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4.4     Special warnings and precautions for use

[...]

Pulmonary events

Severe 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 lungpulmonary 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.
[...]
 

4.6     Fertility, pregnancy and lactation

Pregnancy

Reproduction 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 and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 20–50 of gestation) and late (days 120–150 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 of childbearing potential should be advised to use effective contraception during treatment with Herceptin and for at least 6 months after treatment has concluded. 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.

Lactation

A study conducted in lactating cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin 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 6 months after the last dose.

Underlined text has been added, text with strike through deleted:

4.1      Therapeutic indications

Breast Cancer

Metastatic Breast Cancer (MBC)

Herceptin is indicated for the treatment of patients with HER2 positive metastatic breast cancer:

-           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 metastatic breast cancer, not previously treated with trastuzumab.

Early Breast Cancer (EBC)

Herceptin is indicated for the treatment of patients with HER2 positive early breast cancer.

-           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 Cancer (MGC)

Herceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of 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 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).

4.2      Posology and method of administration

[…]

Breast Cancer (MBC and EBC) and Gastric Cancer (MGC)

Duration of treatment

Patients with MBC or MGC should be treated with Herceptin until progression of disease. Patients with EBC should be treated with Herceptin for 1 year (18 cycles three-weekly) or until disease recurrence, whatever occurs first.

[…]

4.4      Special warnings and precautions for use

HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 5.1).

Currently no data from clinical trials are available on re-treatment of patients with previous exposure to Herceptin in the adjuvant setting.

Cardiotoxicity

General considerations

Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. This may be moderate to severe and has been associated with death (see section 4.8).

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, ECG, echocardiogram, or MUGA scan or magnetic resonance imaging. A careful risk-benefit assessment should be made before deciding to treat with Herceptin. 

Herceptin and anthracyclines should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines.  Because the half-life of Herceptin is approximately 4-5 weeks Herceptin may persist in the circulation for up to 20-25 weeks after stopping Herceptin treatment. Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 25 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. For patients with early breast cancer, 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 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. Caution should be exercised in treating patients with symptomatic heart failure, a history of hypertension or documented coronary artery disease, and in early breast cancer, in those patients with a left ventricular ejection fraction (LVEF) of 55 % or less.

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, 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 medications for this purpose. Discontinuation of Herceptin therapy should be strongly considered in patients who develop clinically significant heart failure unless the benefits for an individual patient are deemed to outweigh the risks.

The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has not been prospectively studied. However, most patients who developed heart failure in the pivotal (H0648g, H0649g, M77001, BO16216, BO16348, BO18255, NSABP B31, NCCTG N9831, BCIRG 006, MO16432) trials improved with standard medical treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin‑converting enzyme inhibitors. 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 cancer

Herceptin and anthracyclines should not be given concurrently in combination in the metastatic breast cancer setting.

Patients with metastatic breast cancer who have previously received anthracyclines are also at risk of cardiotoxicity with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines.

Early breast cancer (EBC)

For patients with early breast cancer, 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.

- aAdjuvant treatment

Herceptin 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).

In EBC, the following patients were excluded from the HERA trial, there are no data about the benefit-risk balance, and therefore treatment can not be recommended in such patients:

·          History of documented congestive heart failure

·          High-risk uncontrolled arrhythmias

·          Angina pectoris requiring a medicinal product

·          Clinically significant valvular disease

·          Evidence of transmural infarction on ECG

·          Poorly controlled hypertension

Early breast cancer (EBC) - nNeoadjuvant-adjuvant treatment

In patients with early breast cancer eligible for neoadjuvant-adjuvant treatment, Herceptin should only be used concurrently with anthracyclines in chemotherapy-naive patients and only with low-dose anthracycline regimens (maximum cumulative doses: doxorubicin 180 mg/m² or epirubicin 360 mg/m²).

If patients have been treated concurrently with low-dose anthracyclines and Herceptin in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery.

The following patients were excluded from the NOAH trial in the neoadjuvant-adjuvant setting and this treatment is not recommended for such patients:

• New York Heart Association (NYHA) class greater or equal II heart disease
• Left ventricular ejection fraction (LVEF) of <55% by MUGA scan or echocardiography
• History of documented congestive cardiac failure, angina pectoris requiring antianginal medication, evidence of transmural infarction on ECG, poorly controlled hypertension (e.g. systolic > 180 mm Hg or diastolic >100 mm Hg), clinically significant valvular heart disease, or high-risk uncontrolled arrhythmias.

Only few patients in the NOAH trial were > 65 years of age. Therefore, clinical experience in this age group is limited, and therefore neoadjuvant-adjuvant  treatment is not recommended for patients older than 65 years.

Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited. In the NOAH trial, Herceptin was administered concurrently with neoadjuvant chemotherapy that contained three cycles of neoadjuvant doxorubin (cumulative doxorubicin dose 180 mg/m²). The incidence of symptomatic cardiac dysfunction was low in the Herceptin arm (2 of 115 patients, 1.7%). Both events occurred during the 1-year treatment course with Herceptin, one event occurred prior to surgery in the neoadjuvant part of the study, and one post surgery. With respect to asymptomatic cardiac dysfunction, in the neoadjuvant part of the study, 4patients in the Herceptin arm (versus one in the HER2+ control arm and nonein the HER2- observational group) had a decline in LVEF of  ³ 10% points to an LVEF of < 50%, and in one of these patients (none in theHER2+ control arm) LVEF declined to < 45%. In the postoperative part of the study, 4 additional patientsin the Herceptin arm had a decline in LVEF of  ³ 10% points to an LVEF of < 50%, versus none

Only few patients in the NOAH trial were > 65 years of age. Therefore, clinical experience in this age group is limited, and therefore neoadjuvant-adjuvant treatment is not recommended for patients older than 65 years.

Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. Cardiac function should be further monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. For early breast cancer patients, cardiac assessment, as performed at baseline, should be repeated every 3 months during treatment every 6 months following discontinuation of treatment until 24 months from the last administration. In patients who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration, or longer if a continuous decrease of LVEF is observed. 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. Caution should be exercised in treating patients with symptomatic heart failure, a history of hypertension or documented coronary artery disease, and in early breast cancer, in those patients with a left ventricular ejection fraction (LVEF) of 55 % or less.

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, 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 the standard medications for this purpose. Discontinuation of Herceptin therapy should be strongly considered in patients who develop clinically significant heart failure unless the benefits for an individual patient are deemed to outweigh the risks.

The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has not been prospectively studied. However, most patients who developed heart failure in the pivotal (H0648g, H0649g, M77001, BO16216, BO16348, BO18255, NSABP B-31, NCCTG N9831, BCIRG 006) trials improved with standard medical treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin‑converting enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy without additional clinical cardiac events.

Infusion reactions, allergic-like reactions and hypersensitivity

Serious adverse reactions to Herceptin infusion that have been reported infrequently include dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema (see section 4.8). 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). 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 events

Severe 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 pulmonary 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.

4.8      Undesirable Effects

Amongst the most serious and/or common adverse reactions reported in Herceptin usage to date are cardiotoxicity, infusion-related reactions, haematotoxicity (in particular neutropenia) and pulmonary adverse events.

In this section, the following categories of frequency have been used: very common (³1/10), common (³1/100 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 should be presented in order of decreasing seriousness.

List of adverse reactions

Presented in the following table are adverse reactions that have been reported in association with the use of Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting. Pivotal trials included:

-           H0648g and H0649g: Herceptin as a monotherapy or in combination with paclitaxel in metastatic -breast cancer.

-           M77001: Docetaxel, with or without Herceptin in metastatic breast cancer.

-           BO16216: Anastrozole with or without Herceptin in HER2 positive and hormone receptor positive metastatic breast cancer.

-           BO16348: Herceptin as a monotherapy following adjuvant chemotherapy in HER2 positive breast cancer.

-           BO18255: Herceptin in combination with a fluoropyrimidine and cisplatin versus chemotherapy alone as first-line therapy in HER2 positive advanced gastric cancer.

-           B-31, N9831: Herceptin administered sequential to adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel.

-           BCIRG 006: Herceptin administered sequential to adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with docetaxel or Herceptin administered in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

-           MO16432: Herceptin administered concurrently in combination with  the neoadjuvant regimen of doxorubicin plus paclitaxel, paclitaxel and cyclophosphamide plus methotrexate plus 5-fluorouracil, followed by postoperative adjuvant Herceptin monotherapy.

All the terms included are based on the highest percentage seen in pivotal clinical trials.

+ Denotes  adverse reactionsthat have been reported in association with a fatal outcome.

1 Denotes  adverse reactionsthat are reported largely in association with Infusion-related reactions. Specific percentages for these are not available.

* Observed with combination therapy following anthracyclines and combined with taxanes

Note: Specific percentage frequencies have been provided in brackets for terms that have been reported in association with a fatal outcome with the frequency designation ‘common’ or ‘very common’. The specific percentage frequencies relate to total number of these events, both fatal and non-fatal.

The following adverse reactionswere reported in pivotal clinical trials with a frequency of  ³ 1/10 in either treatment arm (in HERA, BO16348 ³ 1% at 1 year) and with no significant difference between the Herceptin-containing arm and the comparator arm:  lethargy, hypoaesthesia, pain in extremity, oropharyngeal pain, conjunctivitis, lymphoedema, weight increased, nail toxicity, musculoskeletal pain, pharyngitis, bronchitis, chest discomfort, abdominal pain upper, gastritis, stomatitis, vertigo, hot flush, hypertension, hiccups, palmar-plantar erythrodysaesthesia syndrome, breast pain, onychorrhexis, dyspnoea exertional and dysuria.

Description of selected adverse reactions

Cardiotoxicity

Cardiotoxicity (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).

In 3 pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (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%).

The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has not been prospectively studied. However, most patients who developed heart failure in the pivotal  trials (H0648g, H0649g, M77001, BO16216, BO16348, BO18255, B-31, N9831, BCIRG 006, MO16432) improved with standard medical treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin‑converting enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy with Herceptin without additional clinical cardiac events (for information on identification of risk factors and management see section 4.4).
In the neoadjuvant setting, the experience of concurrent administration of Herceptin and low dose anthracycline regimen is limited.

Infusion reactions, allergic-like reactions and hypersensitivity

It 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, but are not limited to, chills, fever, rash, nausea and vomiting, dyspnoea and headache (see section 4.4).

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.

Haematotoxicity

Febrile neutropenia occured 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 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, 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.

5.1      Pharmacodynamic properties

[…]

Neoadjuvant-adjuvant treatment

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 efficacyutility 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 early breast cancer. 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 chemotherapy

as 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 cycles

which was followed after surgery by

·     additional cycles of adjuvant Herceptin (to complete 1 year of treatment)

The efficacy results from MO16432 are summarized in the table below. The median duration of follow-up in the Herceptin arm was 3.8 years.

* defined as absence of any invasive cancer both in the breast and axillary nodes

An absolute benefit of 13 percentage points in favour of the Herceptin arm was estimated in terms of 3-year event-free survival rate (65 % vs. 52 %).

[…]

Underlined text has been added, text with strike through deleted:

5.2      Pharmacokinetic properties

The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer, and early breast cancer and from a population PK analysis of data from advanced gastric cancer patients. Short 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. Formal drug-drug interaction studies have not been performed with Herceptin.

Breast Cancer

Short 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-life

The elimination half-life is of 28-38 days and subsequently the washout period is up to 27 25 weeks (190 175 days or 5 elimination half-lives).

Steady State pharmacokinetics

Steady state should be reached by approximately 25 weeks (175 days or 5 elimination half-lives). 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 mg•day/l (1677 mg•day/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. In patients with early breast cancer administered Herceptin at a loading dose of 8 mg/kg followed every three weeks by 6 mg/kg, using model-independent or non-compartmental analyses (NCA) the mean steady state trough concentration measured at cycle 13 (week 37) was 63 mg/l,  which was comparable to that reported previously in patients with metastatic breast cancer receiving the weekly regimen.

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 distribution

In all clinical studies, the volume of distribution of the central (V_c) and the peripheral (V_p) compartment was 3.02 l and 2.68 l, respectively, in the typical patient.

Circulating shed antigen

Detectable 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 pharmacokinetics in advanced gastric cancer

Short duration intravenous infusions of 8 mg/kg followed by 6 mg/kg trastuzumab every 3 weeks in patients with advanced gastric cancer demonstrated concentration-dependent clearance comprised of predominantly linear and non-linear components at high (>75 µg/mL) and low (<25 µg/mL) serum concentrations, respectively.

A two compartment nonlinear population pharmacokinetic modelmethod, using based on data from the Phase III study BO18255, was used to estimate the steady state pharmacokinetics in patients with advanced gastric cancer administered trastuzumab 3-weekly 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. In this assessmentAt high concentrations, total clearance is dominated by linear clearance, and the half-life in AGC patients is approximately the typical clearance of trastuzumab was 0.378 l/day and the typical volume of distribution in the central compartment was 3.91 l, with a corresponding median elimination half-life of 14.5 days26 days. The median predicted steady-state AUC values (over a period of 3 weeks at steady state) is equal to 1213 1030 mg·day/lL, the median steady-state C_max is equal to 128 132 mg/l and the median steady-state C_min values is equal to 27.6 23 mg/lL.

There are no data on the level of circulating extracellular domain of the HER2 receptor (shed antigen) in the serum of gastric cancer patients.

Underlined text has been added, text with strike through deleted:

4.1     Therapeutic indications

[…]

Early Breast Cancer (EBC)

Herceptin is indicated for the treatment of patients with HER2 positive early breast cancer: following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see section 5.1).

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.

[…]

4.2     Posology and method of administration

[…]

EBC

Three-weekly and weekly  schedule

In the adjuvant setting as investigated in the BO16348 (HERA) trial, Herceptin was initiated after completion of standard chemotherapy (most commonly, anthracycline-containing regimens or anthracyclines plus a taxane).

As a three-weekly regimen tThe 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).

Weekly schedule

In the adjuvant setting Herceptin was also investigated as a weekly regimen (loading dose of 4 mg/kg followed by 2 mg/kg every week for one year) concomitantly with paclitaxel (administered weekly (80 mg/m2) or every 3 weeks (175 mg/m2) for a total of 12 weeks) following 4 cycles of AC (doxorubicin 60 mg/m2 IV push concurrently with cyclophosphamide 600 mg/m2 over 20–30 minutes).

MGC

Three-weekly schedule

The 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 (MBC and EBC) and Gastric Cancer (MGC)

Duration of treatment

Patients with MBC or MGC should be treated with Herceptin until progression of disease. Patients with EBC should be treated with Herceptin for 1 year (18 cycles three-weekly) or until disease recurrence, whatever occurs first..

[…]

4.4     Special warnings and precautions for use

[…]

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. The cumulative incidence did not increase after 3 years. (see below) In one of the 3 pivotal studies conducted in which a median follow-up of 5.5 years was available (BCIRG006; median follow‑up of 5.5 years) 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).

In EBC, the following patients were excluded from the HERA trial, there are no data about the benefit-risk balance, and therefore treatment can not be recommended in such patients:

·       History of documented congestive heart failure

·       High-risk uncontrolled arrhythmias

·       Angina pectoris requiring a medicinal product

·       Clinically significant valvular disease

·       Evidence of transmural infarction on ECG

·       Poorly controlled hypertension

Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. Cardiac function should be further monitored during treatment (e.g. every  12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. For early breast cancer patients, cardiac assessment, 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. In patients who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur  yearly up to 5 years from the last administration, or longer if a continuous decrease of LVEF is observed at 6, 12 and 24 months following cessation of treatment. 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. Caution should be exercised in treating patients with symptomatic heart failure, a history of hypertension or documented coronary artery disease, and in early breast cancer, in those patients with a left ventricular ejection fraction (LVEF) of 55 % or less.

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, 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 the standard medications for this purpose. Discontinuation of Herceptin therapy should be strongly considered in patients who develop clinically significant heart failure unless the benefits for an individual patient are deemed to outweigh the risks.

The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has not been prospectively studied. However, most patients who developed heart failure in the pivotal (H0648g, H0649g, M77001, BO16216, BO16348, BO18255, NSABP B31, NCCTG N9831, BCIRG 006) trials improved with standard medical treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin‑converting enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy without additional clinical cardiac events.

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4.8     Undesirable Effects

[…]

List of adverse reactions

Presented in the following table are adverse reactions that have been reported in association with the use of Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting. Pivotal trials included:

-        H0648g and H0649g: Herceptin as a monotherapy or in combination with paclitaxel in metastatic -breast cancer.

-        M77001: Docetaxel, with or without Herceptin in metastatic breast cancer.

-        BO16216: Anastrozole with or without Herceptin in HER2 positive and hormone receptor positive metastatic breast cancer.

-        BO16348: Herceptin as a monotherapy following adjuvant chemotherapy in HER2 positive breast cancer.

-        BO18255: Herceptin in combination with a fluoropyrimidine and cisplatin versus chemotherapy alone as first-line therapy in HER2 positive advanced gastric cancer.

-        B-31, N9831: , BCIRG 006: Herceptin  administered sequential to adjuvant chemotherapy with       doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel and Herceptin administered in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

-        BCIRG 006: Herceptin administered sequential to adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with docetaxel or Herceptin administered in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

[…]

Cardiotoxicity

Cardiotoxicity (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).

In 3 pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (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%).

The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has not been prospectively studied. However, most patients who developed heart failure in the pivotal  trials (H0648g, H0649g, M77001, BO16216, BO16348, BO18255, B31, N9831, BCIRG 006) improved with standard medical treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin‑converting enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy with Herceptin without additional clinical cardiac events (for information on identification of risk factors and management see section 4.4).

[…]

Haematotoxicity

Febrile neutropenia occured 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.

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5.1     Pharmacodynamic properties

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EBC

Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast. 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 tumours at least 1 cm in diameter.

In the adjuvant setting, Herceptin was investigated in 4 largea multicentre, randomised, trials:  (HERA)

-        The HERA study was designed to compare one year of three-weekly Herceptin treatment versus observation in patients with HER2 positive early breast cancer following surgery, established chemotherapy and radiotherapy (if applicable). Patients assigned to receive Herceptin were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg every three weeks for one year.

-        The NCCTG N9831 and NSABP B31 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 early breast cancer 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 early breast cancer 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 NCCTG N9831 and NSAPB B31 studies, early breast cancer 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, early breast cancer 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 HERA trial are summarized in the following table:

Study BO16348 (HERA): 12 months follow-up

For the primary endpoint, DFS, the hazard ratio translates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentage points (85.8 % vs 78.2 %) in favour of the Herceptin arm.

In the NCCTG N9831 and NSAPB B31 studies Herceptin was administered in combination with paclitaxel, following AC chemotherapy.

Doxorubicin and cyclophosphamide were administered concurrently as follows:

-      intravenous push doxorubicin, at 60 mg/ m², given every 3 weeks for 4 cycles.

          -      intravenous cyclophosphamide, at 600 mg/ m2 over 30 minutes, given every 3 weeks for 4                cycles.

Paclitaxel, in combination with Herceptin, was administered as follows:

-      intravenous paclitaxel - 80 mg/m² as a continuous i.v. infusion,  given  every  week for 12 weeks.

or

-      intravenous paclitaxel - 175 mg/m² as a continuous i.v. infusion, given every 3 weeks for 4 cycles (day 1 of each cycle).

The efficacy results from the joint analysis of the NCCTG 9831 and NSABP B-31  trials are summarized in the table below. The median duration of follow up was 1.8 years for the patients in the AC→P arm and 2.0 years fror patients in the AC→PH arm.  

A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab

For the primary endpoint, DFS, the addition of Herceptin to paclitaxel chemotherapy resulted in a 52% decrease in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, in terms of 3-year disease-free survival rate estimates of 11.8 percentage points (87.2 % vs 75.4 %) in favour of the AC→PH (Herceptin) arm.

At the time of a safety update after a median of 3.5-3.8 years follow up, an analysis of DFS reconfirms the magnitude of the benefit shown in the definitive analysis of DFS. Despite the cross-over to Herceptin in the control arm, the addition of Herceptin to paclitaxel chemotherapy resulted in a 52% decrease in the risk of disease recurrence. The addition of Herceptin to paclitaxel chemotherapy also resulted in a 37% decrease in the risk of death.

In the BCIRG 006 study Herceptin was administered either in combination with docetaxel, following AC chemotherapy  (AC→DH) or in combination with docetaxel and carboplatin (DCarbH).

Docetaxel was administered as follows:

-      intravenous docetaxel - 100 mg/m² as an i.v. infusion over 1 hour,  given  every  3 weeks for  4 cycles (day 2 of first docetaxel cycle, then day 1 of each subsequent cycle)

or

-      intravenous docetaxel - 75 mg/m² as an i.v. infusion over 1 hour, given every 3 weeks for  6 cycles (day 2 of cycle 1, then day 1 of each subsequent cycle)

which was followed by:

-      carboplatin – at target AUC = 6 mg/mL/min administered by IV infusion over 30-60 minutes repeated every 3 weeks for a  total of six cycles

Herceptin was administered weekly with chemotherapy and 3 weekly thereafter for a total of 52 weeks.

The efficacy results from the BCIRG 006 are summarized in the tables below. 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.

Overview of Efficacy Analyses BCIRG 006  AC→D versus AC→DH

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; AC→DH = doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab; CI = confidence interval

Overview of Efficacy Analyses BCIRG 006  AC→D versus DCarbH

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; DCarbH = docetaxel, carboplatin and trastuzumab; CI = confidence interval

In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolute benefit, in terms of 3-year disease-free survival rate estimates of 5.8 percentage points (86.7 % vs 80.9 %) in favour of the AC→DH (Herceptin) arm and 4.6 percentage points (85.5 % vs 80.9 %) in favour of the DCarbH (Herceptin) arm compared to 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 (either 80 or 90). No disease-free survival (DFS) benefit was noticed in this subgroup of patients (hazard ratio = 1.16, 95% CI [0.73, 1.83] for DCarbH (TCH) vs AC®D (AC®T); hazard ratio 0.97, 95% CI [0.60, 1.55] for AC®DH (AC®TH) vs AC®D).

In addition a post-hoc exploratory analysis was performed on the data sets from the joint analysis (JA) NSABP B-31/NCCTG N9831 and BCIRG006 clinical studies combining DFS events and symptomatic cardiac events and summarised in the following table:

A: doxorubicin; C: cyclophosphamide; P: paclitaxel; D: docetaxel; Carb: carboplatin; H: trastuzumab

CI = confidence interval

Pulmonary events

Severe 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 pulmonary 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.

Text underlined has been added, text with strike through deleted:

4.4     Special warnings and precautions for use

HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 5.1).

Currently no data from clinical trials are available on re-treatment of patients with previous exposure to Herceptin in the adjuvant setting.

Cardiotoxicity

Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. This may be moderate to severe and has been associated with death (see section 4.8).

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, ECG, echocardiogram, or MUGA scan or magnetic resonance imaging. A careful risk-benefit assessment should be made before deciding to treat with Herceptin. 

Herceptin and anthracyclines should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines.  Because the half-life of Herceptin is approximately 3-44-5 weeks Herceptin may persist in the circulation for 20up to 254 weeks after stopping Herceptin treatment. Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 254 weeks after stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored carefully (see below).

4.6     Fertility, pregnancy and lactation

Pregnancy

Reproduction 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 and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 20–50 of gestation) and late (days 120–150 of gestation) foetal development period was observed. It is not known whether Herceptin can cause foetal harm when administered to a pregnant woman or whether it 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 oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus,  have been reported in pregnant women receiving Herceptin. Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin and for at least 6 months after treatment has concluded. 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.

5.2     Pharmacokinetic properties

The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer and early breast cancer. Short 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‑dependent pharmacokinetics. . Formal drug-dDrug interaction studies have not been performed with Herceptin.

Breast Cancer

Half-life

The half-life is approximately 28.5 days (95 % confidence interval, 25.5 –32.8 days). The washout period is up to 24 weeks (95 % confidence interval, 18-24 weeks)

Steady State

Breast Cancer

Half life

The elimination half-life is of 28-38 days and subsequently the washout period is up to 25 weeks (175 days or 5 elimination half-lives).

Steady state pharmacokinetics

Steady state should be reached by approximately 250 weeks (95 % confidence interval, 18 – 24 weeks175 days or 5 elimination half-lives ). In a population pharmacokinetic (two compartment, model-dependent) assessment of Phase I, II, II and IIII clinical trials in metastatic breast cancer, the estimated meanmedian predicted AUC (over a 1-week periodat steady state over a three-week period) was three times 578 mg•day/l ( was 5781677 mg• day/l) with 3 weekly doses  and 1793 mg day/l with one every three week dose;  the estimated meanmedian peak andconcentrations were 104 mg/l and 189 mg/l and the  trough concentrations were 11064.9 mg/l and 6647.3 mg/l, respectively. In patients with early breast cancer administered Herceptin at a loading dose of 8 mg/kg followed every three weeks by 6 mg/kg, using model-independent or non-compartmental analyses (NCA) the mean steady state trough concentrations measured at cycle 13 (week 37) wasof 63 mg/l, were achieved by cycle 13 (week 37).  The concentrations were which was comparable to thatthose reported previously in patients with metastatic breast cancer receiving the weekly regimen.

Clearance(CL)

Clearance decreased with increased dose level. In clinical trials where a loading dose of 4 mg/kgThe typical  trastuzumab followed by a subsequent weekly dose of 2 mg/kg was used, the mean clearance (for a body weight of 68 kg) was  0.225241 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 dDistribution

In all clinical studies, the volume of distribution of the central (V_c) and the peripheral (V_p) compartment wasapproximated serum volume , 2.953.02 l and 2.68 l, respectively, in the typical patient.

4.1     Therapeutic indications

Metastatic Gastric Cancer (MGC)

Herceptin Iin combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of 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 whose tumours have HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH+ result, or by an IHC 3+ result,. as determined by an aAccurate and validated assay methods should be used (see sections 4.4 and 5.1).

5.1     Pharmacodynamic properties

The recommended scoring system to evaluate the IHC staining patterns is as follows:

Detection of HER2 overexpression or HER2 gene amplification in gastric cancer

Only 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, aneither a silver-enhanced in situ hybridization (SISH) or a FISHISH technique has to must be applied. A bright-field technology  for ISH SISH technology is however, recommended to be able to evaluateallow for the parallel evaluation of tumor histology and morphology in parallel. 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 ISH 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 e.g.using either SISH or FISH or SISH on fixed tumour blocks.