Herceptin 150mg Powder for concentrate for solution for infusion

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

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

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

4.8     Undesirable effects

[....]​​​​

Removal of : Pancreatitis

​​

10.     DATE OF REVISION OF THE TEXT

​​

27 October 2017

​​

​​

6.       PHARMACEUTICAL PARTICULARS

6.1     List of excipients

L‑histidine hydrochloride monohydrate

L‑histidine

a,a‑trehalose dihydrate

polysorbate 20

4.9       Overdose

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

5.2     Pharmacokinetic properties

[...]

Circulating shed HER2 ECDantigen

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

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

10.     DATE OF REVISION OF THE TEXT

15 September 2016

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

[....]

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

4.2     Posology and method of administration

Special populations

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

4.8     Undesirable effects

Haematotoxicity

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

5.1     Pharmacodynamic properties

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

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

CI = confidence interval

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

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

4.2     Posology and method of administration

[....]
 

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

4.4     Special warnings and precautions for use

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

[....]

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

[....]

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

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

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

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

[....]

4.8     Undesirable effects

[....]

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

When Herceptin was administered after completion of adjuvant chemotherapy NYHA Cclass III-IV heart failure was observed in 0.6 % of patients in the one-year arm after a median follow-up of 12 months.  In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA Class III & IV) in the Herceptin 1 year treatment arm was 0.8 %, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6 %.

[....]

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

[....]

Immunogenicity

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

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

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

[....]

Study MO22982 investigated switching between the Herceptin intravenous and Herceptin subcutaneous formulation with a primary objective to evaluate patient preference for either intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using subcutaneous formulation in vial and one using subcutaneous formulation in administration system) were investigated using a 2-arm , cross-over design with 488 patients being randomized to one of two different three-weekly Herceptin treatment sequences (IV [Cycles 1-4]→ SC [Cycles 5-8], or SC [Cycles 1-4]→ IV [Cycles 5-8]). Patients were either naïve to Herceptin IV treatment (20.3%) or pre-exposed to Herceptin IV (79.7%). For the sequence IV→SC (SC vial and SC formulation in administration system cohorts combined), adverse eventAE rates (all grades) were described pre-switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8% vs. 56.4%, respectively; for the sequence SC→IV (SC vial and SC formulation in administration system cohorts combined), adverse eventAE rates (all grades) were described pre- and post-switching as 65.4% vs. 48.7%, respectively.

Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment discontinuations due to adverse events were low (<5%) and similar to post-switching rates (Cycles 5-8). No grade 4 or grade 5 adverse events were reported.

[....]

5.1     Pharmacodynamic properties

[....]

Early breast cancer (adjuvant setting)

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

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

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

[....]

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

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

[....]

10.     DATE OF REVISION OF THE TEXT

24 September 2015

4.8     Undesirable effects

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

4.2     Posology and method of administration

[...]

Missed doses

If the patient has misseds a dose of Herceptin by one week or less, then the usual maintenance dose (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administeredgiven as soon as possible. Do not wait until the next planned cycle. Subsequent maintenance doses (weekly regimen: 2  mg/ kg; three-weekly regimen: 6  mg/kg respectively) should then be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively. given according to the previous schedule.

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

[...]

4.4     Special warnings and precautions for use

[...]

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

[...]

4.5       Interaction with other medicinal products and other forms of interaction

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

Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents

Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) wais not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV, respectively).

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

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

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

Effect of antineoplastic agents on trastuzumab pharmacokinetics

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

Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which patients were treated concomitantly with Herceptin and paclitaxel and two Phase II studies in which Herceptin was administered as monotherapy (W016229 and MO16982),  in women with HER2-positive MBC indicates that individual and mean trastuzumabHerceptin trough serum concentrations varied within and across studies but there was no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab. Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with Herceptin, paclitaxel and doxorubicin to trastuzumab PK data in studies where Herceptin was administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab.

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

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

4.6     Fertility, pregnancy and lactation

Women of childbearing potential

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

[...]
 

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

[...]

4.8     Undesirable effects

[spacing issues corrected]

5.2     Pharmacokinetic properties

The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer, early breast cancer and advanced gastric cancer patients. Formal drug-drug interaction studies have not been performed with Herceptin.

Breast cancer

Short duration intravenous infusions of 10, 50, 100, 250, and 500 mg trastuzumab once weekly in patients demonstrated non-linear pharmacokinetics where clearance decreased with  increasing dose.

Half-life

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

Steady State pharmacokinetics

Steady state should be reached by approximately 27 weeks. In a population pharmacokinetic (two compartment, model-dependent) assessment of Phase I, II and III clinical trials in metastatic breast cancer, the median predicted AUC at steady state over a three-week period was three times 578 mg•day/l (1677 mg•day/l) with 3 weekly doses of 2 mg/kg and 1793 mg day/l with one every three week dose of 6 mg/kg; the estimated median peak concentrations were 104 mg/l and 189 mg/l and the trough concentrations were 64.9 mg/l and 47.3 mg/l, respectively.

Early breast cancer patients administered an initial loading dose of 8 mg/kg followed by a three weekly maintenance dose of 6 mg/kg for 1 year, achieved steady state mean C_max of 225 µg/mL and mean C_min of 68.9 µg/mL at day 21 of cycle 18, the last cycle of treatment for 1 year of treatment. These concentrations were comparable to those reported previously in patients with metastatic breast cancer

Clearance (CL)

The typical trastuzumab clearance (for a body weight of 68 kg) was 0.241 l/day.

The effects of patient characteristics (such as age or serum creatinine) on the disposition of trastuzumab have been evaluated. The data suggest that the disposition of trastuzumab is not altered in any of these groups of patients (see section 4.2), however, studies were not specifically designed to investigate the impact of renal impairment upon pharmacokinetics.

Volume of distribution

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

The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or other tumor types, and healthy volunteers, in 18 Phase I, II and III trials receiving Herceptin IV. A two-compartment model with parallel linear and non-linear elimination from the central compartment described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can be deduced. The t_1/2 decreases with decreasing concentrations within a dosing interval (see Table 16). MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment volume (V_c)) and population-predicted steady-state exposures (C_min, C_max and AUC). Linear clearance was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC.  The non‑linear elimination parameter values were 8.81 mg/day for the maximum elimination rate (V_max) and 8.92 µg/mL for the Michaelis-Menten constant (K_m) for the MBC, EBC, and AGC patients. The central compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC.  In the final population PK model, in addition to primary tumor type, body-weight, serum aspartate aminotransferase and albumin were identified as a statistically significant covariates affecting the exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab exposure suggests that these covariates are unlikely to have a clinically meaningful effect on trastuzumab concentrations.

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

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

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

*C_min,ss – C_min at steady state

**C_max,ss = C_max at steady state

*** time to 90% of steady-state

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

Trastuzumab washout

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

Circulating shed antigen

Detectable concentrations of the circulating extracellular domain of the HER2 receptor (shed antigen) are found in the serum of some patients with HER2 overexpressing breast cancers. Determination of shed antigen in baseline serum samples revealed that 64 % (286/447) of patients had detectable shed antigen, which ranged as high as 1880 ng/mL (median = 11 ng/mL). Patients with higher baseline shed antigen levels were more likely to have lower serum trough concentrations of trastuzumab. However, with weekly dosing, most patients with elevated shed antigen levels achieved target serum concentrations of trastuzumab by week 6 and no significant relationship has been observed between baseline shed antigen and clinical response.

Advanced Gastric Cancer

Steady state pharmacokinetics

A two compartment nonlinear population pharmacokinetic model, based on data from Phase III study BO18255, was used to estimate the steady state pharmacokinetics in patients with advanced gastric cancer administered trastuzumab at a loading dose of 8 mg/kg followed by a 3-weekly maintenance dose of 6 mg/kg. The observed serum levels of trastuzumab were lower and thus total clearance was estimated to be higher in AGC patients compared to breast cancer patients receiving the same dosing regimen. The reason for this is unknown. At high concentrations, total clearance is dominated by linear clearance, and the half-life in AGC patients is approximately 26 days. The median predicted steady-state AUC values (over a period of 3 weeks at steady state) is equal to 1213 mg·day/L, the median steady-state C_max is equal to 132 mg/l and the median steady-state C_min values is equal to 27.6 mg/L.

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

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

10.     DATE OF REVISION OF THE TEXT

23 April 2015

4.2     Posology and method of administration

[…]

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

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

[…]

4.8     Undesirable effects

[…]

Details of risk minimisation measures that are consistent with the EU Risk Management Plan are presented in (section 4.4) Warnings and Precautions.

Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and vice versa

Study MO22982 investigated switching between the Herceptin intravenous and Herceptin subcutaneous formulation with a primary objective to evaluate patient preference for either intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using subcutaneous formulation in vial and one using subcutaneous formulation in administration system) were investigated using a 2-arm , cross-over design with 488 patients being randomized to one of two different three-weekly Herceptin treatment sequences (IV [Cycles 1-4]→ SC [Cycles 5-8], or SC [Cycles 1-4]→ IV [Cycles 5-8]). Patients were either naïve to Herceptin IV treatment (20.3%) or pre-exposed to Herceptin IV (79.7%). For the sequence IV→SC (SC vial and SC formulation in administration system cohorts combined), AE rates (all grades) were described pre-switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8% vs. 56.4%, respectively; for the sequence SC→IV (SC vial and SC formulation in administration system cohorts combined), AE rates (all grades) were described pre- and post-switching as 65.4% vs. 48.7%, respectively.

Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment discontinuations due to adverse events were low (<5%) and similar to post-switching rates (Cycles 5-8). No grade 4 or grade 5 adverse events were reported.

[…]

10.     DATE OF REVISION OF THE TEXT

26 February 2015

10.     DATE OF REVISION OF THE TEXT

24 July 2014

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

4.4       Special warnings and precautions for use

[…]

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

Serious adverse reactionsIRRs to Herceptin infusion that have been reported infrequently includinge dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be used to reduce risk of occurrence of these events. The majority of these events occur during or within 2.5 hours of the start of the first infusion.  Should an infusion reaction occur the infusion should be discontinued or the rate of infusion slowed and the patient should be monitored until resolution of all observed symptoms (see section 4.2). These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. The majority of patients experienced resolution of symptoms and subsequently received further infusions of Herceptin. Serious reactions have been treated

[…]

4.8       Undesirable effects

[…]

[…]

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

Underline Text = new text

Strike through text = deleted text

4.2     Posology and method of administration

[ … ]

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 intravenous formulation is not intended for subcutaneous administration and should be administered via an intravenous infusion only.

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

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

Metastatic breast cancer

Three-weekly schedule

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

[ … ]

4.8     Undesirable effects

[ … ]

Table 1 Undesirable Effects Reported with Intravenous Herceptin Monotherapyor in Combination with Chemotherapy in Pivotal Clinical Trials (N = 8386) and in Post-Marketing

[ … ]

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).

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)

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

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

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

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

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

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

In the joint analysis of the NSABP B-31 and NCCTG N9831 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).

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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 7. 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 7            Summary of Efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831 trials at the time of the definitive DFS analysis^*Efficacy Results from the Joint Analysis of the NCCTG 9831 and NSABP B-31 Trials

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→P H 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 8 below:

Table 8 Final Overall Survival Analysis from the joint analysis of trials NSABP
B-31 and NCCTG N9831

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.

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The efficacy results from the BCIRG 006 are summarized in Tables 8 9 and 910. 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 89 Overview of Efficacy Analyses BCIRG 006  AC→D versus AC→DH