monotherapy).
Herceptin has also been used in combination with paclitaxel or docetaxel to treat chemotherapy-naïve patients for metastatic disease. Patients pretreated with adjuvant anthracycline-based chemotherapy were treated with paclitaxel (175 mg / m2 administered as a 3-hour infusion) with or without Herceptin. In the pivotal study with docetaxel (100 mg / m2 administered as a 1 hour infusion) with or without Herceptin, 60% of patients had previously received adjuvant anthracycline-based chemotherapy. Patients were treated with Herceptin until disease progression.
The efficacy of Herceptin in combination with paclitaxel in patients not previously receiving adjuvant anthracycline therapy has not been studied. However, the combination of Herceptin plus docetaxel was effective, regardless of whether the patients had received prior adjuvant therapy or not. with anthracyclines.
The method used to analyze HER2 overexpression and determine the eligibility of patients to participate in pivotal clinical trials on the use of Herceptin monotherapy and Herceptin plus paclitaxel employed HER2 immunohistochemical staining of fixed material from breast tumors. using murine monoclonal antibodies CB11 and 4D5. These tissues were fixed in formalin or Bouin's fixative. This assay method used in clinical studies and performed in a central laboratory used a scale of 0 to 3+. Patients classified by a 2+ or 3+ staining were included, while those with a 0 or 1+ staining were excluded. More than 70% of enrolled patients had 3+ "overexpression." Acquired data suggest that the beneficial effects were greater in patients with higher levels of HER2 (3+) overexpression.
The primary analytical method used to determine HER2 positivity in the pivotal study with docetaxel, with or without Herceptin, was immunohistochemistry. A minority of patients were tested by hybridization. in situ in fluorescence (FISH). In this study, 87% of enrolled patients were characterized by IHC3 + disease, and 95% by IHC3 + and / or FISH-positive disease.
Weekly administration in metastatic breast cancer
Efficacy results from monotherapy and combination studies are summarized in Table 4:
Table 4 Efficacy results from monotherapy and combination therapy studies
TTP = time to progression; "n.a." indicates that it could not be evaluated or that it has not yet been achieved.
1 Study H0649g: IHC3 + patient subpopulations
2 Study H0648g: Subpopulations of IHC3 + patients
3 Study M77001: Intent-to-treat population, results at 24 months
Herceptin combination treatment with anastrozole
Herceptin has been studied in combination with anastrozole for the first-line treatment of postmenopausal patients with hormone receptor-positive HER2 overexpressing MBC (e.g. estrogen receptor (ER) and / or progesterone receptor (PR)). Progression-free survival doubled in the Herceptin in combination with anastrozole arm compared to the anastrozole alone arm (4.8 months versus 2.4 months). For the other parameters, the improvements observed in the combination arm were: total response (16.5% versus 6.7%), clinical benefit (42.7% versus 27.9%), time to progression (4 , 8 months versus 2.4 months). There was no difference between the two arms in terms of time to response and duration of response. Median overall survival was prolonged by 4.6 months for patients in the combination arm. The difference was not statistically significant, however more than half of the patients enrolled in the anastrozole alone arm were treated with a Herceptin-containing regimen after disease progression.
Administration every three weeks in metastatic breast cancer
Efficacy data from non-comparative monotherapy and combination therapy studies are summarized in Table 5 below:
Table 5 Efficacy results from non-comparative studies conducted as monotherapy and in combination therapy
TTP = time to progression; "n.a." indicates that it could not be evaluated or that it has not yet been achieved.
1. Study WO16229: 8 mg / kg loading dose, followed by 6 mg / kg every 3 weeks
2. Study MO16982: loading dose 6 mg / kg per week 3 times; followed by 6 mg / kg every 3 weeks
3. Study BO15935
4. Study MO16419
Progression sites
The frequency of liver progression was significantly reduced in patients treated with the Herceptin-paclitaxel combination compared to paclitaxel alone (21.8% versus 45.7%; p = 0.004). More patients treated with Herceptin and paclitaxel showed central nervous system progression compared to patients treated with paclitaxel alone (12.6% versus 6.5%; p = 0.377).
Early stage breast cancer (adjuvant setting)
Early stage breast cancer is defined as invasive non-metastatic primary breast cancer.
The use of Herceptin in the context of adjuvant therapy was investigated in 4 large, multicentre, randomized studies:
• Study BO16348 was designed to compare treatment with Herceptin every three weeks for one and two years versus observation only in patients with HER2 positive EBC after surgery, standard chemotherapy, and radiotherapy (if applicable). A comparison was also made between treatment with Herceptin for one year and treatment with Herceptin for two years. Patients intended to receive Herceptin were given an initial loading dose of 8 mg / kg, followed by 6 mg / kg every three weeks for one year or two years.
• NSAPB B-31 and NCCTG N9831 studies including a pooled analysis were designed to evaluate the clinical utility of combining Herceptin treatment with paclitaxel after AC chemotherapy; in addition, the NCCTG N9831 study also evaluated sequentially adding Herceptin versus AC → P chemotherapy in patients with HER2 positive EBC after surgery.
• Study BCIRG 006 was designed to evaluate the association of Herceptin treatment with docetaxel after AC chemotherapy or docetaxel and carboplatin in patients with HER2 positive EBC after surgery.
Initial breast cancer in the HERA study was limited to operable, primary, invasive breast adenocarcinoma with positive axillary lymph nodes or negative axillary lymph nodes, if with tumor at least 1 cm in diameter.
In the pooled analysis of NSAPB B-31 and NCCTG N9831, EBC was limited to women with operable high-risk breast cancer, defined as HER2 positive and axillary lymph node positive or HER2 positive and axillary lymph node negative with high risk characteristics ( tumor size> 1 cm and ER negative or tumor size> 2 cm, regardless of hormonal status).
In study BCIRG 006, HER2 positive EBC was limited to node-positive or high-risk node-negative patients defined as absent lymph node involvement (pN0) and at least 1 of the following: tumor size greater than 2 cm, estrogen receptors and for progesterone negative, histological and / or nuclear grade 2-3 or age
Table 6 summarizes the efficacy results from study BO16348 after a median follow-up of 12 months * and 8 years **:
Table 6 Efficacy results from study BO16348
* The 1-year DFS co-primary endpoint versus observation reached the default statistical limit
** Final analysis (including crossover of 52% of patients from observation arm to Herceptin)
*** There is an overall sample discrepancy due to a small number of patients randomized after the cut-off date for the 12-month median follow-up analysis
The results of the interim efficacy analysis exceeded the predetermined statistical limit of the protocol for comparing Herceptin for 1 year versus observation. After a median follow-up of 12 months, the hazard ratio (HR) for disease-free survival (DFS) was 0.54 (95% CI 0.44-0.67) which translates into an absolute benefit, in terms of 2-year disease-free survival rate, of 7.6 percentage points (85, 8% versus 78.2%) in favor of the Herceptin arm.
After a median follow-up of 8 years, a final analysis was performed which found that treatment with Herceptin for one year was associated with a 24% risk reduction compared to observation alone (HR = 0.76, CI at 95% 0.67 - 0.86) This translates into an absolute benefit in terms of an 8-year progression-free survival rate of 6.4 percentage points in favor of Herceptin treatment for one year.
In this final analysis, prolonging Herceptin treatment for two years did not show any additional benefit over treatment for 1 year [HR DFS in the 2-year versus 1-year intent-to-treat (ITT) population = 0.99 (95% CI: 0.87 - 1.13), p-value = 0.90 and HR OS = 0.98 (0.83 - 1.15); p-value = 0.78] The rate of asymptomatic left ventricular dysfunction was increased in the treatment arm for 2 years (8.1% versus 4.6% in the treatment arm for 1 year). More patients had at least one adverse event of grade 3 or 4 in the 2-year treatment arm (20.4%) versus the 1-year treatment arm (16.3%).
In NSAPB B-31 and NCCTG N9831 studies, Herceptin was administered in combination with paclitaxel, following AC chemotherapy.
Doxorubicin and cyclophosphamide were administered concomitantly as follows:
• intravenous push doxorubicin, 60 mg / m2, administered every 3 weeks for 4 cycles.
• intravenous cyclophosphamide, 600 mg / m2 over 30 minutes, administered every 3 weeks for 4 cycles
Paclitaxel, in combination with Herceptin, was administered as follows:
• intravenous paclitaxel - 80 mg / m2 as a continuous intravenous infusion, given once weekly for 12 weeks,
or
• intravenous paclitaxel - 175 mg / m2 as a continuous intravenous infusion, administered once every 3 weeks for 4 cycles (day 1 of each cycle).
The efficacy results from the pooled analysis of NSAPB B-31 and NCCTG 9831 at the time of the final analysis of DFS * are summarized in Table 7. Median duration of follow-up was 1.8 years for patients in the AC arm. → P and 2.0 years for patients in the AC → PH arm.
Table 7 Summary of efficacy results from the pooled analysis of NSABP B-31 and NCCTG 9831 at the time of the final analysis of DFS *
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab
* At the median duration of follow-up of 1.8 years for patients in the AC → P arm and 2.0 years for patients in the AC → PH arm.
** The p-value for OS did not exceed the predetermined statistical limit for the comparison AC → PH versus AC → P.
Relative to the "endpoint primary, DFS, adding Herceptin to paclitaxel chemotherapy resulted in a 52% reduction in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, in terms of disease-free survival rate at 3 years of 11.8% (87.2% versus 75.4%) in favor of the AC → PH (Herceptin) arm.
At the time of a safety update, after a median follow-up of 3.5-3.8 years, an "analysis of DFS reconfirmed the extent of the benefit shown in the final analysis of DFS. cross-over of Herceptin in the control arm, adding Herceptin to paclitaxel chemotherapy resulted in a 52% reduction in the risk of disease recurrence. Adding Herceptin to paclitaxel chemotherapy also resulted in a 37% reduction in disease recurrence. risk of death.
The pre-planned final OS analysis from the combined analysis of NSABP B-31 and NCCTG 9831 studies was conducted at the time of 707 deaths (median follow-up of 8.3 years in the AC → PH group) . Compared to that observed with the AC → P treatment, the AC → PH treatment resulted in a statistically significant improvement in OS (stratified HR = 0.64; 95% CI [0.55 - 0.74]; p-value log-rank
The final OS results from the pooled analysis of NSABP B-31 and NCCTG 9831 are summarized in Table 8 below.
Table 8 Final analysis of overall survival from the combined analysis of NSABP B-31 and NCCTG 9831
A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab
The DFS analysis was also conducted in the final OS analysis that emerged from the combined analysis of the NSABP B-31 and NCCTG N9831 studies. The updated results of the DFS analysis (stratified HR = 0.61; 95% CI [0.54 - 0.69]) showed a DFS benefit similar to that observed in the definitive primary analysis of DFS, despite 24.8% of patients in the AC → P arm crossover to treatment with Herceptin. A disease-free survival rate of 77.2% (95% CI: 75.4% - 79.1%) in the AC → PH arm was estimated at 8 years, with an absolute benefit of 11 , 8% compared to the AC → P arm.
In study BCIRG 006 Herceptin was administered in combination with docetaxel, after chemotherapy with AC (AC → DH) or in combination with docetaxel and carboplatin (DCarbH).
Docetaxel was administered as follows:
• intravenous docetaxel - 100 mg / m2 as a 1 hour intravenous infusion given every 3 weeks for 4 cycles (day 2 of the first docetaxel cycle, then day 1 of each subsequent cycle)
or
• intravenous docetaxel - 75 mg / m2 as a 1 hour intravenous infusion, given every 3 weeks for 6 cycles (day 2 of the first cycle, then day 1 of each subsequent cycle)
followed by:
• carboplatin - at target AUC = 6 mg / ml / min administered as an intravenous infusion lasting 30-60 minutes repeated every 3 weeks for a total of six cycles
Herceptin was given once weekly in combination with chemotherapy and every 3 weeks thereafter for a total of 52 weeks.
The efficacy results from study BCIRG 006 are summarized in Tables 9 and 10. The median duration of follow-up was 2.9 years in the AC → D arm and 3.0 years in each of the AC → DH and DCarbH arms.
Table 9 Summary of efficacy analyzes from study BCIRG 006 AC → D versus AC → DH
AC → D = doxorubicin in combination with cyclophosphamide, followed by docetaxel; AC → DH = doxorubicin in combination with cyclophosphamide, followed by docetaxel in combination with trastuzumab; CI = confidence interval.
Table 10 Summary of efficacy analyzes from study BCIRG 006 AC → D versus DCarbH
AC → D = doxorubicin in combination with cyclophosphamide, followed by docetaxel; DCarbH = docetaxel, carboplatin and trastuzumab; CI = confidence interval
In study BCIRG 006 regarding the "endpoint primary, DFS, the hazard ratio translates into an absolute benefit, in terms of 3-year disease-free survival, of 5.8 percentage points (86.7% versus 80.9%) in favor of the AC → DH arm (Herceptin) and 4.6 percentage points (85.5% versus 80.9%) in favor of the DCarbH (Herceptin) arm over AC → D.
In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the AC DH (AC TH) arm and 217/1073 in the AC → D (AC T) arm had a Karnofsky performance status ≤90 ( 80 or 90). No disease-free survival (DFS) benefit was observed in this subgroup of patients (hazard ratio = 1.16; 95% CI [0.73, 1.83] for the DCarbH (TCH) versus AC arm. D (AC T); hazard ratio 0.97; 95% CI [0.60, 1.55] for the AC DH (AC TH) versus AC D arm).
In addition, an analysis was conducted post-hoc exploratory data from the joint analysis (JA) of NSABP B-31 / NCCTG N9831 and clinical study BCIRG006, combining DFS and symptomatic cardiac events, as summarized in Table 11:
Table 11 Analysis post-hoc exploration of the results from the joint analysis (JA) of NSABP B-31 / NCCTG N9831 and clinical study BCIRG006, combining DFS and symptomatic cardiac events
A: doxurobicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel; Carb: carboplatin; H: trastuzumab
CI = confidence interval
* At the time of final DFS analysis. The median duration of follow-up was 1.8 years in the AC → P arm and 2.0 years in the AC → PH arm.
Early stage breast cancer (neoadjuvant-adjuvant context)
To date, no results are available comparing the efficacy of Herceptin administered with chemotherapy in the adjuvant setting versus the neoadjuvant / adjuvant setting.
In the context of neoadjuvant-adjuvant treatment, study MO16432, a multicenter, randomized clinical trial, was designed to evaluate the clinical efficacy of concomitant administration of Herceptin with neoadjuvant chemotherapy containing both an anthracycline and a taxane, followed by Herceptin as an adjuvant. up to a total of 1 year of treatment. The study enrolled patients with newly diagnosed locally advanced (stage III) or inflammatory EBC. Patients with HER2 + tumors were randomized to receive neoadjuvant chemotherapy concomitantly with neoadjuvant-adjuvant Herceptin or neoadjuvant chemotherapy alone.
In study MO16432, Herceptin (loading dose of 8 mg / kg, followed by 6 mg / kg in maintenance every 3 weeks) was administered concurrently with 10 courses of neoadjuvant chemotherapy as follows:
• Doxorubicin 60 mg / m2 and paclitaxel 150 mg / m2, administered every 3 weeks for 3 cycles,
followed by
• Paclitaxel 175 mg / m2 administered every 3 weeks for 4 cycles,
followed by
• CMF on day 1 and 8 every 4 weeks for 3 cycles,
followed after surgery by
• additional courses of adjuvant Herceptin (upon completion of 1 year of therapy).
The efficacy results from study MO16432 are summarized in Table 12. The median duration of follow-up in the Herceptin arm was 3.8 years.
Table 12 Efficacy results from study MO16432
* defined as the absence of invasive carcinoma in the breast and axillary lymph nodes
An absolute benefit of 13 percentage points in favor of the Herceptin arm in terms of 3-year event-free survival rate (65% versus 52%) was estimated.
Metastatic gastric cancer
Herceptin was studied in a randomized, open-label, phase III ToGA study (BO18255) in combination with chemotherapy versus chemotherapy alone.
Chemotherapy was administered as follows:
• capecitabine - 1000 mg / m2 orally twice daily for 14 days every 3 weeks for 6 cycles (evening of day 1 to morning of day 15 of each cycle)
or
• Intravenous 5-fluorouracil - 800 mg / m2 / day as a continuous intravenous infusion for 5 days, given every 3 weeks for 6 cycles (days 1 to 5 of each cycle)
Each of the two drugs was administered with:
• cisplatin - 80 mg / m2 every 3 weeks for 6 cycles, given on day 1 of each cycle.
The efficacy results from study BO18225 are summarized in Table 13:
Table 13 Efficacy results from study BO18225
FP + H: Fluoropyrimidine / Cisplatin + Herceptin
FP: fluoropyrimidine / cisplatin
a Odds ratio
Patients not previously treated for locally advanced or relapsed and / or metastatic inoperable HER2 positive adenocarcinoma of the stomach or gastroesophageal junction, not candidates for curative treatment, were enrolled in the study. L"endpoint primary was overall survival, defined as the time from the date of randomization to the date of death from any cause. At the time of analysis, a total of 349 randomized patients had died: 182 patients (62.8%) in the control arm and 167 patients (56.8%) in the treatment arm. Most deaths were due to events. related to the underlying tumor.
Post-hoc subgroup analysis indicates that positive treatment effects are limited to tumors with higher levels of HER2 protein (IHC 2 + / FISH + or IHC 3+). Median overall survival in the subgroup with high levels of HER2 overexpression was 11.8 months versus 16 months, HR 0.65 (95% CI 0.51-0.83) and progression-free survival was 5.5 months versus 7.6 months, HR 0.64 (95% CI 0.51-0.79) in the FP arm versus the FP + H arm, respectively. The HR for overall survival was 0.75 (95% CI 0.51-1.11) in the IHC2 + / FISH + and 0.58 (95% CI 0.41-0.81) in the IHC3 + / FISH + group.
In an exploratory subgroup analysis performed in the ToGA study (BO18255), there was no apparent overall survival benefit from adding Herceptin in patients with baseline ECOG PS 2 [HR 0.96 (95% CI 0 , 51-1.79)], non-measurable [HR 1.78 (95% CI 0.87-3.66)] and locally advanced [HR 1.20 (95% CI 0.29-4.97)] disease.
Pediatric population
The European Medicines Agency has lifted the obligation to submit the results of studies with Herceptin in all subsets in the pediatric population in gastric and breast cancer (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
The pharmacokinetics of trastuzumab were evaluated by population pharmacokinetic model analysis using pooled data from 1,582 subjects with HER2-positive MBC, EBC or advanced gastric cancer (AGC), or other cancers. , and healthy volunteers, in 18 phase I, II and III studies in which Herceptin was administered IV. A two-compartment model with parallel linear and non-linear elimination from the central compartment was used to describe the concentration / time profile. Due to non-linear elimination, total clearance increased with decreasing concentration. Therefore, no constant half-life value for trastuzumab can be deduced. t1 / 2 decreases with decreasing concentrations over a dose range (see Table 16). Patients with MBC and EBC had similar values of pharmacokinetic parameters [e.g. clearance (CL), volume of compartment to central (Vc) and the steady-state exposure predicted for the population (Cmin, Cmax and AUC)]. Linear clearance was 0.136 L / day for MBC, 0.112 L / day for EBC and 0.176 L / day for AGC. Non-linear elimination parameter values were 8.81 mg / day for the maximum elimination rate (Vmax) and 8.92 mcg / mL for the Michaelis-Menten constant (Km) for patients with MBC, EBC and AGC. The volume of the central compartment was 2.62 l for patients with MBC and EBC and 3.63 l for patients with AGC. In addition to the primary tumor form, the final population pharmacokinetic model identified body weight, serum aspartate aminotransferase and albumin as statistically covariates significant effects affecting trastuzumab exposure. However, the magnitude of the effect of these covariates on trastuzumab exposure suggested an unlikely clinically significant effect on trastuzumab concentrations.
The exposure values predicted from the population pharmacokinetics (median with 5th - 95th percentile) and the values of the pharmacokinetic parameters at clinically relevant concentrations (Cmax and Cmin) for patients with MBC, EBC and AGC treated by the dosing regimens approved q1w (weekly dosing) and q3w (every three weeks dosing) are shown in Table 14 (Cycle 1), Table 15 (steady state) and Table 16 (pharmacokinetic parameters).
Table 14 Population Predicted Exposure Pharmacokinetic Values at Cycle 1 (Median 5th - 95th Percentile) for Herceptin IV regimens in MBC, EBC and AGC patients
Table 15 Population Predicted Steady State Pharmacokinetic Exposure Values (5th - 95th Percentile) for Herceptin IV Regimens in MBC, EBC and AGC Patients
* Cmin, ss - Cmin at steady state
** Cmax, ss = Cmax at steady state
*** time at 90% of the steady state
Table 16 Population Predicted Pharmacokinetic Parameter Values at Steady State for IV Regimens of Herceptin in MBC, EBC, and AGC Patients
Trastuzumab washout
The washout period of trastuzumab was assessed following intravenous q1w or q3w administration using the population pharmacokinetic model. The results of these simulations indicate that at least 95% of patients will reach concentrations
Circulating soluble antigen
Exploratory analyzes of covariates with information for only one subgroup of patients suggested that subjects with higher levels of HER2-ECD soluble antigen (SHED) had faster non-linear clearance (lower Km) (p SGOT / AST; impact of soluble antigen on clearance is attributable to SGOT / AST levels.
There are no data on the level of circulating extracellular domain of the HER2 receptor (soluble antigen) in the serum of patients with gastric cancer.
05.3 Preclinical safety data
There was no evidence of single or repeated dose-related toxicity in studies of up to 6 months duration, nor of reproductive toxicity in studies of teratology, female fecundity or toxicity in the last period of gestation / placental passage. Herceptin is not genotoxic.A study of trehalose, one of the main excipients of the formulation, did not reveal any toxicity.
Long-term animal studies have not been performed to determine the carcinogenic potential of Herceptin, or to determine its effects on male fertility.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
L-histidine hydrochloride
L-histidine
a, a-trehalose dihydrate
polysorbate 20
06.2 Incompatibility
This medicinal product must not be mixed or diluted with other medicinal products other than those mentioned in section 6.6.
Do not dilute with glucose solutions as these cause aggregation of the protein.
06.3 Period of validity
4 years
After reconstitution with water for injections the reconstituted solution remains physically and chemically stable for 48 hours at 2 ° C to 8 ° C. Residues of the reconstituted solution must be discarded.
Herceptin solutions for infusion in polyvinyl chloride, polyethylene or polypropylene bags containing 9 mg / mL (0.9%) sodium chloride solution for injection remain physically and chemically stable for 24 hours at temperatures not exceeding 30 ° C.
From a microbiological point of view, the reconstituted solution and Herceptin infusion solution should be used immediately. The product should not be stored once reconstituted and diluted, unless this has been done under controlled and validated aseptic conditions. If the product is not used immediately, in-use storage times and conditions are the responsibility of the user.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C)
For storage conditions after first opening, see sections 6.3 and 6.6.
06.5 Nature of the immediate packaging and contents of the package
Herceptin vial:
One 15 mL type I clear glass vial with a fluorine-film laminated butyl rubber closure contains 150 mg of trastuzumab.
Each pack contains one vial.
06.6 Instructions for use and handling
Adhere to suitable aseptic techniques. Each vial of Herceptin is reconstituted with 7.2 mL of sterile water for injections (not supplied). Avoid the use of other solvents for reconstitution. This gives 7.4 mL of single-dose solution, containing approximately 21 mg / mL of trastuzumab, with a pH of approximately 6.0. A volume surplus of 4% guarantees the aspiration from the vial of the programmed dose of 150 mg.
Herceptin must be handled with care during the reconstitution procedure. Excessive foaming caused during reconstitution or shaking of the reconstituted solution can cause problems with the amount of Herceptin that can be withdrawn from the vial.
The reconstituted solution must not be frozen.
Instructions for reconstitution:
1) Using a sterile syringe, slowly inject 7.2 mL of water for injections into the vial containing the lyophilized Herceptin, directing the stream towards the lyophilized substance.
2) Swirl the vial slowly to facilitate reconstitution. DO NOT SHAKE!
Slight foaming during reconstitution is not unusual. Let the vial stand upright for approximately 5 minutes. Once reconstituted, Herceptin assumes the appearance of a clear, colorless to light yellow solution with no visible particles.
Determine the volume of the solution needed:
• based on a loading dose of 4 mg trastuzumab / kg body weight, or a subsequent weekly dose of 2 mg trastuzumab / kg body weight:
• based on a loading dose of 8 mg trastuzumab / kg body weight, or a subsequent dose of 6 mg trastuzumab / kg body weight every 3 weeks:
Withdraw the required amount of solution from the vial and add it to the infusion bag containing 250 mL of 0.9% sodium chloride solution. Do not use solutions containing glucose (see section 6.2). The bag should be carefully inverted to mix the solution to avoid foaming. Once prepared, the infusion should be administered immediately. If diluted according to aseptic methods, it can be stored for 24 hours (store below 30 ° C).
Solutions for parenteral administration should be visually inspected for any particles or discolouration prior to administration.
Herceptin is for single use only, as the product contains no preservatives. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
No incompatibilities were observed between Herceptin and polyvinyl chloride, polyethylene or polypropylene bags.
07.0 MARKETING AUTHORIZATION HOLDER
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/00/145/001
034949014
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 28 August 2000
Date of last renewal: 28 August 2010
10.0 DATE OF REVISION OF THE TEXT
September 2015
