Herceptin 150mg Powder for concentrate for solution for infusion

  • Name:

    Herceptin 150mg Powder for concentrate for solution for infusion

  • Company:
    info
  • Active Ingredients:

    Trastuzumab

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 01/08/19

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Summary of Product Characteristics last updated on medicines.ie: 1/8/2019

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1 - 0 of 34 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 1 August 2019 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to side-effects

Updated on 1 August 2019 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Legal category: Product subject to medical prescription which may not be renewed (A)

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EU SPC and PIL EMEA/H/C/PSUSA/00003010/201809.

Update to the Herceptin CDS (version 19) is required to reflect Tumour Lysis Syndrome (TLS) in the product labelling.

Updated on 25 March 2019 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change to information for healthcare professionals

Updated on 25 March 2019 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

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Extension of the shelf life of the finished product (Herceptin IV) after dilution or reconstitution with respect to physical and chemical stability supported by real time data- up to 30 days at 2˚C - 8˚C and 24 hours at room temperature ≤30˚C) for Herceptin solution for infusion reconstituted product.

Updated on 28 August 2018 PIL

Reasons for updating

  • Change to section 5 - how to store or dispose
  • Change to section 6 - date of revision

Updated on 28 August 2018 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 14 August 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change to other sources of information section

Updated on 17 May 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 26 April 2018 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

 

 

 

 

 

 

 

 

Updated on 26 April 2018 PIL

Reasons for updating

  • Change to section 2 - driving and using machines
  • Change to section 6 - date of revision

Updated on 16 April 2018 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 30 November 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 30 November 2017 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.8     Undesirable effects

[....]​​​​

Removal of : Pancreatitis

​​

10.     DATE OF REVISION OF THE TEXT

​​

27 October 2017

​​

​​

Updated on 21 November 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 21 November 2017 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 14 March 2017 SmPC

Reasons for updating

  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

6.       PHARMACEUTICAL PARTICULARS

 

6.1     List of excipients

 

L‑histidine hydrochloride monohydrate

L‑histidine

a,a‑trehalose dihydrate

polysorbate 20

 

Updated on 13 March 2017 PIL

Reasons for updating

  • Change to section 6 - what the product contains
  • Change to section 6 - date of revision

Updated on 12 October 2016 SmPC

Reasons for updating

  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.9       Overdose

 

There is no experience with overdose in human clinical trials. Single doses of Herceptin alone greater than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of 10 mg/kg q3w following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic gastric cancer patients. Doses up to this level were well tolerated.

 

 

5.2     Pharmacokinetic properties

 

[...]

Circulating shed HER2 ECDantigen

The exploratory analyses of covariates with information in only a subset of patients suggested that patients with greater shed HER2-ECD antigen (SHED) level had faster nonlinear clearance (lower Km) (P < 0.001). There was a correlation between shed antigen and SGOT/AST levels; part of the impact of shed antigen on clearance may have been explained by SGOT/AST levels.

 

Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBC and EBC patients and no apparent impact on trastuzumab clearance was observed. There are no data on the level of circulating extracellular domain of the HER2 receptor (shed antigen) in the serum of gastric cancer patients.

 

10.     DATE OF REVISION OF THE TEXT

 

15 September 2016

 

 

 

 

 

Updated on 29 March 2016 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

[....]

 

For a the full list of excipients, (see section 6.1).

 

 

4.2     Posology and method of administration

 

[....]

Special populations

Dedicated pharmacokinetic studies in the elderly 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.

 

[....]

4.8     Undesirable effects

 

[....]

Haematotoxicity

Febrile neutropenia, and leukopenia, anaemia, thrombocytopenia and neutropenia occurred very commonly. Commonly occurring adverse reactions included anaemia, 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.

 

[....]

5.1     Pharmacodynamic properties

 

[....]

 

Table 11 Post-Hoc Exploratory Analysis Results from the Joint Analysis NSABP B-31/NCCTG N9831* and BCIRG006 Clinical Studies Combining DFS Events and Symptomatic Cardiac Events

 

 

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

Long term follow-up efficacy analysis**

DFS Hazard ratios

(95 % CI)

p-value

 

 

0.61

(0.54, 0.69)

p<0.0001

 

 

0.72

(0.61, 0.85)

p<0.0001

 

 

0.77

(0.65, 0.90)

p=0.0011

Post-hoc exploratory analysis with DFS and symptomatic cardiac events

Long term follow-up**

Hazard ratios

(95 % CI)

 

 

 

0.674

(0.6053, 0.757)

 

 

 

0.770

(0.6657, 0.9087)

 

 

 

0.771

(0.6657, 0.9087)

 

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

CI = confidence interval

* At the time of the definitive analysis of DFS. Median duration of follow up was 1.8 years in the AC→P arm and 2.0 years in the AC→PH arm

** Median duration of long term follow-up for the Joint Analysis clinical studies was 8.3 years (range: 0.1 to 12.1) for the AC→PH armgroup group and 7.9 years (range: 0.0 to 12.2) for the AC→P grouparm;   Median duration of long term follow‑up for the BCIRG 006 study was 10.3 years in both the AC→D arm (range:  0.0 to 12.6 years) arm and the DCarbH arm (range:  0.0 to 13.1 years) arm, and was 10.4 years (range: 0.0 to 12.7) in the AC→DH (range:  0.0‑12.7 years) arm

 

[....]


Updated on 23 March 2016 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 23 October 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



4.2     Posology and method of administration

[....]
 

If left ventricular ejection fraction (LVEF) percentage 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 has declined further, or if 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.

[....]

4.4     Special warnings and precautions for use

 

In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

[....]

The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction has not been prospectively studied. If LVEF percentage 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.

[....]

Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited to two trials (MO16432 and BO22227).

 

In the pivotal trial MO16432, Herceptin was administered concurrently with neoadjuvant chemotherapy containing that contained three to four cycles of doxorubicin an anthracycline (cumulative doxorubicin dose 180 mg/m2 )or epirubicin dose 300  mg/m2).

 

The incidence of symptomatic cardiac dysfunction was 1.7% low in the Herceptin arms (up to 1. 7 %).

 

The pivotal trial BO22227 was designed to demonstrate non-inferiority of treatment with Herceptin subcutaneous formulation versus treatment with Herceptin intravenous formulation based on co-primary PK and efficacy endpoints (trastuzumab Ctrough at pre-dose Cycle 8, and pCR rate at definitive surgery, respectively) (See Section 5.1. of Herceptin subcutaneous formulation SmPC).  In the pivotal trial BO22227, Herceptin was administered concurrently with neoadjuvant chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a median follow-up of 40 months, the incidence of congestive cardiac failure was 0.0% in the Herceptin intravenous arm.

[....]

4.8     Undesirable effects

 

[....]

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 afterto 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 Cclass 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 Class 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 %.

[....]

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 %), and was 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.

[....]

Immunogenicity

 

In the neoadjuvant-adjuvant EBC treatment setting, 8.1 % (24/296) of patients treated with Herceptin intravenous developed antibodies against trastuzumab (regardless of antibody presence at baseline). Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 24 Herceptin intravenous patients.

 

The clinical relevance of these antibodies is not known; nevertheless the pharmacokinetics, efficacy (determined by pathological Complete Response [pCR]) and safety determined by occurrence of administration related reactions (ARRs) of Herceptin intravenous did not appear to be adversely affected by these antibodies.

 

There are no immunogenicity data available for Herceptin in gastric cancer.

[....]

Study 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 IVSC (SC vial and SC formulation in administration system cohorts combined), adverse eventAE 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 SCIV (SC vial and SC formulation in administration system cohorts combined), adverse eventAE 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.

[....]

5.1     Pharmacodynamic properties

 

[....]

Early breast cancer (adjuvant setting)

 

Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast.

In the adjuvant treatment 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 of Herceptin treatment versus one year of 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.

[....]

In the neoadjuvant-adjuvant treatment setting, study MO16432 [....]

The efficacy results from Study MO16432 are summarized in Table 12. The median duration of follow-up in the Herceptin arm was 3.8 years.

 

[....]

10.     DATE OF REVISION OF THE TEXT

 

24 September 2015

 

 

 




 

 













Updated on 21 August 2015 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company


4.8     Undesirable effects

 

[...]


System organ class

Adverse reaction

Frequency

Infections and infestations

Infection

Very common

Nasopharyngitis

Very common

Neutropenic sepsis

Common

Cystitis

Common

Herpes zoster

Common

Influenza

Common

Sinusitis

Common

Skin infection

Common

Rhinitis

Common

Upper respiratory tract infection

Common

Urinary tract infection

Common

Erysipelas

Common

Cellulitis

Common

Pharyngitis

Common

Sepsis

Uncommon

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

Anaemia

Very common

Neutropenia

Very common

White blood cell count decreased/leukopenia

Very common

Thrombocytopenia

Very common

Hypoprothrombinaemia

Not known

Immune thrombocytopenia

Not known

Immune system disorders

Hypersensitivity

Common


[...]


Haematotoxicity

Febrile neutropenia and leukopenia 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.


[...]

 

10.     DATE OF REVISION OF THE TEXT

 

09 July 2015

 



Updated on 20 August 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision

Updated on 27 May 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.2     Posology and method of administration

[...]

Missed doses

If the patient has misseds 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 administeredgiven 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 administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively. given according to the previous schedule.

 

If the patient has misseds a dose of Herceptin by more than one week, a re-loading dose of Herceptin should be administeredgiven over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg) as soon as possible. Subsequent Herceptin maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should then be administered 7 days or 21 days later according to the weekly or three-weekly schedules respectivelygiven (weekly regimen: every week; three-weekly regimen every 3 weeks) from that point.

[...]

4.4     Special warnings and precautions for use

 

[...]

TrastuzumabBecause the  half-life of trastuzumab is approximately 28 - 38 days trastuzumab may persist in the circulation for up to 27 monthsweeks after stopping Herceptin treatment based on population pharmacokinetic analysis of all available data (see section 5.2). 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 monthsweeks after stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.

[...]

4.5       Interaction with other medicinal products and other forms of interaction

 

No formal drug interaction studies have been performed. Clinically significant interactions between Herceptin and with the concomitant medicinal productsation used in clinical trials have not been observed based on the results of a population PK analysis (HO407g, HO551g, HO649g, and HO648g).

 

Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents

 

Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) wais 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 wais unclear. 

 

Data from study JP16003, a single-arm study of Herceptintrastuzumab (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, suggested that concomitant administration of Herceptintrastuzumab hads 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 Herceptintrastuzumab. 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 Herceptintrastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with Herceptintrastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus Herceptintrastuzumab.

 

Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin. Data from Study BO16216 in HER2-positive metastatic breast cancer patients showed that concomitant administration of Herceptin had no effect on the PK of anastrazole.

 

Effect of antineoplastic agents on trastuzumab pharmacokinetics

 

By comparison of simulated serum trastuzumab concentrations after Herceptintrastuzumab 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 trastuzumabHerceptin 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. Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with Herceptin, paclitaxel and doxorubicin to trastuzumab PK data in studies where Herceptin was administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab.

 

Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the PK of trastuzumab.

 

The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of trastuzumab.

 

4.6     Fertility, pregnancy and lactation

 

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin and for at least 7 months after treatment has concluded (see section 5.2).

[...]
 

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, or if a patient becomes pregnant while receiving Herceptin or within 7 months following the last dose of Herceptin, close monitoring by a multidisciplinary team is desirable.

[...]

4.8     Undesirable effects

 

[spacing issues corrected]

5.2     Pharmacokinetic properties

 

The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer, early breast cancer and advanced gastric cancer patients. 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 weeks (190 days or 5 elimination half-lives).

 

Steady State pharmacokinetics

Steady 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 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.

 

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 distribution

In 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.

The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or other tumor types, and healthy volunteers, in 18 Phase I, II and III trials receiving Herceptin IV. A two-compartment model with parallel linear and non-linear elimination from the central compartment described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 16). MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC.  The non‑linear elimination parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 µg/mL for the Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC.  In the final population PK model, in addition to primary tumor type, body-weight, serum aspartate aminotransferase and albumin were identified as a statistically significant covariates affecting the exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab exposure suggests that these covariates are unlikely to have a clinically meaningful effect on trastuzumab concentrations.

 

The population predicted PK exposure values (median with 5th - 95th Percentiles) and PK parameter values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated with the approved q1w and q3w dosing regimens are shown in Table 14 (Cycle 1), Table 15 (steady-state), and Table 16 (PK parameters).

 

Table 114 Population Predicted Cycle 1 PK Exposure Values (median with 5th - 95th Percentiles) for Herceptin IV Dosing Regimens in MBC, EBC and AGC Patients

Regimen

Primary tumor type

N

Cmin

(µg/mL)

Cmax

(µg/mL)

AUC0-21days

(µg.day/mL)

8mg/kg +
6mg/kg q3w

MBC

805

28.7
(2.9 - 46.3)

182
(134 - 280)

1376
(728 - 1998)

EBC

390

30.9
(18.7 - 45.5)

176
(127 - 227)

1390
(1039 - 1895)

AGC

274

23.1
(6.1 - 50.3)

132
(84.2 – 225)

1109
(588 – 1938)

4mg/kg +
2mg/kg qw

MBC

805

37.4
(8.7 - 58.9)

76.5
(49.4 - 114)

1073
(597 – 1584)

EBC

390

38.9
(25.3 - 58.8)

76.0
(54.7 - 104)

1074
(783 - 1502)

 

Table 15 Population Predicted Steady State PK Exposure Values (median with 5th - 95th Percentiles) for Herceptin IV Dosing Regimens in MBC, EBC and AGC Patients

Regimen

Primary tumor type

N

Cmin,ss*

(µg/mL)

Cmax,ss**

(µg/mL)

AUCss, 0-21days

(µg.day/mL)

Time to

steady-state***

(week)

8mg/kg +
6mg/kg q3w

MBC

805

44.2
(1.8 - 85.4)

179
(123 - 266)

1736
(618 - 2756)

12

EBC

390

53.8
(28.7 - 85.8)

184
(134 - 247)

1927
(1332 -2771)

15

AGC

274

32.9
(6.1 – 88.9)

131
(72.5 -251)

1338
(557 - 2875)

9

4mg/kg +
2mg/kg qw

MBC

805

63.1
(11.7 - 107)

107
(54.2 - 164)

1710
(581 - 2715)

12

EBC

390

72.6
(46 - 109)

115
(82.6 - 160)

1893
(1309 -2734)

14

*Cmin,ss Cmin at steady state

**Cmax,ss = Cmax at steady state

*** time to 90% of steady-state

 

Table 16 Population Predicted PK Parameter Values at Steady State for Herceptin IV Dosing Regimens in MBC, EBC and AGC Patients

 

Regimen

Primary tumor type

N

Total CL range from Cmax,ss to Cmin,ss
(L/day)

t1/2 range from Cmax,ss to Cmin,ss

(day)

8mg/kg +
6mg/kg q3w

MBC

805

0.183 - 0.302

15.1 - 23.3

EBC

390

0.158 - 0.253

17.5 – 26.6

AGC

274

0.189 - 0.337

12.6 - 20.6

4mg/kg +
2mg/kg qw

MBC

805

0.213 - 0.259

17.2 - 20.4

EBC

390

0.184 - 0.221

19.7 - 23.2

 

Trastuzumab washout

Trastuzumab washout period was assessed following q1w or q3w intravenous administration using the population PK model. The results of these simulations indicate that at least 95% of patients will reach concentrations that are <1 μg/mL (approximately 3% of the population predicted Cmin,ss, or about 97% washout) by 7 months.

 

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

 

A 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.

The exploratory analyses of covariates with information in only a subset of patients suggested that patients with greater shed HER2-ECD antigen (SHED) level had faster nonlinear clearance (lower Km) (P < 0.001). There was a correlation between shed antigen and SGOT/AST levels; part of the impact of shed antigen on clearance may have been explained by SGOT/AST levels.

 

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

 

10.     DATE OF REVISION OF THE TEXT

 

23 April 2015

 

Updated on 30 March 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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4.2     Posology and method of administration

 

[…]

 

Limited information is currently available on switches from one formulation to the other.Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and vice versa, using the three-weekly (q3w) dosing regimen, was investigated in study MO22982 (see section 4.8).

 

In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not Kadcyla (trastuzumab emtansine).

 

[…]

 

 

4.8     Undesirable effects

 

[…]

 

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 versa

 

Study 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.

 

[…]

 

 

10.     DATE OF REVISION OF THE TEXT

 

26 February 2015

 

Updated on 27 March 2015 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision
  • Change to dosage and administration

Updated on 27 August 2014 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

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10.     DATE OF REVISION OF THE TEXT

 

24 July 2014

 

Updated on 22 August 2014 PIL

Reasons for updating

  • Change to date of revision

Updated on 28 July 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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

4.4       Special warnings and precautions for use

[…]

Infusion-related reactions (IRRs), allergic-like reactions and hypersensitivity

Serious adverse reactionsIRRs to Herceptin infusion that have been reported infrequently includinge 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

[…]

4.8       Undesirable effects

[…]

System organ class

Adverse reaction

Frequency

Infections and infestations

Infection

Very common

Nasopharyngitis

Very common

+Pneumonia

Common

Neutropenic sepsis

Common

Cystitis

Common

Herpes zoster

Common

Influenza

Common

Nasopharyngitis

Common

Sinusitis

Common

Skin infection

Common

Rhinitis

Common

Upper respiratory tract infection

Common

Urinary tract infection

Common

Erysipelas

Common

Cellulitis

Common

Pharyngitis

Common

Sepsis

Uncommon

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

Anaemia

Very common

Neutropenia

Very common

White blood cell count decreased/leukopenia

Very common

Thrombocytopenia

Very cCommon

 

Hypoprothrombinaemia

Not known

Immune system disorders

Hypersensitivity

Common

+Anaphylactic reaction

Not known

+Anaphylactic shock

Not known

Metabolism and nutrition disorders

Weight decreased/Weight loss

Very Ccommon

Anorexia

Very Ccommon

Hyperkalaemia

Not known

Psychiatric disorders

Insomnia

Very common

Anxiety

Common

Depression

Common

Insomnia

Common

Thinking abnormal

Common

Nervous system disorders

1Tremor

Very common

Dizziness

Very common

Headache

Very common

Paraesthesia

Very common

Dysgeusia

Very common

Peripheral neuropathy

Common

Paraesthesia

Common

Hypertonia

Common

Somnolence

Common

Dysgeusia

Common

Ataxia

Common

Paresis

Rare

Brain oedema

Not known

Eye disorders

Conjunctivitis

Very common

Lacrimation increased

Very common

Dry eye

Common

Papilloedema

Not known

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

1Palpitation

Very common

1Cardiac flutter

Very common

Ejection fraction decreased*

Very common

+Cardiac failure (congestive)

Common

+1Supraventricular tachyarrhythmia

Common

Cardiomyopathy

Common

 

Pericardial effusion

Uncommon

Cardiogenic shock

Not known

Pericarditis

Not known

Bradycardia

Not known

Gallop rhythm present

Not known

Vascular disorders

Hot flush

Very common

+1 Hypotension

Common

Vasodilatation

Common

Respiratory, thoracic and mediastinal disorders

+1Wheezing

Very common

+Dyspnoea

Very common

Cough

Very common

Epistaxis

Very common

Rhinorrhoea

Very common

+Pneumonia

Common

Asthma

Common

Lung disorder

Common

Pharyngitis

Common

+Pleural effusion

UncommonCommon

Pneumonitis

Rare

+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

+Bronchospasm

Not known

+Hypoxia

Not known

+Oxygen saturation decreased

Not known

Laryngeal oedema

Not known

Orthopnoea

Not known

Pulmonary oedema

Not known

Interstitial lung disease

Not known

Gastrointestinal disorders

Diarrhoea

Very common

Vomiting

Very common

Nausea

Very common

1 Lip swelling

Very common

Abdominal pain

Very common

Dyspepsia

Very common

Constipation

Very common

Stomatitis

Very common

Pancreatitis

Common

 

Haemorrhoids

Common

 

Dry mouth

Common

Hepatobiliary disorders

Hepatocellular Injury

Common

Hepatitis

Common

Liver Tenderness

Common

Jaundice

Rare

Hepatic Failure

Not known

Skin and subcutaneous tissue disorders

Erythema

Very common

Rash

Very common

1 Swelling face

Very common

Alopecia

Very common

Nail disorder

Very common

Palmar-plantar erythrodysaesthesia syndrome

Very common

Acne

Common

Dry skin

Common

Ecchymosis

Common

Hyperhydrosis

Common

Maculopapular rash

Common

Pruritus

Common

Onychoclasis

Common

Dermatitis

Common

Urticaria

Uncommon

Angioedema

Not known

Musculoskeletal and connective tissue disorders

Arthralgia

Very common

1Muscle tightness

Very common

Myalgia

Very common

Arthritis

Common

Back pain

Common

Bone pain

Common

Muscle spasms

Common

Neck pain

Common

Pain in extremity

Common

Renal and urinary disorders

Renal disorder

Common

Glomerulonephritis membranous

Not known

Glomerulonephropathy

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

Chills

Very common

Fatigue

Very common

Influenza-like symptoms

Very common

Infusion related reaction

Very common

Pain

Very common

Pyrexia

Very common

Mucosal inflammation

Very common

Peripheral oedema

CommonVery common

Malaise

Common