Herceptin 600 mg Solution for Injection in Vial

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.

4.8     Undesirable effects

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Removal of : Pancreatitis

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10.     DATE OF REVISION OF THE TEXT

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27 October 2017

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4.2     Posology and method of administration

 

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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.

 

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4.8     Undesirable effects

 

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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.

 

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5.1     Pharmacodynamic properties

 

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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

 

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6.3     Shelf life

 

18 21 months.

 

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10.     DATE OF REVISION OF THE TEXT

 

2 February 2016

 

4.2     Posology and method of administration

 

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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.

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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.

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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.

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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.

 

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4.8     Undesirable effects

 

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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. 

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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 %.

Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥50 % after the event) was evident for 71.4 % of Herceptin-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5 % of patients. Approximately 17 % of cardiac dysfunction related events occurred after completion of Herceptin.

 

In the pivotal metastatic trials of intravenous Herceptin, the incidence of cardiac dysfunction varied between 9 % and 12 % when it was combined with paclitaxel compared with 1 % – 4 % for paclitaxel alone. For monotherapy, the rate was 6 % – 9 %. The highest rate of cardiac dysfunction was seen in patients receiving Herceptin concurrently with anthracycline/cyclophosphamide (27 %), 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.

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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.

 

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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.

 

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Study MO22982 investigated switching between the Herceptin intravenous and Herceptin subcutaneous formulation with a primary objective to evaluate patient preference for either the 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.

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5.1     Pharmacodynamic properties

 

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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.

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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 C_trough 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.

 

 

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5.3     Preclinical safety data

 

Herceptin Intravenous formulation

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Herceptin Subcutaneous formulation

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10.     DATE OF REVISION OF THE TEXT

 

24 September 2015

 

4.8     Undesirable effects

 

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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

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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.

 

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10.     DATE OF REVISION OF THE TEXT

 

09 July 2015

 

4.4     Special warnings and precautions for use

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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.

 

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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.

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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).

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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.

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4.8     Undesirable effects

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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, C_trough pre dose Cycle 8, showed non-inferiority of the Herceptin subcutaneous compared to the Herceptin intravenous dose adjusted by body weight.

 

The mean C_trough 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 C_trough 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 C_trough 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 T_max following subcutaneous administration was approximately 3 days, with high interindividual variability (range 1-14 days). The mean C_max 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 AUC_{0‑21 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 AUC_{0‑21 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 (V_c) 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 (V_c) was 2.91 L. The Michaelis-Menten parameter values were 11.9 mg/day and 33.9 µg/mL for V_max and K_m, 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 C_min,ss, or about 97% washout) by 7 months.

 

10.     DATE OF REVISION OF THE TEXT

 

23 April 2015

 

 

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4.2     Posology and method of administration

 

[…]

 

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

 

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

 

[…]

 

 

 

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).

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



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, C_trough 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

 

[....][....][....]

 

[....][....][....]

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

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

4.4       Special warnings and precautions for use

[…]

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

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

[…]

4.8       Undesirable effects

[…]

System organ class	Adverse reaction	Frequency
Infections and infestations	Infection	Very common
	Nasopharyngitis	Very common
	+Pneumonia	Common
	Neutropenic sepsis	Common
	Cystitis	Common
	Herpes zoster	Common
	Influenza	Common
	Nasopharyngitis	Common
	Sinusitis	Common
	Skin infection	Common
	Rhinitis	Common
	Upper respiratory tract infection	Common
	Urinary tract infection	Common
	Erysipelas	Common
	Cellulitis	Common
	Pharyngitis	Common
	Sepsis	Uncommon
Neoplasms benign, malignant and unspecified (incl. Cysts and polyps)	Malignant neoplasm progression	Not known
	Neoplasm progression	Not known
Blood and lymphatic system disorders	Febrile neutropenia	Very common
	Anaemia	Very common
	Neutropenia	Very common
	White blood cell count decreased/leukopenia	Very common
	Thrombocytopenia	Very cCommon
	Hypoprothrombinaemia	Not known
Immune system disorders	Hypersensitivity	Common
	+Anaphylactic reaction	Not known
	+Anaphylactic shock	Not known
Metabolism and nutrition disorders	Weight decreased/Weight loss	Very Ccommon
	Anorexia	Very Ccommon
	Hyperkalaemia	Not known
Psychiatric disorders	Insomnia	Very common
	Anxiety	Common
	Depression	Common
	Insomnia	Common
	Thinking abnormal	Common
Nervous system disorders	1Tremor	Very common
	Dizziness	Very common
	Headache	Very common
	Paraesthesia	Very common
	Dysgeusia	Very common
	Peripheral neuropathy	Common
	Paraesthesia	Common
	Hypertonia	Common
	Somnolence	Common
	Dysgeusia	Common
	Ataxia	Common
	Paresis	Rare
	Brain oedema	Not known
Eye disorders	Conjunctivitis	Very common
	Lacrimation increased	Very common
	Dry eye	Common
	Papilloedema	Not known
	Retinal haemorrhage	Not known
Ear and labyrinth disorders	Deafness	Uncommon
Cardiac disorders	1 Blood pressure decreased	Very common
	1 Blood pressure increased	Very common
	1 Heart beat irregular	Very common
	1Palpitation	Very common
	1Cardiac flutter	Very common
	Ejection fraction decreased*	Very common
	+Cardiac failure (congestive)	Common
	+1Supraventricular tachyarrhythmia	Common
	Cardiomyopathy	Common
	Pericardial effusion	Uncommon
	Cardiogenic shock	Not known
	Pericarditis	Not known
	Bradycardia	Not known
	Gallop rhythm present	Not known
Vascular disorders	Hot flush	Very common
	+1 Hypotension	Common
	Vasodilatation	Common
Respiratory, thoracic and mediastinal disorders	+1Wheezing	Very common
	+Dyspnoea	Very common
	Cough	Very common
	Epistaxis	Very common
	Rhinorrhoea	Very common
	+Pneumonia	Common
	Asthma	Common
	Lung disorder	Common
	Pharyngitis	Common
	+Pleural effusion	UncommonCommon
	Pneumonitis	Rare
	+Pulmonary fibrosis	Not known
	+Respiratory distress	Not known
	+Respiratory failure	Not known
	+Lung infiltration	Not known
	+Acute pulmonary oedema	Not known
	+Acute respiratory distress syndrome	Not known
	+Bronchospasm	Not known
	+Hypoxia	Not known
	+Oxygen saturation decreased	Not known
	Laryngeal oedema	Not known
	Orthopnoea	Not known
	Pulmonary oedema	Not known
	Interstitial lung disease	Not known
Gastrointestinal disorders	Diarrhoea	Very common
	Vomiting	Very common
	Nausea	Very common
	1 Lip swelling	Very common
	Abdominal pain	Very common
	Dyspepsia	Very common
	Constipation	Very common
	Stomatitis	Very common
	Pancreatitis	Common
	Haemorrhoids	Common
	Dry mouth	Common
Hepatobiliary disorders	Hepatocellular Injury	Common
	Hepatitis	Common
	Liver Tenderness	Common
	Jaundice	Rare
	Hepatic Failure	Not known
Skin and subcutaneous tissue disorders	Erythema	Very common
	Rash	Very common
	1 Swelling face	Very common
	Alopecia	Very common
	Nail disorder	Very common
	Palmar-plantar erythrodysaesthesia syndrome	Very common
	Acne	Common
	Dry skin	Common
	Ecchymosis	Common
	Hyperhydrosis	Common
	Maculopapular rash	Common
	Pruritus	Common
	Onychoclasis	Common
	Dermatitis	Common
	Urticaria	Uncommon
	Angioedema	Not known
Musculoskeletal and connective tissue disorders	Arthralgia	Very common
	1Muscle tightness	Very common
	Myalgia	Very common
	Arthritis	Common
	Back pain	Common
	Bone pain	Common
	Muscle spasms	Common
	Neck pain	Common
	Pain in extremity	Common
Renal and urinary disorders	Renal disorder	Common
	Glomerulonephritis membranous	Not known
	Glomerulonephropathy	Not known
	Renal failure	Not known
Pregnancy, puerperium and perinatal conditions	Oligohydramnios	Not known
	Renal hypoplasia	Not known
	Pulmonary hypoplasia	Not known
Reproductive system and breast disorders	Breast inflammation/mastitis	Common
General disorders and administration site conditions	Asthenia	Very common
	Chest pain	Very common
	Chills	Very common
	Fatigue	Very common
	Influenza-like symptoms	Very common
	Infusion related reaction	Very common
	Pain	Very common
	Pyrexia	Very common
	Mucosal inflammation	Very common
	Peripheral oedema	CommonVery common
	Malaise	Common
	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