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When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

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

Date of revision of text on the SPC:27-10-2017

Legal Category:POM

Black Triangle (CHM): NO

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4.8     Undesirable effects

[....]

Removal of : Pancreatitis

10.     DATE OF REVISION OF THE TEXT

27 October 2017

Reasons for adding or 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

Date of revision of text on the SPC:18-02-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



4.2     Posology and method of administration

 

[....]

Special populations

Dedicated pharmacokinetic studies in the elderlyolder 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 10: 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 group grouparm 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

 

[....]






Reasons for adding or updating:

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

Date of revision of text on the SPC:02-02-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



6.3     Shelf life

 

18 21 months.


[....]

10.     DATE OF REVISION OF THE TEXT

 

2 February 2016

 

 

Reasons for adding or 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

Date of revision of text on the SPC:24-09-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



4.2     Posology and method of administration

[...]

Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulations and vice versa, using the three-weekly (q3w) dosing regimen, was investigated in study MO22982 (see section 4.8).

[...]

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.

[...]

Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, history of or existing CHF (NYHA Class II IV), LVEF of < 55%, other cardiomyopathy, cardiac [....]

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 containingthat 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 %).

 

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 and 0.7% in the Herceptin subcutaneous arm.  In patients with lower body weights (<59 kg, the lowest body weight quartile) the fixed dose used in the Herceptin subcutaneous arm was not associated with an increased risk of cardiac events or significant drop in LVEF.

 

[...]

4.8     Undesirable effects

[...] 

 

Some adverse events / reactions were reported with a higher frequency for the subcutaneous formulation:

  • Serious adverse events (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation): 14.1 % for the intravenous formulation versus 21.5 % for the subcutaneous formulation. The difference in serious adverse eventSAE rates between formulations was mainly due to infections with or without neutropenia (4.4 % versus 8.1 %) and cardiac disorders (0.7 % versus 1.7 %);
  • Post-operative wound infections (severe and/or serious): 1.7  % versus 3.0  % for the intravenous formulation versus subcutaneous formulation, respectively;
  • Administration-related reactions: 37.2 % versus 47.8 % for the intravenous formulation versus subcutaneous formulation, respectively during the treatment phase;
  • Hypertension: 4.7 % versus 9.8 % for the intravenous formulation versus subcutaneous formulation respectively. 

[....]

Cardiac dysfunction

 

Congestive heart failure (NYHA Class II-IV) is a common adverse reaction to Herceptin. It has been associated with a fatal outcome. Signs and symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with Herceptin (see section 4.4).

 

In 3 pivotal EBC clinical trials of adjuvant intravenous 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 %.

[...]

Administration-related reactions

 

In the pivotal trial, the rate of all grade ARRs was 37.2 % with the Herceptin intravenous formulation and 47.8 % with the Herceptin subcutaneous formulation; severe grade 3 reactions were reported in 2.0 % and 1.7 % of the patients, respectively during the treatment phase; no severe grade 4 or 5 reactions were observed. All of the severe ARRs with the Herceptin subcutaneous formulation occurred during concurrent administration with chemotherapy. The most frequent severe reaction was drug hypersensitivity.

 

The systemic reactions included hypersensitivity, hypotension, tachycardia, cough, and dyspnoea. The local reactions included erythema, pruritus, oedema, and rash and pain at the site of the injection.

[...]

Immunogenicity

 

In the neoadjuvant-adjuvant EBC treatment setting, 87.1 % (24/296) of patients treated with Herceptin intravenous formulation and 14.96 % (44/295) of patients receivingtreated with Herceptin subcutaneous vialformulation 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 and 4 of 44 Herceptin subcutaneous vial patients. 20.016.3 % of patients treated with Herceptin subcutaneous formulation developed antibodies against the excipient hyaluronidase (rHuPH20).

 

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

[....] 

 

5.1     Pharmacodynamic properties

 

[...]

Intravenous formulation

 

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.

[....]

Study BO22227 was designedconducted to demonstrate non-inferiority of treatment with Herceptin subcutaneous formulation versus 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). A total of 595 patients with HER2-positive, operable or locally advanced breast cancer (LABC) including inflammatory breast cancer received eight cycles of either Herceptin intravenous formulation or Herceptin subcutaneous formulation concurrently with chemotherapy (4 cycles of docetaxel, 75 mg/m2 intravenous infusion, followed by 4 cycles of FEC ([5-Fluorouracil, 500 mg/m2; epirubicin, 75 mg/m2; cyclophosphamide, 500 mg/m2 each intravenous bolus or infusion]), followed by surgery, and continued therapy with Herceptin intravenous formulation or Herceptin subcutaneous formulation as originally randomized for 10 additional cycles, for a total of one year of treatment.

 

The analysis of the efficacy co-primary endpoint, pCR, defined as absence of invasive neoplastic cells in the breast, resulted in rates of 40.7 % (95 % CI: 34.7, 46.9) in the Herceptin intravenous arm and 45.4 % (95 % CI: 39.2 %, 51.7 %) in the Herceptin subcutaneous arm, a difference of 4.7 percentage points in favour of the Herceptin subcutaneous arm. The lower boundary of the one-sided 97.5 % confidence interval for the difference in pCR rates was -4.0, establishing the non-inferiority of Herceptin subcutaneous for the co-primary endpointimplying  non-inferiority of the Herceptin subcutaneous formulation compared to the Herceptin intravenous formulation.

 

Table 12: Summary of pathological Complete Response (pCR)

 

Herceptin IV  

 (N = 263)

Herceptin SC (N=260)

pCR (absence ofinvasive neoplastic cells in breast

107 (40.7%)

118 (45.4%)

     Non-responders

156 (59.3%)

142 (54.6%)

Exact 95% CI for pCR Rate* 

(34.7; 46.9)

(39.2; 51.7)

Difference in pCR (SC minus IV arm)

4.70

Lower bound one-sided 97.5% CI for the difference in pCR**

-4.0

*Confidence interval for one sample binomial using Pearson-Clopper method

**Continuity correction of Anderson and Hauck (1986) has been used in this calculation

 

Analyses with longer term follow-up of a median duration exceeding 40 months supported the non-inferior efficacy of Herceptin subcutaneous compared to Herceptin intravenous with comparable results of both EFS and OS (3-year EFS rates of 73% in the Herceptin intravenous arm and 76% in the Herceptin subcutaneous arm, and 3-year OS rates of 90% in the Herceptin intravenous arm and 92% in the Herceptin subcutaneous arm).

For non-inferiority of the PK co-primary endpoint, steady-state trastuzumab Ctrough value at the end of treatment Cycle 7, refer to section 5.2. Pharmacokinetic Properties.

For the PK co-primary endpoint refer to section 5.2. For the comparative safety profile see section 4.8.

 

Study MO28048 investigating the safety and tolerability of Herceptin subcutaneous formulation as adjuvant therapy in HER2 positive EBC patients who were enrolled in either a Herceptin subcutaneous vial cohort (N=1868 patients, including 20 patients receiving neoadjuvant therapy) or a Herceptin subcutaneous administration system cohort (N=710 patients, including 21 patients receiving neoadjuvant therapy) resulted in no new safety signals. Results were consistent with the known safety profile for Herceptin intravenous and Herceptin subcutaneous formulations. In addition, treatment of lower body weight patients with Herceptin subcutaneous fixed dose in adjuvant EBC was not associated with increased safety risk, adverse events and serious adverse events, compared to the higher body weight patients.

 

[....]

5.3     Preclinical safety data

 

Herceptin Intravenous formulation

[....]

Herceptin Subcutaneous formulation

[....]

10.     DATE OF REVISION OF THE TEXT

 

24 September 2015

 







 

 

Reasons for adding or updating:

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

Date of revision of text on the SPC:09-07-2015

Legal Category:POM

Black Triangle (CHM): NO

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

 


Reasons for adding or updating:

  • 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 - Fertility, 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

Date of revision of text on the SPC:23-04-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



4.4     Special warnings and precautions for use

[...]

General considerations

 

Patients treated with Herceptin are at increased risk for developing congestive heart failure (CHF) (New York Heart Association [NYHA] class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. These may be moderate to severe and have been associated with death (see section 4.8). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of <55%, older age.

[...]

TBecause 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 iwas 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 showedsuggested 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 showed 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 / Contraception

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).

 

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 intravenous formulation and have revealed no evidence of impaired fertility or harm to the fetus. Placental transfer of trastuzumab during the early (days 20‑50 of gestation) and late (days 120‑150 of gestation) fetal 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 fetus.

 

In the post-marketing setting, cases of fetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus, have been reported in pregnant women receiving Herceptin. Women who become pregnant should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with Herceptin, or if a patient becomes pregnant while receiving Herceptin or within 7 months following last dose of Herceptin, close monitoring by a multidisciplinary team is desirable.

[...]

4.8     Undesirable effects

[...]

Immunogenicity

 

In the neoadjuvant-adjuvant setting, 7.1 % of patients treated with Herceptin intravenous formulation and 14.6 % of patients treated with Herceptin subcutaneous formulation developed antibodies against trastuzumab (regardless of antibody presence at baseline). 165.3 % of patients treated with Herceptin subcutaneous formulation developed antibodies against the excipient hyaluronidase (rHuPH20).

The clinical relevance of these antibodies is not known. However the pharmacokinetics, efficacy (determined by pathological Complete Response [pCR]) and safety of Herceptin intravenous formulation and Herceptin subcutaneous formulation did not appear to be adversely affected by these antibodies.

[...]

5.2     Pharmacokinetic properties

 

Breast cancer

 

Herceptin has been studied thoroughly following intravenous administration in the MBC and EBC setting. The intravenous doses used most frequently are 8 mg/kg loading dose on day 1 followed by maintenance doses of 6 mg/kg every 3 weeks. These doses were chosen to maintain a steady state trough concentration necessary for complete saturation of the Her2 ligand. Intravenous pharmacokinetics have been well-characterized in all studies performed and the results have been further analysed using the population pharmacokinetics approach. 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 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 MBC and EBC the estimated value for typical trastuzumab clearance (for a body weight of 68 kg) was 0.241 L/day. The volume of distribution of the central (Vc) and peripheral (Vp) compartment was 3.02 L and 2.68 L, respectively, in the typical patient. The effects of patient characteristics (such as age or serum creatinine) on the disposition of trastuzumab were studied and data suggest that the disposition of trastuzumab is not altered in any of these groups of patients.

 

 

Subcutaneous formulation

 

The pharmacokinetics of trastuzumab at a dose of 600 mg administered three-weekly by the subcutaneous route was compared to the intravenous route (8 mg/kg loading dose, 6 mg/kg maintenance every three weeks) in the phase III study BO22227. The pharmacokinetic results for the co primary endpoint, Ctrough pre dose Cycle 8, showed non-inferiority of the Herceptin subcutaneous compared to the Herceptin intravenous dose adjusted by body weight.

 

The mean Ctrough during the neoadjuvant treatment phase, at the pre dose Cycle 8 time point, was higher in the Herceptin subcutaneous arm (78.7 µg/mL) than the Herceptin intravenous arm (57.8 µg/mL) of the study. During the adjuvant phase of treatment, at the pre-dose Cycle 13 time point, the mean Ctrough values were 90.4 µg/mL and 62.1 µg/mL, respectively. Based on the observed data in study BO22227, While steady state with the intravenous formulation was reached at cycle 8., With Herceptin subcutaneous formulation, concentrations were approximately at steady-state following Cycle 7 dose (pre-dose Cycle 8) with small increase in concentration (<15%)concentrations tended to increase further up to cycle 13 with the subcutaneous administration. The mean Ctrough at the subcutaneous pre- dose cycle 18 was 90.7 µg/mL and is similar to that of cycle 13, suggesting no further increase after cycle 13.

 

The median Tmax following subcutaneous administration was approximately 3 days, with high interindividual variability (range 1-14 days). The mean Cmax was expectedly lower in the Herceptintrastuzumab subcutaneous formulation (149 μg/mL) than in the intravenous arm (end of infusion value: 221 μg/mL).

 

The mean AUC0‑21 days following the Cycle 7 dose was approximately 10 % higher with the Herceptin subcutaneous formulation as compared to the Herceptin intravenous formulation, with mean AUC values of 2268 µg/mL•day and 2056 µg/mL•day, respectively. The AUC0‑21 days following Cycle 12 dose was approximately 20 % higher with the Herceptin subcutaneous formulation than the Herceptin intravenous dose, with mean AUC values of 2610 µg/mL•day and 2179 µg/mL•day, respectively. Due to the significant impact of body weight on trastuzumab clearance and the use of a fixed dose for the subcutaneous administration the difference in exposure between subcutaneous and intravenous administration was dependent on body weight: in patients with a body weight < 51 kg, mean steady state AUC of trastuzumab was about 80% higher after subcutaneous than after intravenous treatment whereas in the highest BW group (> 90 kg) AUC was 20% lower after subcutaneous than after intravenous treatment.

 

A population PK analysis (PopPK) where a base model was constructed using pooled data from the phase III study BO22227 in HER2-positive patients with EBC, was used to describe the data observed following intravenous and subcutaneous administration. Bioavailability of the subcutaneous formulation was estimated to be 82.2 %, clearance (CL) was 0.216 L/day, and the central compartment volume (Vc) was 2.89 L. These PK estimates are similar to those seen for the Herceptin intravenous formulation in MBC and consistent with typical values reported for a humanized IgG1 monoclonal antibody. The impact of body weight on these predicted Herceptin PK parameters was shown to be statistically significant. A population PK model with parallel linear and nonlinear elimination from the central compartment was constructed using pooled Herceptin SC and Herceptin IV PK data from the phase III study BO22227 to describe the observed PK concentrations following Herceptin IV and Herceptin SC administration in EBC patients. Bioavailability of trastuzumab given as the subcutaneous formulation was estimated to be 77.1%, and the first order absorption rate constant was estimated to be 0.4 day-1. Linear clearance was 0.111 L/day and the central compartment volume (Vc) was 2.91 L. The Michaelis-Menten parameter values were 11.9 mg/day and 33.9 µg/mL for Vmax and Km, respectively. Body weight and serum alanine aminotransferase (SGPT/ALT) showed a statistically significant influence on PK, however, simulations demonstrated that no dose adjustments are required in EBC patients. The population predicted PK exposure parameter values (median with 5th - 95th Percentiles) for Herceptin SC dosing regimens in EBC patients are shown in Table 12 below.

Table 12  Population Predicted PK Exposure Values (median with 5th - 95th Percentiles) for the Herceptin SC 600 mg Q3W Dosing Regimen in EBC patients

 

Primary tumor type and Regimen

Cycle

N

Cmin

(µg/mL)

Cmax

(µg/mL)

AUC0-21days

(µg.day/mL)

EBC 600 mg Herceptin SC q3w

Cycle 1

297

28.2

(14.8 - 40.9)

79.3

(56.1 - 109)

1065

(718 - 1504)

Cycle 7 (steady state)

297

75.0

(35.1 - 123)

149

(86.1 - 214)

2337

(1258 - 3478)

 

Trastuzumab washout

Trastuzumab washout period was assessed following subcutaneous 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.

 

 

10.     DATE OF REVISION OF THE TEXT

 

23 April 2015

 

 

Reasons for adding or 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

Date of revision of text on the SPC:26-02-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



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.

 

[…]

 

Method of administration

 

The 600 mg dose should be administered as a subcutaneous injection only over 2‑5 minutes every three weeks. The injection site should be alternated between the left and right thigh. New injections should be given at least 2.5 cm from the old site and never into areas where the skin is red, bruised, tender, or hard. During the treatment course with Herceptin subcutaneous formulation other medicinal products for subcutaneous administration should preferably be injected at different sites. Patients should be observed for six hours after the first injection and for two hours after subsequent injections for signs or symptoms of administration-related reactions (see sections 4.4 and 4.8).

 

For instructions on use and handling of Herceptin subcutaneous formulation refer to section 6.6.

 

 

10.     DATE OF REVISION OF THE TEXT

 

26 February 2015

 

Reasons for adding or updating:

  • Change to section 1 - Name of the medicinal product
  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:24-07-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



1.         NAME OF THE MEDICINAL PRODUCT

 

Herceptin 600 mg/5 mL solution for injection in vial

 


4.2     Posology and method of administration

 

[....]

Posology

 

The recommended dose for Herceptin subcutaneous formulation is 600 mg/5 mL irrespective of the patient’s body weight. No loading dose is required. This dose should be administered subcutaneously over 2‑5 minutes every three weeks.


[...]

5.2     Pharmacokinetic properties

 

[....]

Subcutaneous formulation

 

The pharmacokinetics of trastuzumab at a dose of 600 mg administered three-weekly by the subcutaneous route was compared to the intravenous route (8 mg/kg loading dose, 6 mg/kg maintenance every three weeks) in the phase III study BO22227. The pharmacokinetic results for the co primary endpoint, Ctrough pre dose Cycle 8, showed non-inferiority of the Herceptin subcutaneous compared to the Herceptin intravenous dose adjusted by body weight.

[....]


10.     DATE OF REVISION OF THE TEXT

 

24 July 2014

 

Reasons for adding or updating:

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

Date of revision of text on the SPC:26-06-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



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

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

 

Oedema

Common

Injury, poisoning and procedural complications

Contusion

Common

 

[…]

When Herceptin was administered after completion of adjuvant chemotherapy NYHA class III-IV heart failure was observed in 0.6 % of patients in the one-year arm after a median follow-up of 12 months. In study BO16348, aAfter a median follow-up of 8 years the incidence of severe CHF (NYHA III & IV) in the Herceptin following 1 year treatment arm of Herceptin therapy (combined analysis of the two Herceptin treatment arms) was 0.89 %, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.66.35 %.

Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 % after the event) was evident for 70 71.4 % of Herceptin-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 83.179.5 % of Herceptin-treated patients. Approximately 107 % of cardiac endpoints occurred after completion of Herceptin

[…]

Ireland

IMBHPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpraimb.ie

e-mail: medsafetyimbpharmacovigilance@imbhpra.ie

 

10.       DATE OF REVISION OF THE TEXT

26 June 2014

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:20-02-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text = new text

Strike through text = deleted text

 

 

4.2     Posology and method of administration

 

[ … ]

 

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 trastuzumab emtansine.

 

Posology

 

The recommended dose for Herceptin subcutaneous formulation is 600 mg/5 mL irrespective of the patient’s body weight. No loading dose is required. This dose should be administered subcutaneously over 2‑5 minutes every three weeks.

 

[ … ]

 

4.8     Undesirable effects

 

[ … ]

 

Table 1: Undesirable effects reported with intravenous Herceptin monotherapy or in combination with chemotherapy in pivotal clinical trials (N = 8386) and in post-marketing

 

System organ class

Adverse reaction

Frequency

Infections and infestations

Infection

Very common

+Pneumonia

Common

Neutropenic sepsis

Common

Cystitis

Common

Herpes zoster

Common

Infection

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

Sepsis

Uncommon

[ … ]

 

 

 

Skin and subcutaneous tissue disorders

Erythema

Very common

Rash

Very common

1 Swelling face

Very common

Alopecia

Very common

Nail disorder

Very common

Acne

Common

Dry skin

Common

Ecchymosis

Common

Hyperhydrosis

Common

Maculopapular rash

Common

Nail disorder

Common

Pruritus

Common

Onychoclasis

Common

Dermatitis

Common

Urticaria

Uncommon

Angioedema

Not known

[ … ]

 

 

 

 

 

[ … ]

 

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse (see details below).

 

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

 

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

[ … ]

 

 

Early breast cancer (adjuvant setting)

 

Intravenous formulation

 

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

In the adjuvant setting, Herceptin was investigated in 4 large multicentre, randomised, trials.

-        Study BO16348 was designed to compare one and two years of three-weekly Herceptin treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable). In addition, comparison of two years versus one year Herceptin treatment was performed. Patients assigned to receive Herceptin were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg every three weeks for either one or two years.

-        Studies NSABP B-31 and NCCTG N9831 and NSABP B-31 that comprise the joint analysis were designed to investigate the clinical utility of combining Herceptin treatment with paclitaxel following AC chemotherapy, additionally the NCCTG N9831 study also investigated adding Herceptin sequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery.

-        Study BCIRG 006 study was designed to investigate combining Herceptin treatment with docetaxel either following AC chemotherapy or in combination with docetaxel and carboplatin in patients with HER2 positive EBC following surgery.

 

Early breast cancer in the BO16348 Study was limited to operable, primary, invasive adenocarcinoma of the breast, with axillary nodes positive or axillary nodes negative if tumors at least 1 cm in diameter.

 

In the joint analysis of the NSABP B-31 and NCCTG N9831 and NSABP B-31 studies, EBC was limited to women with operable breast cancer at high risk, defined as HER2-positive and axillary lymph node positive or HER2 positive and lymph node negative with high risk features (tumor size > 1 cm and ER negative or tumor size > 2 cm, regardless of hormonal status).

 

[ … ]

 

In this final analysis, extending Herceptin treatment for a duration of two years did not show additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years versus 1 year=0.99 (95 % CI: 0.87, 1.13), p-value=0.90 and OS HR=0.98 (0.83, 1.15); p-value= 0.78]. The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1 % versus 4.6 % in the 1-year treatment arm). More patients experienced at least one grade 3 or 4 adverse event in the 2-year treatment arm (20.4 %) compared with the 1-year treatment arm (16.3 %).

 

In the NSABP B-31 and NCCTG N9831 and NSABP B-31 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 intravenous infusion, given every week for 12 weeks.

or

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

 

The efficacy results from the joint analysis of the NSABP B-31 and NCCTG 9831 and NSABP B-31 trials at the time of the definitive analysis of DFS* are summarized in Table 6. The median duration of follow up was 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm.

 

Table 6: Summary of Efficacy results from the joint analysis studies NSABP B-31 and NCCTG N9831 at the time of the definitive DFS analysis*Efficacy results from the joint analysis of the NCCTG 9831 and NSABP B-31 trials

 

Parameter

 

ACP

(n=1679)

ACPH

(n=1672)

Hazard Ratio vs ACP

(95 % CI)

p-value

 

Disease-free survival

No. patients with event (%)

 

261 (15.5)

 

133 (8.0)

 

0.48 (0.39, 0.59)

p<0.0001

Distant Recurrence

No. patients with event

 

193 (11.5)

 

96 (5.7)

 

0.47 (0.37, 0.60)

p<0.0001

Death (OS event):

No. patients with event

 

92 (5.5)

 

62 (3.7)

 

0.67 (0.48, 0.92)

p=0.014**

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

* at median duration of follow up of 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm

** p value for OS did not cross the pre-specified statistical boundary for comparison of AC→PH vs. AC→P

 

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 % versus 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.

 

The pre-planned final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC→PH group). Treatment with AC→PH resulted in a statistically significant improvement in OS compared with AC®P (stratified HR=0.64; 95% CI [0.55, 0.74]; log-rank p-value < 0.0001).  At 8 years, the survival rate was estimated to be 86.9% in the AC®PH arm and 79.4% in the AC®P arm, an absolute benefit of 7.4% (95% CI 4.9%, 10.0%).

The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are summarized in Table 7:

Table 7: Final Overall Survival Analysis from the joint analysis of trials NSABP
B-31 and NCCTG N9831

 

Parameter

 

AC→P

(N=2032)

AC→PH

(N=2031)

p-value versus AC→P

 

Hazard Ratio versus AC→P

(95% CI)

Death (OS event):

No. patients with event (%)

 

418 (20.6%)

 

289 (14.2%)

 

< 0.0001

 

0.64

(0.55, 0.74)

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

DFS analysis was also performed at the final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95% CI [0.54, 0.69]) showed a similar DFS benefit compared to the definitive primary DFS analysis, despite 24.8% patients in the AC→P arm who crossed over to receive Herceptin. At 8 years, the disease-free survival rate was estimated to be 77.2% (95% CI: 75.4, 79.1) in the AC→PH arm, an absolute benefit of 11.8% compared with the AC→P arm.

 

[ … ]

 

 

The efficacy results from the BCIRG 006 are summarized in Tables 7 8 and 89. The median duration of follow up was 2.9 years in the AC→D arm and 3.0 years in each of the AC→DH and DCarbH arms.

 

Table 78: Overview of efficacy analyses BCIRG 006 AC→D versus AC→DH

 

Parameter

 

AC→D

(n=1073)

AC→DH

(n=1074)

Hazard Ratio vs ACD

(95 % CI)

p-value

 

Disease-free survival

 

 

 

No. patients with event

195

134

0.61 (0.49, 0.77)

p<0.0001

 

Distant recurrence

 

 

 

 

No. patients with event

144

95

0.59 (0.46, 0.77)

p<0.0001

 

Death (OS event)

 

 

 

 

No. patients with event

80

49

0.58 (0.40, 0.83)

p=0.0024

 

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

 

Table 89: Overview of efficacy analyses BCIRG 006 AC→D versus DCarbH

 

Parameter

 

AC→D

(n=1073)

DCarbH

(n=1074)

Hazard Ratio vs ACD

(95 % CI)

 

Disease-free survival

 

 

 

No. patients with event

195

145

0.67 (0.54, 0.83)

p=0.0003

 

Distant recurrence

 

 

 

 

No. patients with event

144

103

0.65 (0.50, 0.84)

p=0.0008

 

Death (OS event)

 

 

 

 

No. patients with event

80

56

0.66 (0.47, 0.93)

p=0.0182

 

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

 

[ … ]

 

 

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 Table 910:

 

Table 910: 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

Post-hoc exploratory analysis with DFS and symptomatic cardiac events

Hazard ratios

(95 % CI)

 

 

 

0.64

(0.53, 0.77)

 

 

 

0.70

(0.57, 0.87)

 

 

 

0.71

(0.57, 0.87)

 

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

 

Early breast cancer – (neoadjuvant-adjuvant setting)

 

Intravenous formulation

 

[ … ]

 

 

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 Table 1011. The median duration of follow-up in the Herceptin arm was 3.8 years.

 

Table 1011: Efficacy results from MO16432

 

Parameter

 

Chemo + Herceptin

(n=115)

Chemo only

(n=116)

 

 

Event-free survival

 

 

Hazard Ratio

(95 % CI)

No. patients with event

46

59

0.65 (0.44, 0.96)
p=0.0275

 

Total pathological complete
response* (95 % CI)

40 %

(31.0, 49.6)

20.7 %

(13.7, 29.2)

P=0.0014

 

Overall survival

 

 

Hazard Ratio

(95 % CI)

No. patients with event

22

33

0.59 (0.35, 1.02)
p=0.0555

* 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 % versus. 52 %).

 

Subcutaneous formulation

 

[ … ]

 

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

20 February 2014

Reasons for adding or 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 4.8 - Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:18-12-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



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

 

 

4.2     Posology and method of administration

 

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Herceptin treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy (see section 4.4), and should be administered by a healthcare professional only.

 

It is important to check the product labels to ensure that the correct formulation (intravenous or subcutaneous fixed dose) is being administered to the patient, as prescribed. Herceptin subcutaneous formulation is not intended for intravenous administration and should be administered via a subcutaneous injection only.

Limited information is currently available on switches from one formulation to the other.

 

Posology

 

 

The recommended dose for Herceptin subcutaneous formulation is 600 mg/5 mL irrespective of the patient’s body weight. No loading dose is required. This dose should be administered subcutaneously over 2‑5 minutes every three weeks.

 

In the pivotal trial (BO22227) Herceptin subcutaneous formulation was administered in the neoadjuvant/adjuvant setting in patients with early breast cancer. The preoperative chemotherapy regimen consisted of docetaxel (75 mg/m²) followed by FEC (5FU, epirubicin and cyclophosphamide) at a standard dose.

 

 

See section 5.1 for chemotherapy combination dosing.

 

Duration of treatment

Patients with MBC should be treated with Herceptin until progression of disease. Patients with EBC should be treated with Herceptin for 1 year or until disease recurrence, whatever occurs first.whichever occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).

 

Dose reduction

No reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time. Refer to the Summary of Product Characteristics (SmPC) for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.

 

If left ventricular ejection fraction (LVEF) drops ≥ 10 ejection fraction (EF) points from baseline AND to below 50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic congestive heart failure (CHF) has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.

 

Missed doses

If the patient misses a dose of Herceptin subcutaneous formulation, it is recommended to administer the next 600 mg dose (i.e. the missed dose) as soon as possible. The interval between consecutive Herceptin subcutaneous formulation administrations should not be less than three weeks.

 

Special populations

Dedicated pharmacokinetic studies in older people and those with renal or hepatic impairment have not been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.

 

Paediatric population

There is no relevant use of Herceptin in the paediatric population.

 

Method of administration

 

The 600 mg dose should be administered as a subcutaneous injection only over 2‑5 minutes. The injection site should be alternated between the left and right thigh. New injections should be given at least 2.5 cm from the old site and never into areas where the skin is red, bruised, tender, or hard. During the treatment course with Herceptin subcutaneous formulation other medicinal products for subcutaneous administration should preferably be injected at different sites. Patients should be observed for six hours after the first injection and for two hours after subsequent injections for signs or symptoms of administration-related reactions (see sections 4.4 and 4.8).

 

For instructions on use and handling of Herceptin subcutaneous formulation refer to section 6.6.

 

4.4     Special warnings and precautions for use

 

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

 

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.

 

Cardiac dysfunction

 

General considerations

 

Patients treated with Herceptin are at increased risk for developing congestive heart failure (CHF) (New York Heart Association [NYHA] class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. These may be moderate to severe and have been associated with death (see section 4.8). In addition, caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of <55%, older age.

 

All candidates for treatment with Herceptin, but especially those with prior anthracycline and cyclophosphamide exposure, should undergo baseline cardiac assessment including history and physical examination and electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. A careful risk-benefit assessment should be made before deciding to treat with Herceptin.

 

Because the half-life of trastuzumab is approximately 28‑38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping Herceptin treatment. Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.

 

Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. In all patients cardiac function should be monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6‑8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been seen.

 

The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction has not been prospectively studied. If LVEF drops ≥ 10 ejection fraction (EF) points from baseline AND to below 50%, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or symptomatic CHF has developed, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.

 

If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with standard medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction in the pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy without additional clinical cardiac events.

 

Metastatic breast cancer

 

Herceptin and anthracyclines should not be given concurrently in combination in the MBC setting.

 

Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines.

 

Early breast cancer

 

For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin. In patients who receive anthracycline-containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of Herceptin, or longer if a continuous decrease of LVEF is observed.

 

Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, history of or existing CHF (NYHA II –IV), LVEF of < 55%, other cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medical treatment eligible), and haemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC pivotal trials with Herceptin and therefore treatment cannot be recommended in such patients.

 

Adjuvant treatment

 

Herceptin and anthracyclines should not be given concurrently in the adjuvant treatment setting.

 

In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when Herceptin (intravenous formulation) was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when Herceptin (intravenous formulation) 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 (up to 2.37 %) in patients who were administered Herceptin concurrently with a taxane following anthracycline therapy, compared to approximately 1 % in the two comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin and Herceptin).

 

Risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low LVEF (<55%) at baseline, prior to or following the initiation of paclitaxel treatment, decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products. In patients receiving Herceptin after completion of adjuvant chemotherapy the risk of cardiac dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of Herceptin and a body mass index (BMI) >25 kg/m2.

 

Neoadjuvant-adjuvant treatment

 

In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin should be used concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose anthracycline regimens, i.e., with maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin 360 mg/m2.

 

If patients have been treated concurrently with a full course of low-dose anthracyclines and Herceptin in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In other situations, the decision on the need for additional cytotoxic chemotherapy is determined based on individual factors.

 

Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is currently limited to two trials. Herceptin was administered concurrently with neoadjuvant chemotherapy that contained three to four cycles of an anthracycline (cumulative doxorubicin dose 180 mg/m2 or epirubicin dose 300 mg/m2). The incidence of symptomatic cardiac dysfunction was low in the Herceptin arms (up to 1.7 %).

 

Clinical experience is limited in patients above 65 years of age.

 

Administration‑related reactions

 

Administration‑related reactions (ARRs) are known to occur with Herceptin subcutaneous formulation. Pre-medication may be used to reduce risk of occurrence of ARRs.

 

Although serious ARRs, including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress, were not reported in the clinical trial with the Herceptin subcutaneous formulation, caution should be exercised as these have been associated with the intravenous formulation. Patients should be observed for ARRs for six hours after the first injection and for two hours after subsequent injections. They can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. Serious reactions to intravenous Herceptin have been treated successfully with supportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactions were 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 ARR. Therefore, these patients should not be treated with Herceptin (see section 4.3).

 

Pulmonary events

 

Caution is recommended with Herceptin subcutaneous formulation as severe pulmonary events have been reported with the use of the intravenous formulation in the post-marketing setting (see section 4.8). These events have occasionally been fatal and may occur as part of an infusion-related reaction or with delayed onset. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. 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.

 

4.5       Interaction with other medicinal products and other forms of interaction

 

No formal drug interaction studies have been performed. Clinically significant interactions with the concomitant medication 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 suggest that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) is not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV,resp.). respectively).

However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite is unclear. 

Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg IV loading dose and 2 mg/kg IV weekly) and docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggest that concomitant administration of trastuzumab has no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The results of this small substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.

 

Effect of antineoplastic agents on trastuzumab pharmacokinetics

 

By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy (4 mg/kg loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2- positive MBC (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the pharmacokinetics of trastuzumab was found.

Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which patients were treated concomitantly with Herceptin and paclitaxel and two Phase II studies in which Herceptin was administered as monotherapy (W016229 and MO16982), in women with HER2-positive MBC indicates that individual and mean Herceptin trough serum concentrations varied within and across studies but there was no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab.

 

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

 

4.8     Undesirable effects

 

Summary of the safety profile

 

Amongst the most serious and/or common adverse reactions reported in Herceptin usage (intravenous and subcutaneous formulations) to date are cardiac dysfunction, administration-related reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions.

 

The safety profile of Herceptin subcutaneous formulation (evaluated in 298 and 297 patients treated with the intravenous and subcutaneous formulations respectively) from the pivotal trial in EBC was overall similar to the known safety profile of the intravenous formulation.

 

Severe adverse events (defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE grade ≥3) version 3.0) were equally distributed between both Herceptin formulations (52.3 % versus 53.5 % in the intravenous formulation versus subcutaneous formulation respectively).

 

Some adverse events / reactions were reported with a higher frequency for the subcutaneous formulation:

  • Serious adverse events (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation): 14.1 % for the intravenous formulation versus 21.5 % for the subcutaneous formulation. The difference in SAE rates between formulations was mainly due to infections with or without neutropenia (4.4 % versus 8.1 %) and cardiac disorders (0.7 % versus 1.7 %);
  • Post-operative wound infections (severe and/or serious): 1.7  % versus 3.0  % for the intravenous formulation versus subcutaneous formulation, respectively;
  • Administration-related reactions: 37.2 % versus 47.8 % for the intravenous formulation versus subcutaneous formulation, respectively;
  • Hypertension: 4.7 % versus 9.8 % for the intravenous formulation versus subcutaneous formulation respectively. 

 

Tabulated list of adverse reactions with the intravenous formulation

 

In this section, the following categories of frequency have been used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

Presented in Table 1 are adverse reactions that have been reported in association with the use of intravenous Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting.

 

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

 

Table 1: Undesirable effects reported with intravenous Herceptin monotherapy or in combination with chemotherapy in pivotal clinical trials (N = 67098386) and in post-marketing

 

System organ class

Adverse reaction

Frequency

Infections and infestations

+Pneumonia

Common

Neutropenic sepsis

Common

Cystitis

Common

Herpes zoster

Common

Infection

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

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

Common

 

Hypoprothrombinaemia

Not known

Immune system disorders

Hypersensitivity

Common

+Anaphylactic reaction

Not known

+Anaphylactic shock

Not known

Metabolism and nutrition disorders

Weight decreased/Weight loss

Common

Anorexia

Common

Hyperkalaemia

Not known

Psychiatric disorders

Anxiety

Common

Depression

Common

Insomnia

Common

Thinking abnormal

Common

Nervous system disorders

1Tremor

Very common

Dizziness

Very common

Headache

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

Asthma

Common

Lung disorder

Common

Pharyngitis

Common

+Pleural effusion

Uncommon

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

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

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

Acne

Common

Dry skin

Common

Ecchymosis

Common

Hyperhydrosis

Common

Maculopapular rash

Common

Nail disorder

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

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

Common

Malaise

Common

 

Oedema

Common

Injury, poisoning and procedural complications

Contusion

Common

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

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

* Observed with combination therapy following anthracyclines and combined with taxanes

 

Description of selected adverse reactions

 

Cardiac dysfunction

 

Congestive heart failure (NYHA II-IV) is a common adverse reaction to Herceptin. It has been associated with a fatal outcome. Signs and symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with Herceptin (see section 4.4).

 

In 3 pivotal EBC clinical trials of adjuvant intravenous Herceptin given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic congestive heart failure) was similar in patients who were administered chemotherapy alone (ie did not receive Herceptin) and in patients who were administered Herceptin sequentially to a taxane (0.3-0.4 %). The rate was highest in patients who were administered Herceptin concurrently with a taxane (2.0 %). In the neoadjuvant setting, the experience of concurrent administration of Herceptin and low dose anthracycline regimen is limited (see section 4.4).

 

When Herceptin was administered after completion of adjuvant chemotherapy NYHA class III-IV heart failure was observed in 0.6 % of patients in the one-year arm after a median follow-up of 12 months. After a median follow-up of 8 years the incidence of severe CHF (NYHA III & IV) following 1 year of Herceptin therapy (combined analysis of the two Herceptin treatment arms) was 0.89 %, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 6.35 %.

Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 % after the event) was evident for 70 % of Herceptin-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 83.1 % of Herceptin-treated patients. Approximately 10 % of cardiac endpoints occurred after completion of Herceptin.

 

In the pivotal metastatic trials of intravenous Herceptin, the incidence of cardiac dysfunction varied between 9 % and 12 % when it was combined with paclitaxel compared with 1 % – 4 % for paclitaxel alone. For monotherapy, the rate was 6 % – 9 %. The highest rate of cardiac dysfunction was seen in patients receiving Herceptin concurrently with anthracycline/cyclophosphamide (27 %), significantly higher than for anthracycline/cyclophosphamide alone (7 % – 10 %). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2 % in patients receiving Herceptin and docetaxel, compared with 0 % in patients receiving docetaxel alone. Most of the patients (79 %) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF.

 

Administration‑related reactions/hypersensitivity

 

Administration‑related reactions (ARRs)/hypersensitivity reactions such as chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, rash, nausea, vomiting and headache were seen in Herceptin clinical trials (see section 4.4). The rate of ARRs of all grades varied between studies depending on the indication, the data collection methodology, and whether trastuzumab was given concurrently with chemotherapy or as monotherapy.

 

Anaphylactoid reactions have been observed in isolated cases.

 

Haematotoxicity

 

Febrile neutropenia occurred very commonly. Commonly occurring adverse reactions included anaemia, leukopenia, thrombocytopenia and neutropenia. The frequency of occurrence of hypoprothrombinemia is not known. The risk of neutropenia may be slightly increased when trastuzumab is administered with docetaxel following anthracycline therapy.

 

Pulmonary 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).

 

Description of selected adverse reactions with the subcutaneous formulation

 

Administration-related reactions

 

In the pivotal trial, the rate of all grade ARRs was 37.2 % with the Herceptin intravenous formulation and 47.8 % with the Herceptin subcutaneous formulation; severe grade 3 reactions were reported in 2.0 % and 1.7 % of the patients, respectively; no severe grade 4 or 5 reactions were observed. All of the severe ARRs with the Herceptin subcutaneous formulation occurred during concurrent administration with chemotherapy. The most frequent severe reaction was drug hypersensitivity.

 

The systemic reactions included hypersensitivity, hypotension, tachycardia, cough, and dyspnoea. The local reactions included erythema, pruritus, oedema and rash at the site of the injection.

 

 

Infections

The rate of severe infections (NCI CTCAE grade ≥3) was 5.0 % versus 7.1 %, in the Herceptin intravenous formulation arm and the Herceptin subcutaneous formulation arm respectively.

 

The rate of serious infections (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation) was 4.4 % in the Herceptin intravenous formulation arm and 8.1 % in the Herceptin subcutaneous formulation arm. The difference between formulations was mainly observed during the adjuvant treatment phase (monotherapy) and was mainly due to postoperative wound infections, but also to various other infections such as respiratory tract infections, acute pyelonephritis and sepsis. They resolved within a mean of 13 days in the Herceptin intravenous treatment arm and a mean of 17 days in the Herceptin subcutaneous treatment arm.

 

Hypertensive events

 

In the pivotal trial BO22227, there were more than twice as many patients reporting all grade hypertension with the Herceptin subcutaneous  formulation (4.7 % versus 9.8 % in the intravenous and subcutaneous formulations respectively), with a greater proportion of patients with severe events (NCI CTCAE grade ≥3) <1 % versus 2.0 % the intravenous and subcutaneous formulations respectively. All but one patient who reported severe hypertension had a history of hypertension before they entered the study. Some of the severe events occurred on the day of the injection.

 

Immunogenicity

 

In the neoadjuvant-adjuvant setting, 7.1 % of patients treated with Herceptin intravenous formulation and 14.6 % of patients treated with Herceptin subcutaneous formulation developed antibodies against trastuzumab (regardless of antibody presence at baseline). 15.3 % of patients treated with Herceptin subcutaneous formulation developed antibodies against the excipient hyaluronidase (rHuPH20).

The clinical relevance of these antibodies is not known. However the pharmacokinetics, efficacy (determined by pathological Complete Response [pCR]) and safety of Herceptin intravenous formulation and Herceptin subcutaneous formulation did not appear to be adversely affected by these antibodies.

 

Details of risk minimisation measures that are consistent with the EU Risk Management Plan are presented in Section 4.4.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below). via the national reporting system listed in Appendix V.

 

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

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5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03

 

Herceptin subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously.

 

Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20% ‑ 30% of primary breast cancers. Studies indicate that breast cancer patients whose tumours overexpress HER2 have a shortened disease‑free survival compared to patients whose tumours do not overexpress HER2. The extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and measured in serum samples.

 

Mechanism of action

 

Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of HER2’s extracellular domain. Binding of trastuzumab to HER2 inhibits ligand-independent HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of HER2. As a result, trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent mediator of antibody‑dependent cell‑mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

 

Detection of HER2 overexpression or HER2 gene amplification

 

Detection of HER2 overexpression or HER2 gene amplification in breast cancer

Herceptin should only be used in patients whose tumours have HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. HER2 overexpression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see section 4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for Herceptin treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a positive FISH or CISH result.

 

To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, which can ensure validation of the testing procedures.

 

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:

 

Table 2: Recommended scoring system to evaluate the IHC staining patterns

 

Score

Staining pattern

HER2 overexpression assessment