- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Metastatic breast cancerHerceptin is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer: (MBC):- as monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease. Prior chemotherapy must have included at least an anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor positive patients must also have failed hormonal therapy, unless patients are unsuitable for these treatments.- in combination with paclitaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease and for whom an anthracycline is not suitable.- in combination with docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.- in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive MBC, not previously treated with trastuzumab.
Early breast cancerHerceptin is indicated for the treatment of adult patients with HER2 positive early breast cancer. (EBC).- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see section 5.1).- following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel.- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin. - in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin therapy, for locally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 4.4 and 5.1).Herceptin should only be used in patients with metastatic or early breast cancer whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay (see sections 4.4 and 5.1).
Metastatic gastric cancerHerceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.Herceptin should only be used in patients with metastatic gastric cancer (MGC) whose tumours have HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC 3+ result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1).
Metastatic breast cancer
Three-weekly scheduleThe recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
Weekly scheduleThe recommended initial loading dose of Herceptin is 4 mg/kg body weight. The recommended weekly maintenance dose of Herceptin is 2 mg/kg body weight, beginning one week after the loading dose.
Administration in combination with paclitaxel or docetaxelIn the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the first dose of Herceptin (for dose, see the Summary of Product Characteristics (SmPC) for paclitaxel or docetaxel) and immediately after the subsequent doses of Herceptin if the preceding dose of Herceptin was well tolerated.
Administration in combination with an aromatase inhibitorIn the pivotal trial (BO16216) Herceptin and anastrozole were administered from day 1. There were no restrictions on the relative timing of Herceptin and anastrozole at administration (for dose, see the SmPC for anastrozole or other aromatase inhibitors).
Early breast cancer
Three-weekly and weekly scheduleAs a three-weekly regimen the recommended initial loading dose of Herceptin is 8 mg/kg body weight. The recommended maintenance dose of Herceptin at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose. As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide. See section 5.1 for chemotherapy combination dosing.
Metastatic gastric cancer
Three-weekly scheduleThe recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.
Breast cancer and gastric cancer
Duration of treatmentPatients with MBC or MGC should be treated with Herceptin until progression of disease. Patients with EBC should be treated with Herceptin for 1 year or until disease recurrence, whichever occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).
Dose reductionNo reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time. Refer to the SmPC for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.If left ventricular ejection fraction (LVEF) drops ≥ 10 ejection fraction (EF) points from baseline AND to below 50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic congestive heart failure (CHF) has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.
Missed dosesIf the patient misses a dose of Herceptin by one week or less, then the usual maintenance dose (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be given as soon as possible. Do not wait until the next planned cycle. Subsequent maintenance doses (weekly regimen: 2 mg/ kg; three-weekly regimen: 6 mg/kg respectively) should then be given according to the previous schedule. If the patient misses a dose of Herceptin by more than one week, a re-loading dose of Herceptin should be given over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg). Subsequent Herceptin maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should then be given (weekly regimen: every week; three-weekly regimen every 3 weeks) from that point.
Special populationsDedicated pharmacokinetic studies in older people and those with renal or hepatic impairment have not been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.
Paediatric populationThere is no relevant use of Herceptin in the paediatric population.
Method of administrationHerceptin loading dose should be administered as a 90-minute intravenous infusion. Do not administer as an intravenous push or bolus. Herceptin intravenous infusion should be administered by a health-care provider prepared to manage anaphylaxis and an emergency kit should be available. Patients should be observed for at least six hours after the start of the first infusion and for two hours after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms (see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute infusion.For instructions on reconstitution of Herceptin intravenous formulation before administration, see section 6.6.
General considerationsPatients treated with Herceptin are at increased risk for developing CHF) (New York Heart Association [NYHA] class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy. These may be moderate to severe and have been associated with death (see section 4.8). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of <55%, older age.All candidates for treatment with Herceptin, but especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. A careful risk-benefit assessment should be made before deciding to treat with Herceptin. Because the half-life of trastuzumab is approximately 28 - 38 days trastuzumab may persist in the circulation for up to 27 weeks after stopping Herceptin treatment. Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping Herceptin. If anthracyclines are used, the patient's cardiac function should be monitored carefully.Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. In all patients cardiac function should be monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6 - 8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been seen. The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction has not been prospectively studied. If LVEF drops ≥10 ejection fraction (EF) points from baseline AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with standard medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy without additional clinical cardiac events.
Metastatic breast cancerHerceptin and anthracyclines should not be given concurrently in combination in the MBC setting. Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines.
Early breast cancerFor patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. In patients who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of Herceptin, or longer if a continuous decrease of LVEF is observed.Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, history of or existing CHF (NYHA II IV), LVEF of < 55%, other cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medical treatment eligible), and hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC pivotal trials with Herceptin and therefore treatment cannot be recommended in such patients.
Adjuvant treatmentHerceptin and anthracyclines should not be given concurrently in combination in the adjuvant treatment setting.In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when Herceptin was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when Herceptin was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of 5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events was observed in patients who were administered Herceptin concurrently with a taxane following anthracycline therapy up to 2.37% compared to approximately 1% in the two comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin and Herceptin).Risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low LVEF (<55%) at baseline, prior to or following the initiation of paclitaxel treatment, decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products. In patients receiving Herceptin after completion of adjuvant chemotherapy the risk of cardiac dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of Herceptin and a body mass index (BMI) >25 kg/m2.
Neoadjuvant-adjuvant treatmentIn patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin should be used concurrently 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 have been treated concurrently with a full course of low-dose anthracyclines and Herceptin in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In other situations, the decision on the need for additional cytotoxic chemotherapy is determined based on individual factors.Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited to two trials. Herceptin was administered concurrently with neoadjuvant chemotherapy that contained three to four cycles of an anthracycline (cumulative doxorubicin dose 180 mg/m2 or epirubicin dose 300 mg/m2). The incidence of symptomatic cardiac dysfunction was low in the Herceptin arms (up to 1.7 %). Clinical experience is limited in patients above 65 years of age.
Infusion-related reactions (IRRs) and hypersensitivitySerious IRRs to Herceptin infusion including dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be used to reduce risk of occurrence of these events. The majority of these events occur during or within 2.5 hours of the start of the first infusion. Should an infusion reaction occur the infusion should be discontinued or the rate of infusion 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 an antihistamine such as diphenhydramine. The majority of patients experienced resolution of symptoms and subsequently received further infusions of Herceptin. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction. Therefore, these patients should not be treated with Herceptin (see section 4.3).Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical deterioration have also been reported. Fatalities have occurred within hours and up to one week following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms and pulmonary symptoms more than six hours after the start of the Herceptin infusion. Patients should be warned of the possibility of such a late onset and should be instructed to contact their physician if these symptoms occur.
Pulmonary eventsSevere pulmonary events have been reported with the use of Herceptin in the post-marketing setting (see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Herceptin (see section 4.3). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.
Effect of trastuzumab on the pharmacokinetics of other antineoplastic agentsPharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC suggest that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) is not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV, respectively).However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite is unclear. Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg IV loading dose and 2 mg/kg IV weekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggest that concomitant administration of trastuzumab has no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The results of this small substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.
Effect of antineoplastic agents on trastuzumab pharmacokineticsBy comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy (4 mg/kg loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2- positive MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the pharmacokinetics of trastuzumab was found.Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which patients were treated concomitantly with Herceptin and paclitaxel and two Phase II studies in which Herceptin was administered as monotherapy (W016229 and MO16982), in women with HER2-positive MBC indicates that individual and mean Herceptin trough serum concentrations varied within and across studies but there was no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab.The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of trastuzumab.
Women of childbearing potentialWomen of childbearing potential should be advised to use effective contraception during treatment with Herceptin and for at least 7 months after treatment has concluded.
PregnancyReproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 2050 of gestation) and late (days 120150 of gestation) foetal development period was observed. It is not known whether Herceptin can affect reproductive capacity. As animal reproduction studies are not always predictive of human response, Herceptin should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. In the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving Herceptin. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Herceptin, close monitoring by a multidisciplinary team is desirable.
Breast-feedingA study conducted in lactating cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin intravenous formulation demonstrated that trastuzumab is secreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age. It is not known whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to the infant is unknown, women should not breast-feed during Herceptin therapy and for 7 months after the last dose.
FertilityThere is no fertility data available.
Summary of the safety profileAmongst the most serious and/or common adverse reactions reported in Herceptin usage (intravenous and subcutaneous formulations) to date are cardiac dysfunction, infusion-related reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions.
Tabulated list of adverse reactionsIn this section, the following categories of frequency have been used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.Presented in Table 1 are adverse reactions that have been reported in association with the use of intravenous Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting. All the terms included are based on the highest percentage seen in pivotal clinical trials.Table 1 Undesirable Effects Reported with Intravenous Herceptin Monotherapy or in Combination with Chemotherapy in Pivotal Clinical Trials (N = 8386) and in Post-Marketing
|System organ class||Adverse reaction||Frequency|
|Infections and infestations||Infection||Very common|
|Upper respiratory tract infection||Common|
|Urinary tract infection||Common|
|Neoplasms benign, malignant and unspecified (incl. Cysts and polyps)||Malignant neoplasm progression||Not known|
|Neoplasm progression||Not known|
|Blood and lymphatic system disorders||Febrile neutropenia||Very common|
|White blood cell count decreased/leukopenia||Very common|
|Immune system disorders||Hypersensitivity||Common|
|+Anaphylactic reaction||Not known|
|+Anaphylactic shock||Not known|
|Metabolism and nutrition disorders||Weight decreased/Weight loss||Very common|
|Psychiatric disorders||Insomnia||Very common|
|Nervous system disorders||1Tremor||Very common|
|Brain oedema||Not known|
|Eye disorders||Conjunctivitis||Very common|
|Lacrimation increased||Very common|
|Retinal haemorrhage||Not known|
|Ear and labyrinth disorders||Deafness||Uncommon|
|Cardiac disorders||1 Blood pressure decreased||Very common|
|1 Blood pressure increased||Very common|
|1 Heart beat irregular||Very common|
|1Cardiac flutter||Very common|
|Ejection fraction decreased*||Very common|
|+Cardiac failure (congestive)||Common|
|Cardiogenic shock||Not known|
|Gallop rhythm present||Not known|
|Vascular disorders||Hot flush||Very common|
|Respiratory, thoracic and mediastinal disorders||+1Wheezing||Very common|
|+Pulmonary fibrosis||Not known|
|+Respiratory distress||Not known|
|+Respiratory failure||Not known|
|+Lung infiltration||Not known|
|+Acute pulmonary oedema||Not known|
|+Acute respiratory distress syndrome||Not known|
|+Oxygen saturation decreased||Not known|
|Laryngeal oedema||Not known|
|Pulmonary oedema||Not known|
|Interstitial lung disease||Not known|
|Gastrointestinal disorders||Diarrhoea||Very common|
|1 Lip swelling||Very common|
|Abdominal pain||Very common|
|Hepatobiliary disorders||Hepatocellular injury||Common|
|Hepatic failure||Not known|
|Skin and subcutaneous tissue disorders||Erythema||Very common|
|1 Swelling face||Very common|
|Nail disorder||Very common|
|Palmar-plantar erythrodysaesthesia syndrome||Very common|
|Musculoskeletal and connective tissue disorders||Arthralgia||Very common|
|1Muscle tightness||Very common|
|Pain in extremity||Common|
|Renal and urinary disorders||Renal disorder||Common|
|Glomerulonephritis membranous||Not known|
|Renal failure||Not known|
|Pregnancy, puerperium and perinatal conditions||Oligohydramnios||Not known|
|Renal hypoplasia||Not known|
|Pulmonary hypoplasia||Not known|
|Reproductive system and breast disorders||Breast inflammation/mastitis||Common|
|General disorders and administration site conditions||Asthenia||Very common|
|Chest pain||Very common|
|Influenza-like symptoms||Very common|
|Infusion related reaction||Very common|
|Mucosal inflammation||Very common|
|Peripheral oedema||Very common|
|Injury, poisoning and procedural complications||Contusion||Common|
Description of selected adverse reactionsCardiac dysfunctionCongestive heart failure, NYHA 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 oedema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with Herceptin (see section 4.4). In 3 pivotal clinical trials of adjuvant Herceptin given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic Congestive Heart Failure) was similar in patients who were administered chemotherapy alone (ie did not receive Herceptin) and in patients who were administered Herceptin sequentially to a taxane (0.3-0.4 %). The rate was highest in patients who were administered Herceptin concurrently with a taxane (2.0 %). In the neoadjuvant setting, the experience of concurrent administration of Herceptin and low dose anthracycline regimen is limited (see section 4.4). When Herceptin was administered after completion of adjuvant chemotherapy NYHA class III-IV heart failure was observed in 0.6 % of patients in the one-year arm 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 III & IV) in the Herceptin 1 year treatment arm was 0.8 %, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6 %.Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 % after the event) was evident for 71.4 % of Herceptin-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5 % of patients. Approximately 17 % of cardiac dysfunction related events occurred after completion of Herceptin.In the pivotal metastatic trials of intravenous Herceptin, the incidence of cardiac dysfunction varied between 9 % and 12 % when it was combined with paclitaxel compared with 1 % 4 % for paclitaxel alone. For monotherapy, the rate was 6 % 9 %. The highest rate of cardiac dysfunction was seen in patients receiving Herceptin concurrently with anthracycline/cyclophosphamide (27 %), significantly higher than for anthracycline/cyclophosphamide alone (7 % 10 %). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2 % in patients receiving Herceptin and docetaxel, compared with 0 % in patients receiving docetaxel alone. Most of the patients (79 %) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF.
Infusion reactions, allergic-like reactions and hypersensitivityIt is estimated that approximately 40 % of patients who are treated with Herceptin will experience some form of infusion-related reaction. However, the majority of infusion-related reactions are mild to moderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e. during infusions one, two and three and lessen in frequency in subsequent infusions. 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 grades varied between studies depending on the indication, the data collection methodology, and whether trastuzumab was given concurrently with chemotherapy or as monotherapy.Severe anaphylactic reactions requiring immediate additional intervention can occur usually during either the first or second infusion of Herceptin (see section 4.4) and have been associated with a fatal outcome. Anaphylactoid reactions have been observed in isolated cases.
HaematotoxicityFebrile neutropenia occurred very commonly. Commonly occurring adverse reactions included anaemia, leukopenia, thrombocytopenia and neutropenia. The frequency of occurrence of hypoprothrombinemia is not known. The risk of neutropenia may be slightly increased when trastuzumab is administered with docetaxel following anthracycline therapy.
Pulmonary eventsSevere 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, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency (see section 4.4).Details of risk minimisation measures that are consistent with the EU Risk Management Plan are presented in (section 4.4) Warnings and Precautions. Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and vice versaStudy MO22982 investigated switching between the Herceptin intravenous and Herceptin subcutaneous formulation with a primary objective to evaluate patient preference for either intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using subcutaneous formulation in vial and one using subcutaneous formulation in administration system) were investigated using a 2-arm , cross-over design with 488 patients being randomized to one of two different three-weekly Herceptin treatment sequences (IV [Cycles 1-4]→ SC [Cycles 5-8], or SC [Cycles 1-4]→ IV [Cycles 5-8]). Patients were either naïve to Herceptin IV treatment (20.3%) or pre-exposed to Herceptin IV (79.7%). For the sequence IV→SC (SC vial and SC formulation in administration system cohorts combined), AE rates (all grades) were described pre-switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8% vs. 56.4%, respectively; for the sequence SC→IV (SC vial and SC formulation in administration system cohorts combined), AE rates (all grades) were described pre- and post-switching as 65.4% vs. 48.7%, respectively. Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment discontinuations due to adverse events were low (<5%) and similar to post-switching rates (Cycles 5-8). No grade 4 or grade 5 adverse events were reported.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).Malta ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal IrelandHPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.iee-mail: email@example.comUnited KingdomYellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard
Mechanism of actionTrastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2's extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
Detection of HER2 overexpression or HER2 gene amplification
Detection of HER2 overexpression or HER2 gene amplification in breast cancerHerceptin should only be used in patients whose tumours have HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. HER2 overexpression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section 4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Herceptin treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive FISH or CISH result. To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, which can ensure validation of the testing procedures.The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:Table 2 Recommended Scoring System to Evaluate the IHC Staining Patterns in Breast Cancer
|Score||Staining pattern||HER2 overexpression assessment|
|0||No staining is observed or membrane staining is observed in < 10 % of the tumour cells||Negative|
|1+||A faint/barely perceptible membrane staining is detected in > 10 % of the tumour cells. The cells are only stained in part of their membrane.||Negative|
|2+||A weak to moderate complete membrane staining is detected in > 10 % of the tumour cells.||Equivocal|
|3+||Strong complete membrane staining is detected in > 10 % of the tumour cells.||Positive|
Detection of HER2 over expression or HER2 gene amplification in gastric cancerOnly an accurate and validated assay should be used to detect HER2 over expression or HER2 gene amplification. IHC is recommended as the first testing modality and in cases where HER2 gene amplification status is also required, either a silver-enhanced in situ hybridization (SISH) or a FISH technique must be applied. SISH technology is however, recommended to allow for the parallel evaluation of tumor histology and morphology. To ensure validation of testing procedures and the generation of accurate and reproducible results, HER2 testing must be performed in a laboratory staffed by trained personnel. Full instructions on assay performance and results interpretation should be taken from the product information leaflet provided with the HER2 testing assays used.In the ToGA (BO18255) trial, patients whose tumours were either IHC3+ or FISH positive were defined as HER2 positive and thus included in the trial. Based on the clinical trial results, the beneficial effects were limited to patients with the highest level of HER2 protein overexpression, defined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result. In a method comparison study (study D008548) a high degree of concordance (>95 %) was observed for SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients.HER2 over expression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks; HER2 gene amplification should be detected using in situ hybridisation using either SISH or FISH on fixed tumour blocks. The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3:Table 3 Recommended Scoring System to Evaluate the IHC Staining Patterns in Gastric Cancer
|Score||Surgical specimen - staining pattern||Biopsy specimen staining pattern||HER2 overexpression assessment|
|0||No reactivity or membranous reactivity in < 10 % of tumour cells||No reactivity or membranous reactivity in any tumour cell||Negative|
|1+||Faint ⁄ barely perceptible membranous reactivity in ≥ 10 % of tumour cells; cells are reactive only in part of their membrane||Tumour cell cluster with a faint ⁄ barely perceptible membranous reactivity irrespective of percentage of tumour cells stained||Negative|
|2+||Weak to moderate complete, basolateral or lateral membranous reactivity in ≥ 10 % of tumour cells||Tumour cell cluster with a weak to moderate complete, basolateral or lateral membranous reactivity irrespective of percentage of tumour cells stained||Equivocal|
|3+||Strong complete, basolateral or lateral membranous reactivity in ≥ 10 % of tumour cells||Tumour cell cluster with a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumour cells stained||Positive|
Clinical efficacy and safety
Metastatic breast cancerHerceptin has been used in clinical trials as monotherapy for patients with MBC who have tumours that overexpress HER2 and who have failed one or more chemotherapy regimens for their metastatic disease (Herceptin alone).Herceptin has also been used in combination with paclitaxel or docetaxel for the treatment of patients who have not received chemotherapy for their metastatic disease. Patients who had previously received anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m2 infused over 3 hours) with or without Herceptin. In the pivotal trial of docetaxel (100 mg/m2 infused over 1 hour) with or without Herceptin, 60 % of the patients had received prior anthracycline-based adjuvant chemotherapy. Patients were treated with Herceptin until progression of disease.The efficacy of Herceptin in combination with paclitaxel in patients who did not receive prior adjuvant anthracyclines has not been studied. However, Herceptin plus docetaxel was efficacious in patients whether or not they had received prior adjuvant anthracyclines.The test method for HER2 overexpression used to determine eligibility of patients in the pivotal Herceptin monotherapy and Herceptin plus paclitaxel clinical trials employed immunohistochemical staining for HER2 of fixed material from breast tumours using the murine monoclonal antibodies CB11 and 4D5. These tissues were fixed in formalin or Bouin's fixative. This investigative clinical trial assay performed in a central laboratory utilised a 0 to 3+ scale. Patients classified as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded. Greater than 70 % of patients enrolled exhibited 3+ overexpression. The data suggest that beneficial effects were greater among those patients with higher levels of overexpression of HER2 (3+).The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or without Herceptin, was immunohistochemistry. A minority of patients was tested using fluorescence in-situ hybridisation (FISH). In this trial, 87 % of patients entered had disease that was IHC3+, and 95 % of patients entered had disease that was IHC3+ and/or FISH-positive.
Weekly dosing in metastatic breast cancerThe efficacy results from the monotherapy and combination therapy studies are summarised in Table 4:Table 4 Efficacy Results from the Monotherapy and Combination Therapy Studies
|Herceptin1N=172||Herceptin plus paclitaxel2N=68||Paclitaxel2N=77||Herceptin plus docetaxel3N=92||Docetaxel3N=94|
|Response rate (95 %CI)||18 % (13 - 25)||49 % (36 - 61)||17 % (9 - 27)||61 % (50-71)||34 % (25-45)|
|Median duration of response (months) (95 %CI)||9.1 (5.6-10.3)||8.3 (7.3-8.8)||4.6 (3.7-7.4)||11.7 (9.3 15.0)||5.7 (4.6-7.6)|
|Median TTP (months) (95 %CI)||3.2 (2.6-3.5)||7.1 (6.2-12.0)||3.0 (2.0-4.4)||11.7 (9.2-13.5)||6.1 (5.4-7.2)|
|Median Survival (months) (95 %CI)||16.4 (12.3-ne)||24.8 (18.6-33.7)||17.9 (11.2-23.8)||31.2 (27.3-40.8)||22.74 (19.1-30.8)|
Combination treatment with Herceptin and anastrozoleHerceptin has been studied in combination with anastrozole for first line treatment of MBC in HER2 overexpressing, hormone-receptor (i.e. estrogen-receptor (ER) and/or progesterone-receptor (PR)) positive postmenopausal patients. Progression free survival was doubled in the Herceptin plus anastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the other parameters the improvements seen for the combination were for overall response (16.5 % versus 6.7 %); clinical benefit rate (42.7 % versus 27.9 %); time to progression (4.8 months versus 2.4 months). For time to response and duration of response no difference could be recorded between the arms. The median overall survival was extended by 4.6 months for patients in the combination arm. The difference was not statistically significant, however more than half of the patients in the anastrozole alone arm crossed over to a Herceptin containing regimen after progression of disease.
Three -weekly dosing in metastatic breast cancerThe efficacy results from the non-comparative monotherapy and combination therapy studies are summarised in Table 5:Table 5 Efficacy Results from the Non-Comparative Monotherapy and Combination Therapy Studies
|Herceptin1N=105||Herceptin2N=72||Herceptin plus paclitaxel3N=32||Herceptin plus docetaxel4N=110|
|Response rate (95 %CI)||24 % (15 - 35)||27 % (14 - 43)||59 % (41-76)||73 % (63-81)|
|Median duration of response (months) (range)||10.1 (2.8-35.6)||7.9 (2.1-18.8)||10.5 (1.8-21)||13.4 (2.1-55.1)|
|Median TTP (months) (95 %CI)||3.4 (2.8-4.1)||7.7 (4.2-8.3)||12.2 (6.2-ne)||13.6 (11-16)|
|Median Survival (months) (95 %CI)||ne||ne||ne||47.3 (32-ne)|
Sites of progressionThe frequency of progression in the liver was significantly reduced in patients treated with the combination of Herceptin and paclitaxel, compared to paclitaxel alone (21.8 % versus 45.7 %; p=0.004). More patients treated with Herceptin and paclitaxel progressed in the central nervous system than those treated with paclitaxel alone (12.6 % versus 6.5 %; p=0.377).
Early breast cancer (adjuvant setting)Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast.In the adjuvant setting, Herceptin was investigated in 4 large multicentre, randomised, trials. - Study BO16348 was designed to compare one and two years of three-weekly Herceptin treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable). In addition, comparison of two years versus one year Herceptin treatment was performed. Patients assigned to receive Herceptin were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg every three weeks for either one or two years.- The NSABP B-31 and NCCTG N9831 studies that comprise the joint analysis were designed to investigate the clinical utility of combining Herceptin treatment with paclitaxel following AC chemotherapy, additionally the NCCTG N9831 study also investigated adding Herceptin sequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery.- The BCIRG 006 study was designed to investigate combining Herceptin treatment with docetaxel either following AC chemotherapy or in combination with docetaxel and carboplatin in patients with HER2 positive EBC following surgery.Early breast cancer in the HERA trial was limited to operable, primary, invasive adenocarcinoma of the breast, with axillary nodes positive or axillary nodes negative if tumors at least 1 cm in diameter. In the joint analysis of the NSABP B-31 and NCCTG N9831 studies, EBC was limited to women with operable breast cancer at high risk, defined as HER2-positive and axillary lymph node positive or HER2 positive and lymph node negative with high risk features (tumor size > 1 cm and ER negative or tumor size > 2 cm, regardless of hormonal status). In the BCIRG 006 study HER2 positive, EBC was defined as either lymph node positive or high risk node negative patients with no (pN0) lymph node involvement, and at least 1 of the following factors: tumour size greater than 2 cm, estrogen receptor and progesterone receptor negative, histological and/or nuclear grade 2-3, or age < 35 years).The efficacy results from the BO16348 trial following 12 months* and 8 years** median follow-up are summarized in Table 6:Table 6 Efficacy Results from Study BO16348
|Median follow-up 12 months*||Median follow-up 8 years**|
|Parameter||Observation N=1693||Herceptin 1 Year N = 1693||Observation N= 1697***||Herceptin 1 Year N = 1702***|
|- No. patients with event||219 (12.9 %)||127 (7.5 %)||570 (33.6 %)||471 (27.7 %)|
|- No. patients without event||1474 (87.1 %)||1566 (92.5 %)||1127 (66.4 %)||1231 (72.3 %)|
|P-value versus Observation||< 0.0001||< 0.0001|
|Hazard Ratio versus Observation||0.54||0.76|
|- No. patients with event||208 (12.3 %)||113 (6.7 %)||506 (29.8 %)||399 (23.4 %)|
|- No. patients without event||1485 (87.7 %)||1580 (93.3 %)||1191 (70.2 %)||1303 (76.6 %)|
|P-value versus Observation||< 0.0001||< 0.0001|
|Hazard Ratio versus Observation||0.51||0.73|
|Distant disease-free survival|
|- No. patients with event||184 (10.9 %)||99 (5.8 %)||488 (28.8 %)||399 (23.4 %)|
|- No. patients without event||1508 (89.1 %)||1594 (94.6 %)||1209 (71.2 %)||1303 (76.6 %)|
|P-value versus Observation||< 0.0001||< 0.0001|
|Hazard Ratio versus Observation||0.50||0.76|
|Overall survival (death)|
|- No. patients with event||40 (2.4 %)||31 (1.8 %)||350 (20.6 %)||278 (16.3 %)|
|- No. patients without event||1653 (97.6 %)||1662 (98.2 %)||1347 (79.4 %)||1424 (83.7 %)|
|P-value versus Observation||0.24||0.0005|
|Hazard Ratio versus Observation||0.75||0.76|
|Parameter||AC→P (n=1679)||AC→PH (n=1672)||Hazard Ratio vs AC→P (95% CI) p-value|
|Disease-free survival No. patients with event (%)||261 (15.5)||133 (8.0)||0.48 (0.39, 0.59) p<0.0001|
|Distant Recurrence No. patients with event||193 (11.5)||96 (5.7)||0.47 (0.37, 0.60) p<0.0001|
|Death (OS event): No. patients with event||92 (5.5)||62 (3.7)||0.67 (0.48, 0.92) p=0.014**|
|Parameter||AC→P(N=2032)||AC→PH(N=2031)||p-value versusAC→P||Hazard Ratio versus AC→P(95% CI)|
|Death (OS event):No. patients with event (%)||418 (20.6%)||289 (14.2%)||< 0.0001||0.64(0.55, 0.74)|
|Parameter||AC→D (n=1073)||AC→DH (n=1074)||Hazard Ratio vs AC→D (95 % CI) p-value|
|Disease-free survival No. patients with event||195||134||0.61 (0.49, 0.77) p<0.0001|
|Distant recurrenceNo. patients with event||144||95||0.59 (0.46, 0.77) p<0.0001|
|Death (OS event)No. patients with event||80||49||0.58 (0.40, 0.83) p=0.0024|
|Parameter||AC→D (n=1073)||DCarbH (n=1074)||Hazard Ratio vs AC→D (95 % CI)|
|Disease-free survival No. patients with event||195||145||0.67 (0.54, 0.83) p=0.0003|
|Distant recurrence No. patients with event||144||103||0.65 (0.50, 0.84) p=0.0008|
|Death (OS event) No. patients with event||80||56||0.66 (0.47, 0.93) p=0.0182|
|AC→PH (vs. AC→P) (NSABP B-31 and NCCTG N9831)*||AC→DH (vs. AC→D) (BCIRG 006)||DCarbH (vs. AC→D) (BCIRG 006)|
|Primary efficacy analysis DFS Hazard ratios (95 % CI) p-value||0.48 (0.39, 0.59) p<0.0001||0.61 (0.49, 0.77) p< 0.0001||0.67 (0.54, 0.83) p=0.0003|
|Post-hoc exploratory analysis with DFS and symptomatic cardiac events Hazard ratios (95 % CI)|
0.64 (0.53, 0.77)
0.70 (0.57, 0.87)
0.71 (0.57, 0.87)
Early breast cancer (neoadjuvant-adjuvant setting)So far, no results are available which compare the efficacy of Herceptin administered with chemotherapy in the adjuvant setting with that obtained in the neo-adjuvant/adjuvant setting. In the neoadjuvant-adjuvant setting, study MO16432, a multicentre randomised trial, was designed to investigate the clinical efficacy of concurrent administration of Herceptin with neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant Herceptin, up to a total treatment duration of 1 year. The study recruited patients with newly diagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours were randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant Herceptin, or neoadjuvant chemotherapy alone.In study MO16432, Herceptin (8 mg/kg loading dose, followed by 6 mg/kg maintenance every 3 weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapyas follows:• Doxorubicin 60mg/m2 and paclitaxel 150 mg/m2, administered 3-weekly for 3 cycles,which was followed by• Paclitaxel 175 mg/m2 administered 3-weekly for 4 cycles,which was followed by• CMF on day 1 and 8 every 4 weeks for 3 cycleswhich was followed after surgery by• additional cycles of adjuvant Herceptin (to complete 1 year of treatment)The efficacy results from 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 MO16432
|Parameter||Chemo + Herceptin (n=115)||Chemo only (n=116)|
|Event-free survival||Hazard Ratio (95% CI)|
|No. patients with event||46||59||0.65 (0.44, 0.96) p=0.0275|
|Total pathological complete response* (95 % CI)||40 % (31.0, 49.6)||20.7 % (13.7, 29.2)||P=0.0014|
|Overall survival||Hazard Ratio (95 % CI)|
|No. patients with event||22||33||0.59 (0.35, 1.02) p=0.0555|
Metastatic gastric cancerHerceptin has been investigated in one randomised, open-label phase III trial ToGA (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 over 5 days, given every 3 weeks for 6 cycles (days 1 to 5 of each cycle) Either of which was administered with:- cisplatin - 80 mg/m2 every 3 weeks for 6 cycles on day 1 of each cycle.The efficacy results from study BO18225 are summarized in Table 13: Table 13 Efficacy Results from BO18225
|Parameter||FPN = 290||FP +HN = 294||HR (95 % CI)||p-value|
|Overall Survival, Median months||11.1||13.8||0.74 (0.60-0.91)||0.0046|
|Progression-Free Survival, Median months||5.5||6.7||0.71 (0.59-0.85)||0.0002|
|Time to Disease Progression, Median months||5.6||7.1||0.70 (0.58-0.85)||0.0003|
|Overall Response Rate, %||34.5 %||47.3 %||1.70a (1.22, 2.38)||0.0017|
|Duration of Response, Median months||4.8||6.9||0.54 (0.40-0.73)||< 0.0001|
Immunogenicity903 breast cancer patients treated with Herceptin, alone or in combination with chemotherapy, have been evaluated for antibody production. Human anti-trastuzumab antibodies were detected in one patient, who had no allergic manifestations.There are no immunogenicity data available for Herceptin in gastric cancer.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Herceptin in all subsets of the paediatric population in breast and gastric cancer (see section 4.2 for information on paediatric use).
Breast cancerShort duration intravenous infusions of 10, 50, 100, 250, and 500 mg trastuzumab once weekly in patients demonstrated non-linear pharmacokinetics where clearance decreased with increasing dose.
Half-lifeThe elimination half-life is of 28-38 days and subsequently the washout period is up to 27 weeks (190 days or 5 elimination half-lives).
Steady State pharmacokineticsSteady state should be reached by approximately 27 weeks. In a population pharmacokinetic (two compartment, model-dependent) assessment of Phase I, II and III clinical trials in metastatic breast cancer, the median predicted AUC at steady state over a three-week period was three times 578 mgday/l (1677 mgday/l) with 3 weekly doses of 2 mg/kg and 1793 mg day/l with one every three week dose of 6 mg/kg; the estimated median peak concentrations were 104 mg/l and 189 mg/l and the trough concentrations were 64.9 mg/l and 47.3 mg/l, respectively. Early breast cancer patients administered an initial loading dose of 8 mg/kg followed by a three weekly maintenance dose of 6 mg/kg for 1 year, achieved steady state mean Cmax of 225 µg/mL and mean Cmin of 68.9 µg/mL at day 21 of cycle 18, the last cycle of treatment for 1 year of treatment. These concentrations were comparable to those reported previously in patients with metastatic breast cancer
Clearance (CL)The typical trastuzumab clearance (for a body weight of 68 kg) was 0.241 l/day.The effects of patient characteristics (such as age or serum creatinine) on the disposition of trastuzumab have been evaluated. The data suggest that the disposition of trastuzumab is not altered in any of these groups of patients (see section 4.2), however, studies were not specifically designed to investigate the impact of renal impairment upon pharmacokinetics.
Volume of distributionIn all clinical studies, the volume of distribution of the central (Vc) and the peripheral (Vp) compartment was 3.02 l and 2.68 l, respectively, in the typical patient.
Circulating shed antigenDetectable concentrations of the circulating extracellular domain of the HER2 receptor (shed antigen) are found in the serum of some patients with HER2 overexpressing breast cancers. Determination of shed antigen in baseline serum samples revealed that 64 % (286/447) of patients had detectable shed antigen, which ranged as high as 1880 ng/mL (median = 11 ng/mL). Patients with higher baseline shed antigen levels were more likely to have lower serum trough concentrations of trastuzumab. However, with weekly dosing, most patients with elevated shed antigen levels achieved target serum concentrations of trastuzumab by week 6 and no significant relationship has been observed between baseline shed antigen and clinical response.
Advanced Gastric Cancer
Steady state pharmacokineticsA two compartment nonlinear population pharmacokinetic model, based on data from Phase III study BO18255, was used to estimate the steady state pharmacokinetics in patients with advanced gastric cancer administered trastuzumab at a loading dose of 8 mg/kg followed by a 3-weekly maintenance dose of 6 mg/kg. The observed serum levels of trastuzumab were lower and thus total clearance was estimated to be higher in AGC patients compared to breast cancer patients receiving the same dosing regimen. The reason for this is unknown. At high concentrations, total clearance is dominated by linear clearance, and the half-life in AGC patients is approximately 26 days. The median predicted steady-state AUC values (over a period of 3 weeks at steady state) is equal to 1213 mg•day/L, the median steady-state Cmax is equal to 132 mg/l and the median steady-state Cmin values is equal to 27.6 mg/L.There are no data on the level of circulating extracellular domain of the HER2 receptor (shed antigen) in the serum of gastric cancer patients.
Herceptin vial:One 15 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film containing 150 mg of trastuzumab.Each carton contains one vial.
Instructions for reconstitution:1) Using a sterile syringe, slowly inject 7.2 mL of water for injections in the vial containing the lyophilised Herceptin, directing the stream into the lyophilised cake.2) Swirl the vial gently to aid reconstitution. DO NOT SHAKE!Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The reconstituted Herceptin results in a colourless to pale yellow transparent solution and should be essentially free of visible particulates.Determine the volume of the solution required:• 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 3-weekly dose of 6 mg trastuzumab/kg body weight: The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 250 mL of 0.9 % sodium chloride solution. Do not use with glucose-containing solutions (see section 6.2). The bag should be gently inverted to mix the solution in order to avoid foaming. Once the infusion is prepared it should be administered immediately. If diluted aseptically, it may be stored for 24 hours (do not store above 30°C).Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration.Herceptin is for single-use only, as the product contains no preservatives. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. No incompatibilities between Herceptin and polyvinylchloride, polyethylene or polypropylene bags have been observed.
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