ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Herceptin 150 mg powder for concentrate for solution for infusion
2.
One vial contains 150 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by
mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchange
chromatography including specific viral inactivation and removal procedures.
The reconstituted Herceptin solution contains 21 mg/ml of trastuzumab.
For a full list of excipients, (see section 6.1).
3.
Powder for concentrate for solution for infusion.
Herceptin is a white to pale yellow lyophilised powder.
4.
Breast Cancer
Metastatic Breast Cancer (MBC)
Herceptin is indicated for the treatment of patients with HER2 positive metastatic breast cancer:
-
as monotherapy for the treatment of those patients who have received at least two chemotherapy
regimens for their metastatic disease. Prior chemotherapy must have included at least an
anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor
positive patients must also have failed hormonal therapy, unless patients are unsuitable for these
treatments.
-
in combination with paclitaxel for the treatment of those patients who have not received
chemotherapy for their metastatic disease and for whom an anthracycline is not suitable.
-
in combination with docetaxel for the treatment of those patients who have not received
chemotherapy for their metastatic disease.
-
in combination with an aromatase inhibitor for the treatment of postmenopausal patients with
hormone-receptor positive metastatic breast cancer, not previously treated with trastuzumab.
Early Breast Cancer (EBC)
Herceptin is indicated for the treatment of patients with HER2 positive early breast cancer following
surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see section 5.1).
Herceptin should only be used in patients with metastatic or early breast cancer whose tumours have
either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated
assay (see sections 4.4 and 5.1).
2
Metastatic Gastric Cancer (MGC)
Herceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the
treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-
esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.
Herceptin should only be used in patients with metastatic gastric cancer whose tumours have HER2
overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC 3+ result.
Accurate and validated assay methods should be used (see Sections 4.4 and 5.1).
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 administraton of cytotoxic chemotherapy
(see section 4.4).
MBC
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.
Weekly schedule
The recommended initial loading dose of Herceptin is 4 mg/kg body weight. The recommended
weekly maintenance dose of Herceptin is 2 mg/kg body weight, beginning one week after the loading
dose.
Administration in combination with paclitaxel or docetaxel
In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the
first dose of Herceptin (for dose, see the Summary of Product Characteristics for paclitaxel or
docetaxel) and immediately after the subsequent doses of Herceptin if the preceding dose of Herceptin
was well tolerated.
Administration in combination with an aromatase inhibitor
In the pivotal trial (BO16216) Herceptin and anastrozole were administered from day 1. There were no
restrictions on the relative timing of Herceptin and anastrozole at administration (for dose, see the
Summary of Product Characteristics for anastrozole or other aromatase inhibitors).
EBC
Three-weekly schedule
In the adjuvant setting as investigated in the BO16348 (HERA) trial, Herceptin was initiated after
completion of standard chemotherapy (most commonly, anthracycline-containing regimens or
anthracyclines plus a taxane).
The recommended initial loading dose of Herceptin is 8 mg/kg body weight. The recommended
maintenance dose of Herceptin at three-weekly intervals is 6 mg/kg body weight, beginning three
weeks after the loading dose.
Weekly schedule
In the adjuvant setting Herceptin was also investigated as a weekly regimen (loading dose of 4 mg/kg
followed by 2 mg/kg every week for one year) concomitantly with paclitaxel (administered weekly
(80 mg/m2) or every 3 weeks (175 mg/m2) for a total of 12 weeks) following 4 cycles of AC
(doxorubicin 60 mg/m2 IV push concurrently with cyclophosphamide 600 mg/m2 over 20–30
minutes).
3
MGC
Three-weekly schedule
The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose
at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose..
Breast Cancer (MBC and EBC) and Gastric Cancer (MGC)
Duration of treatment
Patients with MBC or MGC should be treated with Herceptin until progression of disease. Patients
with EBC should be treated with Herceptin for 1 year (18 cycles three-weekly) or until disease
recurrence.
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 for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or
delays.
Missed doses
If the patient misses 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 given 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 given according to the previous schedule.
If the patient misses a dose of Herceptin by more than one week, a re-loading dose of Herceptin
should be given over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen:
8 mg/kg). Subsequent Herceptin maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen
6 mg/kg respectively) should then be given (weekly regimen: every week; three-weekly regimen every
3 weeks) from that point.
Special patient populations
Clinical data show that the disposition of Herceptin is not altered based on age or serum creatinine
(see section 5.2). In clinical trials, elderly patients did not receive reduced doses of Herceptin.
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not
been carried out. However in a population pharmacokinetic analysis, age and renal impairment were
not shown to affect trastuzumab disposition.
Paediatric population
Herceptin is not recommended for use in children below 18 years of age due to insufficient data on
safety and efficacy.
Method of administration
Herceptin loading dose should be administered as a 90-minute intravenous infusion.
Do not administer
as an intravenous push or bolus.
Herceptin intravenous infusion should be administered by a health-
care provider prepared to manage anaphylaxis
and an emergency kit should be available.
Patients
should be observed for at least six hours after the start of the first infusion and for two hours after the
start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms
(see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control such
symptoms. The infusion may be resumed when symptoms abate.
If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute
infusion.
For instructions on use and handling of Herceptin refer to section 6.6.
4
4.3
Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients.
Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary
oxygen therapy.
HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of
the testing procedures (see section 5.1).
Currently no data from clinical trials are available on re-treatment of patients with previous exposure
to Herceptin in the adjuvant setting
.
Cardiotoxicity
Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients
receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly
following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. This may be moderate
to severe and has been associated with death (see section 4.8).
All candidates for treatment with Herceptin, but especially those with prior anthracycline and
cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and
physical examination, ECG, echocardiogram, or MUGA scan or magnetic resonance imaging. A
careful risk-benefit assessment should be made before deciding to treat with Herceptin.
Herceptin and anthracyclines should not be used currently in combination except in a well-controlled
clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are
also at risk of cardiotoxicity with Herceptin treatment, although the risk is lower than with concurrent
use of Herceptin and anthracyclines. Because the half-life of Herceptin is approximately 4-5 weeks
Herceptin may persist in the circulation for up to 20-25 weeks after stopping Herceptin treatment.
Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of
cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 25 weeks
after stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored
carefully (see below)
In EBC, the following patients were excluded from the HERA trial, there are no data about the
benefit-risk balance, and therefore treatment can not be recommended in such patients:
•
History of documented congestive heart failure
•
High-risk uncontrolled arrhythmias
•
Angina pectoris requiring a medicinal product
•
Clinically significant valvular disease
•
Evidence of transmural infarction on ECG
•
Poorly controlled hypertension
Formal cardiological assessment should be considered in patients in whom there are cardiovascular
concerns following baseline screening. Cardiac function should be further monitored during treatment
(e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. For
early breast cancer patients, cardiac assessment, as performed at baseline, should be repeated every 3
months during treatment and at 6, 12 and 24 months following cessation of treatment. Patients who
develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6-8
weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic,
the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has
been seen. Caution should be exercised in treating patients with symptomatic heart failure, a history of
hypertension or documented coronary artery disease, and in early breast cancer, in those patients with
a left ventricular ejection fraction (LVEF) of 55 % or less.
5
If LVEF drops 10 ejection fraction (EF) points from baseline AND to below 50 %, treatment should
be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has
not improved, or declined further, discontinuation of Herceptin should be strongly considered, unless
the benefits for the individual patient are deemed to outweigh the risks. All such patients should be
referred for assessment by a cardiologist and followed up.
If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with the
standard medications for this purpose. Discontinuation of Herceptin therapy should be strongly
considered in patients who develop clinically significant heart failure unless the benefits for an
individual patient are deemed to outweigh the risks.
The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has
not been prospectively studied. However, most patients who developed heart failure in the pivotal
(H0648g, H0649g, M77001, BO16216, BO16348, BO18255) trials improved with standard medical
treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin-converting
enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit
of Herceptin treatment continued on therapy without additional clinical cardiac events.
Infusion reactions, allergic-like reactions and hypersensitivity
Serious adverse reactions to Herceptin infusion that have been reported infrequently include dyspnoea,
hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrythmia, reduced
oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema (see section 4.8). The
majority of these events occur during or within 2.5 hours of the start of the first infusion. Should an
infusion reaction occur the infusion should be discontinued or the rate of infusion slowed and the
patient should be monitored until resolution of all observed symptoms (see section 4.2). The majority
of patients experienced resolution of symptoms and subsequently received further infusions of
Herceptin. Serious reactions have been treated successfully with supportive therapy such as oxygen,
beta-agonists, and corticosteroids. In rare cases, these reactions are associated with a clinical course
culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of
advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction.
Therefore, these patients should not be treated with Herceptin (see section 4.3).
Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical
deterioration have also been reported. Fatalities have occurred within hours and up to one week
following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms
and pulmonary symptoms more than six hours after the start of the Herceptin infusion. Patients should
be warned of the possibility of such a late onset and should be instructed to contact their physician if
these symptoms occur.
Pulmonary events
Severe pulmonary events have been reported with the use of Herceptin in the post-marketing setting
(see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lung
disease including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis,
pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been
reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy
with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine,
vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or
with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced
malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients
should not be treated with Herceptin (see section 4.3). Caution should be exercised for pneumonitis,
especially in patients being treated concomitantly with taxanes.
4.5
No interaction studies have been performed. A risk for interactions with the concomitant use of other
medicinal products cannot be excluded.
6
Pregnancy
Reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times that of the
weekly human maintenance dose of 2 mg/kg Herceptin and have revealed no evidence of impaired
fertility or harm to the foetus. Placental transfer of trastuzumab during the early ( days 20–50 of
gestation) and late (days 120–150 of gestation) foetal development period was observed. It is not
known whether Herceptin can affect reproductive capacity. As animal reproduction studies are not
always predictive of human response, Herceptin should be avoided during pregnancy unless the
potential benefit for the mother outweighs the potential risk to the foetus.
In the post-marketing setting, cases of oligohydramnios, some associated with fatal pulmonary
hypoplasia of the foetus, have been reported in pregnant women receiving Herceptin. Women of
childbearing potential should be advised to use effective contraception during treatment with
Herceptin and for at least 6 months after treatment has concluded. Women who become pregnant
should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with
Herceptin, close monitoring by a multidisciplinary team is desirable.
Lactation
A study conducted in lactating cynomolgus monkeys at doses 25 times that of the weekly human
maintenance dose of 2 mg/kg Herceptin demonstrated that trastuzumab is secreted in the milk. The
presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects
on their growth or development from birth to 1 month of age. It is not known whether trastuzumab is
secreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to the
infant is unknown, women should not breast-feed during Herceptin therapy and for 6 months after the
last dose.
No studies on the effects on the ability to drive and to use machines have been performed. Patients
experiencing infusion-related symptoms should be advised not to drive and use machines until
symptoms abate.
4.8 Undesirable Effects
Amongst the most serious and/or common adverse reactions reported in Herceptin usage to date are
cardiotoxicity, infusion-related reactions, haematotoxicity (in particular neutropenia) and pulmonary
adverse events.
In this section, the following categories of frequency have been used: very common (≥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 should be presented in order of decreasing seriousness.
List of adverse reactions
Presented in the following table are adverse reactions that have been reported in association with the
use of Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the post-
marketing setting. Pivotal trials included:
-
H0648g and H0649g: Herceptin as a monotherapy or in combination with paclitaxel in
metastatic -breast cancer.
-
BO16216: Anastrozole with or without Herceptin in HER2 positive and hormone receptor
positive metastatic breast cancer.
-
BO16348: Herceptin as a monotherapy following adjuvant chemotherapy in HER2 positive
breast cancer.
7
-
M77001: Docetaxel, with or without Herceptin in metastatic breast cancer.
-
BO18255: Herceptin in combination with a fluoropyrimidine and cisplatin versus chemotherapy
alone as first-line therapy in HER2 positive advanced gastric cancer.
All the terms included are based on the highest percentage seen in pivotal clinical trials.
System organ class
Adverse reaction
Frequency
Infections and infestations
+
Pneumonia
Common (
<1 %)
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
Common
Neutropenia
Common
Thrombocytopenia
Common
White blood cell count
decreased/leukopenia
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
1
Tremor
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
Dry eye
Common
Lacrimation increased
Common
8
System organ class
Adverse reaction
Frequency
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
1
Palpitation
Very common
1
Cardiac flutter
Very common
+
Cardiac failure (congestive)
Common (2 %)
+1
Supraventricular tachyarrhythmia
Common
Cardiomyopathy
Common
Ejection fraction decreased
Common
Pericardial effusion
Uncommon
Cardiogenic shock
Not known
Pericarditis
Not known
Bradycardia
Not known
Gallop rhythm present
Not known
Vascular disorders
+1
Hypotension
Common
Vasodilatation
Common
Respiratory, thoracic and
mediastinal disorders
+1
Wheezing
Very common
+
Dyspnoea
Very common (14 %)
Asthma
Common
Cough
Common
Epistaxis
Common
Lung disorder
Common
Pharyngitis
Common
Rhinorrhoea
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
Pancreatitis
Common
Dyspepsia
Common
Haemorrhoids
Common
Constipation
Common
Dry mouth
Common
Hepatobiliary disorders
Hepatitis
Common
9
System organ class
Adverse reaction
Frequency
Liver Tenderness
Common
Jaundice
Rare
Hepatic Failure
Not known
Hepatocellular Damage
Not known
Skin and subcutaneous
disorders
Erythema
Very common
Rash
Very common
1
Swelling face
Very common
Acne
Common
Alopecia
Common
Dry skin
Common
Ecchymosis
Common
Hyperhydrosis
Common
Maculopapular rash
Common
Nail disorder
Common
Pruritus
Common
Angioedema
Not known
Dermatitis
Not known
Urticaria
Not known
Musculoskeletal and
connective tissue disorders
Arthralgia
Very common
1
Muscle tightness
Very common
Myalgia
Very common
Arthritis
Common
Back pain
Common
Bone pain
Common
Muscle spasms
Common
Neck pain
Common
Renal and urinary
conditions
Renal disorder
Common
Glomerulonephritis membranous
Not known
Glomerulonephropathy
Not known
Renal failure
Not known
Pregnancy, puerperium and
perinatal disorders
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
Peripheral oedema
Common
Malaise
Common
Mucosal inflammation
Common
Oedema
Common
Injury, poisoning and
procedural complications
Contusion
Common
+ Denotes adverse reactionsthat have been reported in association with a fatal outcome.
1 Denotes adverse reactionsthat are reported largely in association with Infusion-related reactions. Specific
percentages for these are not available.
10
Note:
Specific percentage frequencies have been provided in brackets for terms that have been reported in
association with a fatal outcome with the frequency designation ‘common’ or ‘very common’. The specific
percentage frequencies relate to total number of these events, both fatal and non-fatal.
The following adverse reactionswere reported in pivotal clinical trials with a frequency of ≥ 1/10 in
either treatment arm (in HERA, BO16348 ≥ 1% at 1 year) and with no significant difference between
the Herceptin-containing arm and the comparator arm: lethargy, hypoaesthesia, pain in extremity,
oropharyngeal pain, conjunctivitis, lymphoedema, weight increased, nail toxicity, musculoskeletal
pain, pharyngitis, bronchitis, chest discomfort, abdominal pain upper, gastritis, stomatitis, vertigo, hot
flush, hypertension, hiccups, palmar-plantar erythrodysaesthesia syndrome, breast pain,
onychorrhexis, dyspnoea exertional and dysuria.
Description of selected adverse reactions
Cardiotoxicity
Cardiotoxicity (heart failure), NYHA II - IV is a common adverse reaction associated with the use of
Herceptin and has been associated with a fatal outcome (see section 4.4).
The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has
not been prospectively studied. However, most patients who developed heart failure in the pivotal
trials (H0648g, H0649g, M77001, BO16216, BO16348, BO18255) improved with standard medical
treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin-converting
enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit
of Herceptin treatment continued on therapy with Herceptin without additional clinical cardiac events.
Infusion reactions, allergic-like reactions and hypersensitivity
It is estimated that approximately 40 % of patients who are treated with Herceptin will experience
some form of infusion-related reaction. However, the majority of infusion-related reactions are mild to
moderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e. during
infusions one, two and three and lessen in frequency in subsequent infusions. Reactions include, but
are not limited to, chills, fever, rash, nausea and vomiting, dyspnoea and headache (see section 4.4).
Severe anaphylactic reactions requiring immediate additional intervention can occur usually during
either the first or second infusion of Herceptin (see section 4.4) and have been associated with a fatal
outcome.
Haematotoxicity
Febrile neutropenia occured very commonly. Commonly occurring adverse reactions included
anaemia, leukopenia, thrombocytopenia and neutropenia. The frequency of occurrence of
hypoprothrombinemia is not known.
Pulmonary events
Severe pulmonary adverse reactions occur in association with the use of Herceptin and have been
associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute
respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute
pulmonary oedema and respiratory insufficiency (see section 4.4).
Details of risk minimisation measures that are consistent with the EU Risk Management Plan are
presented in (section 4.4) Warnings and Precautions.
4.9
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. Doses up to this level were well
tolerated.
11
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03
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 of HER2-positivity rates in gastric cancer (GC) using immunohistochemistry
(IHC) and fluorescence
in situ
hybridization (FISH) or chromogenic
in situ
hybridization (CISH) have
shown that there is a broad variation of HER2-positivity ranging from 6.8 % to 34.0% for IHC and
7.1 % to 42.6 % for FISH. 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 follows:
Score
Staining pattern
HER2 overexpression
assessment
0
No staining is observed or membrane staining is
observed in < 10 % of the tumour cells
Negative
1+
A faint/barely perceptible membrane staining is
detected in > 10 % of the tumour cells. The cells are
only stained in part of their membrane.
Negative
2+
A weak to moderate complete membrane staining is
detected in > 10 % of the tumour cells.
Equivocal
3+
Strong complete membrane staining is detected in
> 10 % of the tumour cells.
Positive
In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to
the chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the
HER2 gene per tumour cell if no chromosome 17 control is used.
12
In general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus
in greater than 50 % of tumour cells.
For full instructions on assay performance and interpretation please refer to the package inserts of
validated FISH and CISH assays. Official recommendations on HER2 testing may also apply.
For any other method that may be used for the assessment of HER2 protein or gene expression, the
analyses should only be performed by laboratories that provide adequate state-of-the-art performance
of validated methods. Such methods must clearly be precise and accurate enough to demonstrate
overexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and
strong (congruent with 3+) overexpression of HER2.
Detection of HER2 over expression or HER2 gene amplification in gastric cancer
Only an accurate and validated assay should be used to detect HER2 over expression or HER2 gene
amplification. IHC is recommended as the first testing modality and in cases where HER2 gene
amplification status is also required, either a silver-enhanced
in situ
hybridization (SISH) or a FISH
technique must be applied. SISH technology is however, recommended to allow for the parallel
evaluation of tumor histology and morphology. To ensure validation of testing procedures and the
generation of accurate and reproducible results, HER2 testing must be performed in a laboratory
staffed by trained personnel. Full instructions on assay performance and results interpretation should
be taken from the product information leaflet provided with the HER2 testing assays used.
In the ToGA (BO18255) trial, patients whose tumours were either IHC3+ or FISH positive were
defined as HER2 positive and thus included in the trial. Based on the clinical trial results, the
beneficial effects were limited to patients with the highest level of HER2 protein overexpression,
defined by a 3+ score by IHC, or a 2+ score by IHC and a positive FISH result.
In a method comparison study (study D008548) a high degree of concordance (>95%) was observed
for SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients.
HER2 over expression should be detected using an immunohistochemistry (IHC)-based assessment of
fixed tumour blocks; HER2 gene amplification should be detected using
in situ
hybridisation using
either SISH or FISH on fixed tumour blocks.
13
The recommended scoring system to evaluate the IHC staining patterns is as follows:
Score
Surgical specimen - staining
pattern
Biopsy specimen –
staining pattern
HER2
overexpression
assessment
0
No reactivity or membranous
reactivity in < 10 % of tumour
cells
No reactivity or membranous
reactivity in any tumour cell
Negative
1+
Faint ⁄ barely perceptible
membranous reactivity in ≥
10 % of tumour cells; cells are
reactive only in part of their
membrane
Tumour cell cluster with a faint ⁄
barely perceptible membranous
reactivity irrespective of
percentage of tumour cells
stained
Negative
Weak to moderate complete,
basolateral or lateral
membranous reactivity in
≥ 10 % of tumour cells
Tumour cell cluster with a weak
to moderate complete,
basolateral or lateral
membranous reactivity
irrespective of percentage of
tumour cells stained
2+
Equivocal
3+
Strong complete, basolateral
or lateral membranous
reactivity in ≥ 10 % of tumour
cells
Tumour cell cluster with a
strong complete, basolateral or
lateral membranous reactivity
irrespective of percentage of
tumour cells stained
Positive
In general, SISH or FISH is considered positive if the ratio of the HER2 gene copy number per tumour
cell to the chromosome 17 copy number is greater than or equal to 2.
Clinical efficacy and safety
MBC
Herceptin has been used in clinical trials as monotherapy for patients with metastatic breast cancer
who have tumours that overexpress HER2 and who have failed one or more chemotherapy regimens
for their metastatic disease (Herceptin alone).
Herceptin has also been used in combination with paclitaxel or docetaxel for the treatment of patients
who have not received chemotherapy for their metastatic disease. Patients who had previously
received anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m
2
infused
over 3 hours) with or without Herceptin. In the pivotal trial of docetaxel (100 mg/m
2
infused over
1 hour) with or without Herceptin, 60 % of the patients had received prior anthracycline-based
adjuvant chemotherapy. Patients were treated with Herceptin until progression of disease.
The efficacy of Herceptin in combination with paclitaxel in patients who did not receive prior adjuvant
anthracyclines has not been studied. However, Herceptin plus docetaxel was efficacious in patients
whether or not they had received prior adjuvant anthracyclines.
The test method for HER2 overexpression used to determine eligibility of patients in the pivotal
Herceptin monotherapy and Herceptin plus paclitaxel clinical trials employed immunohistochemical
staining for HER2 of fixed material from breast tumours using the murine monoclonal antibodies
CB11 and 4D5. These tissues were fixed in formalin or Bouin’s
fixative. This investigative clinical
trial assay performed in a central laboratory utilised a 0 to 3+ scale. Patients classified as staining 2+
or 3+ were included, while those staining 0 or 1+ were excluded. Greater than 70 % of patients
enrolled exhibited 3+ overexpression. The data suggest that beneficial effects were greater among
those patients with higher levels of overexpression of HER2 (3+).
14
The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or
without Herceptin, was immunohistochemistry. A minority of patients was tested using fluorescence
in-situ
hybridisation (FISH). In this trial, 87 % of patients entered had disease that was IHC3+, and
95 % of patients entered had disease that was IHC3+ and/or FISH-positive.
Weekly dosing in MBC
The efficacy results from the monotherapy and combination therapy studies are summarised in the
following table:
Parameter
Monotherapy
Combination Therapy
Herceptin
1
Herceptin
plus
paclitaxel
2
N=68
Paclitaxel
2
Herceptin
plus
docetaxel
3
N=92
Docetaxel
3
N=172
N=77
N=94
Response rate
(95 %CI)
18 %
(13 - 25)
49 %
(36 - 61)
17 %
(9 - 27)
61 %
(50-71)
34 %
(25-45)
Median duration of
response (months)
(95
%CI)
9.1
(5.6-10.3)
8.3
(7.3-8.8)
4.6
(3.7-7.4)
11.7
(9.3 – 15.0)
5.7
(4.6-7.6)
Median TTP
(months) (95 %CI)
3.2
(2.6-3.5)
7.1
(6.2-12.0)
3.0
(2.0-4.4)
11.7
(9.2-13.5)
6.1
(5.4-7.2)
22.74
(19.1-30.8)
TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached.
1.
16.4
(12.3-ne)
24.8
(18.6-33.7)
17.9
(11.2-23.8)
31.2
(27.3-40.8)
Study H0649g: IHC3+ patient subset
2.
Study M77001: Full analysis set (intent-to-treat) , 24 months results
Combination treatment with Herceptin and anastrozole
Herceptin has been studied in combination with anastrozole for first line treatment of metastatic breast
cancer in HER2 overexpressing, hormone-receptor (i.e. estrogen-receptor (ER) and/or progesterone-
receptor (PR)) positive postmenopausal patients. Progression free survival was doubled in the
Herceptin plus anastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the other
parameters the improvements seen for the combination were for overall response (16.5 % versus
6.7 %); clinical benefit rate (42.7 % versus 27.9 %); time to progression (4.8 months versus 2.4
months). For time to response and duration of response no difference could be recorded between the
arms. The median overall survival was extended by 4.6 months for patients in the combination arm.
The difference was not statistically significant, however more than half of the patients in the
anastrozole alone arm crossed over to a Herceptin containing regimen after progression of disease.
Three -weekly dosing in MBC
The efficacy results from the non-comparative monotherapy and combination therapy studies are
summarised in the following table:
15
Median Survival
(months) (95 %CI)
3.
Study H0648g: IHC3+ patient subset
Parameter
Monotherapy
Combination Therapy
Herceptin
1
N=105
Herceptin
2
N=72
Herceptin plus
paclitaxel
3
N=32
Herceptin plus
Docetaxel
4
N=110
Response rate
(95 %CI)
24 %
(15 - 35)
27 %
(14 - 43)
59 %
(41-76)
73 %
(63-81)
Median duration of
response (months)
(range)
10.1
(2.8-35.6)
7.9
(2.1-18.8)
10.5
(1.8-21)
13.4
(2.1-55.1)
Median TTP
(months) (95 %CI)
3.4
(2.8-4.1)
7.7
(4.2-8.3)
12.2
(6.2-ne)
13.6
(11-16)
47.3
(32-ne)
TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached.
1.
ne
ne
ne
Study WO16229: loading dose 8 mg/kg, followed by 6 mg/kg 3 weekly schedule
2.
Study MO16982: loading dose 6 mg/kg weekly x 3; followed by 6 mg/kg 3-weekly schedule
3.
Study MO16419
Sites of progression
The frequency of progression in the liver was significantly reduced in patients treated with the
combination of Herceptin and paclitaxel, compared to paclitaxel alone (21.8 % vs. 45.7 %; p=0.004).
More patients treated with Herceptin and paclitaxel progressed in the central nervous system than
those treated with paclitaxel alone (12.6 % vs. 6.5 %; p=0.377).
EBC
Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast. Early breast
cancer in the HERA trial was limited to operable, primary, invasive adenocarcinoma of the breast,
with axillary nodes positive or axillary nodes negative if tumours at least 1 cm in diameter.
In the adjuvant setting, Herceptin was investigated in a multicentre, randomised, trial (HERA)
designed to compare one year of three-weekly Herceptin treatment versus observation in patients with
HER2 positive early breast cancer following surgery, established chemotherapy and radiotherapy (if
applicable). Patients assigned to receive Herceptin were given an initial loading dose of 8 mg/kg,
followed by 6 mg/kg every three weeks for one year.
The efficacy results from the HERA trial are summarized in the following table:
Parameter
Observation
N=1693
Herceptin 1 Year
N = 1693
P-value vs
Observation
Hazard Ratio vs
Observation
Disease-free survival
- No. patients with event
219 (12.9 %) 127 (7.5 %)
< 0.0001
0.54
- No. patients without event 1474 (87.1 %) 1566 (92.5 %)
Recurrence-free survival
- No. patients with event
208 (12.3 %) 113 (6.7 %)
< 0.0001
0.51
- No. patients without event 1485 (87.7 %) 1580 (93.3 %)
Distant disease-free survival
- No. patients with event
184 (10.9 %) 99 (5.8 %)
< 0.0001
0.50
- No. patients without event 1508 (89.1 %) 1594 (94.2 %)
Study BO16348 (HERA): 12 months follow-up
For the primary endpoint, DFS, the hazard ratio translates into an absolute benefit, in terms of a 2-year
disease-free survival rate, of 7.6 percentage points (85.8 % vs 78.2 %) in favour of the Herceptin arm.
16
Median Survival
(months) (95 %CI)
4.
Study BO15935
MGC
Herceptin has been investigated in one randomised, open-label phase III trial ToGA (BO18255) in
combination with chemotherapy versus chemotherapy alone.
Chemotherapy was administered as follows:
- capecitabine - 1000 mg/m
2
orally twice daily for 14 days every 3 weeks for 6 cycles
(evening of day 1 to morning of day 15 of each cycle)
or
- intravenous 5-fluorouracil - 800 mg/m
2
/day as a continuous i.v. infusion over 5 days, given
every 3 weeks for 6 cycles (days 1 to 5 of each cycle)
Either of which was administered with:
- cisplatin - 80 mg/m
2
every 3 weeks for 6 cycles on day 1 of each cycle.
The efficacy results from study BO18225 are summarized in the following table:
Parameter
FP
N = 290
FP +H
N = 294
HR (95 % CI)
p-value
Overall Survival, Median months
11.1
13.8
0.74 (0.60-0.91)
0.0046
Progression-Free Survival,
Median months
5.5
6.7
0.71 (0.59-0.85)
0.0002
Time to Disease Progression,
Median months
5.6
7.1
0.70 (0.58-0.85)
0.0003
Overall Response Rate, %
34.5 %
47.3 %
1.70
a
(1.22, 2.38)
0.0017
Duration of Response, Median
months
4.8
6.9
0.54 (0.40-0.73)
< 0.0001
FP + H:
Fluoropyrimidine/cisplatin + Herceptin
FP: Fluoropyrimidine/cisplatin
a Odds ratio
Patients were recruited to the trial who were previously untreated for HER2-positive inoperable
locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal
junction not amenable to curative therapy. The primary endpoint was overall survival which was
defined as the time from the date of randomization to the date of death from any cause. At the time of
the analysis a total of 349 randomized patients had died: 182 patients (62.8 %) in the control arm and
167 patients (56.8 %) in the treatment arm. The majority of the deaths were due to events related to the
underlying cancer.
Post-hoc subgroup analyses indicate that positive treatment effects are limited to targeting tumours
with higher levels of HER2 protein (IHC 2+/FISH+ or IHC 3+). The median overall survival for the
high HER2 expressing group was 11.8 months versus 16 months, HR 0.65 (95 % CI 0.51-0.83) and
the median progression free survival was 5.5 months versus 7.6 months, HR 0.64 (95 % CI 0.51-0.79)
for FP versus FP + H, respectively. For overall survival, the HR was 0.75 (95 % CI 0.51-1.11) in the
IHC 2+/FISH+ group and the HR was 0.58 (95 % CI 0.41-0.81) in the IHC 3+/FISH+ group
In an exploratory subgroup analysis performed in the TOGA (BO18255) trial there was no apparent
benefit on overall survival with the addition of Herceptin in patients with ECOG PS 2 at baseline [HR
0.96 (95 % CI 0.51-1.79)], non measurable [HR 1.78 (95 % CI 0.87-3.66)] and locally advanced
disease [HR 1.20 (95 % CI 0.29-4.97)].
17
Immunogenicity
903 breast cancer patients treated with Herceptin, alone or in combination with chemotherapy, have
been evaluated for antibody production. Human anti-trastuzumab antibodies were detected in
one patient, who had no allergic manifestations.
There are no immunogenicity data available for Herceptin in gastric cancer.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Herceptin in all subsets of the paediatric population in Breast and Gastric cancer. See section 4.2 for
information on paediatric use.
5.2 Pharmacokinetic properties
The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer and
early breast cancer. Short duration intravenous infusions of 10, 50, 100, 250, and 500 mg trastuzumab
once weekly in patients demonstrated non-linear pharmacokinetics where clearance decreased with
increasing dose. Formal drug-drug interaction studies have not been performed with Herceptin.
Breast Cancer
Half-life
The elimination half-life is of 28-38 days and subsequently the washout period is up to 25 weeks (175
days or 5 elimination half-lives).
Steady State pharmacokinetics
Steady state should be reached by approximately 25 weeks (175 days or 5 elimination half-lives). In a
population pharmacokinetic (two compartment, model-dependent) assessment of Phase I, II and III
clinical trials in metastatic breast cancer, the median predicted AUC at steady state over a three-week
period was three times 578 mg•day/l (1677 mg•day/l) with 3 weekly doses and 1793 mg day/l with
one every three week dose; the estimated median peak concentrations were 104 mg/l and 189 mg/l and
the trough concentrations were 64.9 mg/l and 47.3 mg/l, respectively. In patients with early breast
cancer administered Herceptin at a loading dose of 8 mg/kg followed every three weeks by 6 mg/kg,
using model-independent or non-compartmental analyses (NCA) the mean steady state trough
concentration measured at cycle 13 (week 37) was 63 mg/l, which was comparable to that reported
previously in patients with metastatic breast cancer receiving the weekly regimen.
Clearance (CL)
The typical trastuzumab clearance (for a body weight of 68 kg) was 0.241 l/day.
The effects of patient characteristics (such as age or serum creatinine) on the disposition of
trastuzumab have been evaluated. The data suggest that the disposition of trastuzumab is not altered in
any of these groups of patients (see section 4.2), however, studies were not specifically designed to
investigate the impact of renal impairment upon pharmacokinetics.
Volume of distribution
In all clinical studies, the volume of distribution of the central (V
c
) and the peripheral (V
p
)
compartment was 3.02 l and 2.68 l, respectively, in the typical patient.
Circulating shed antigen
Detectable concentrations of the circulating extracellular domain of the HER2 receptor (shed antigen)
are found in the serum of some patients with HER2 overexpressing breast cancers. Determination of
shed antigen in baseline serum samples revealed that 64 % (286/447) of patients had detectable shed
antigen, which ranged as high as 1880 ng/ml (median = 11 ng/ml). Patients with higher baseline shed
antigen levels were more likely to have lower serum trough concentrations of trastuzumab. However,
18
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.
Gastric Cancer
Steady state pharmacokinetics in advanced gastric cancer
A two compartment population pharmacokinetic method, using data from the Phase III study
BO18255, was used to estimate the steady state pharmacokinetics in patients with advanced gastric
cancer administered trastuzumab 3-weekly at a loading dose of 8 mg/kg followed by a 3-weekly
maintenance dose of 6 mg/kg. In this assessment, the typical clearance of trastuzumab was 0.378 l/day
and the typical volume of distribution in the central compartment was 3.91 l, with a corresponding
median elimination half-life of 14.5 days. The median predicted steady-state AUC values (over a
period of 3 weeks at steady state) is equal to 1030 mg•day/l, the median steady-state C
max
is equal to
128 mg/l and the median steady-state C
min
values is equal to 23 mg/l.
There are no data on the level of circulating extracellular domain of the HER2 receptor (shed antigen)
in the serum of gastric cancer patients.
5.3 Preclinical safety data
There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, or
reproductive toxicity in teratology, female fertility or late gestational toxicity/placental transfer
studies. Herceptin is not genotoxic. A study of trehalose, a major formulation excipient did not reveal
any toxicities.
No long-term animal studies have been performed to establish the carcinogenic potential of Herceptin,
or to determine its effects on fertility in males.
6.
6.1 List of excipients
L-histidine hydrochloride
L-histidine
α,α-trehalose dihydrate
polysorbate 20
6.2
Incompatibilities
Herceptin should not be mixed or diluted with other products except those mentioned under section
6.6.
Do not dilute with glucose solutions since these cause aggregation of the protein.
6.3 Shelf life
4 years
After reconstitution with water for injections the reconstituted solution is physically and chemically
stable for 48 hours at 2°C – 8°C. Any remaining reconstituted solution should be discarded.
Solutions of Herceptin for infusion are physically and chemically stable in polyvinylchloride,
polyethylene or polypropylene bags containing sodium chloride 9 mg/ml (0.9%) solution for injection
for 24 hours at temperatures not exceeding 30°C.
19
From a microbiological point of view, the reconstituted solution and Herceptin infusion solution
should be used immediately. The product is not intended to be stored after reconstitution and dilution
unless this has taken place under controlled and validated aseptic conditions. If not used immediately,
in-use storage times and conditions are the responsibility of the user.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
6.5 Nature and contents of container
Herceptin vial:
One 15 ml clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film
containing 150 mg of trastuzumab.
Each carton contains one vial.
6.6 Special Precautions for disposal and other handling
Appropriate aseptic technique should be used. Each vial of Herceptin is reconstituted with 7.2 ml of
water for injections (not supplied). Use of other reconstitution solvents should be avoided.
This yields a 7.4 ml solution for single-dose use, containing approximately 21 mg/ml trastuzumab, at a
pH of approximately 6.0. A volume overage of 4 % ensures that the labelled dose of 150 mg can be
withdrawn from each vial.
Herceptin should be carefully handled during reconstitution. Causing excessive foaming during
reconstitution or shaking the reconstituted solution may result in problems with the amount of
Herceptin that can be withdrawn from the vial.
The reconstituted solution should not be frozen.
Instructions for reconstitution:
1) Using a sterile syringe, slowly inject 7.2 ml of water for injections in the vial containing the
lyophilised Herceptin, directing the stream into the lyophilised cake.
2) Swirl the vial gently to aid reconstitution. DO NOT SHAKE!
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed
for approximately 5 minutes. The reconstituted Herceptin results in a colourless to pale yellow
transparent solution and should be essentially free of visible particulates.
Determine the volume of the solution required:
•
based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose
of 2 mg trastuzumab/kg body weight:
Volume
(ml) =
Body weight
(kg) x
dose
(
4
mg/kg for loading or
2
mg/kg for maintenance)
21
(mg/ml, concentration of reconstituted solution)
•
based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3-weekly dose
of 6 mg trastuzumab/kg body weight:
Volume
(ml) =
Body weight
(kg) x
dose
(
8
mg/kg for loading or 6 mg/kg for maintenance)
The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag
containing 250 ml of 0.9 % sodium chloride solution. Do not use with glucose-containing solutions
(see section 6.2). The bag should be gently inverted to mix the solution in order to avoid foaming.
20
21
(mg/ml, concentration of reconstituted solution)
Once the infusion is prepared it should be administered immediately. If diluted aseptically, it may be
stored for 24 hours (do not store above 30°C).
Parenteral medicinal products should be inspected visually for particulate matter and discoloration
prior to administration.
Herceptin is for single-use only, as the product contains no preservatives. Any unused product or
waste material should be disposed of in accordance with local requirements.
No incompatibilities between Herceptin and polyvinylchloride, polyethylene or polypropylene bags
have been observed.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
EU/1/00/145/001
9.
Date of first authorisation: 28 August 2000
Date of latest renewal: 4 September 2010
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
21
ANNEX II
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE(S) AND MANUFACTURING
AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
22
A.
MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) of the biological active substance(s)
Roche Diagnostics GmBH, Pharma Biotechnology Production
Nonnenwald 2
82372 Penzberg
Germany
Genentech Inc.
1000 New Horizons Way
Vacaville, CA 95688
USA
Name and address of the manufacturer(s) responsible for batch release
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
B.
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Risk Management Plan
The MAH commits to performing the trials and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan, as agreed in version 5.0 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
23
The MAH will continue to submit periodic safety update reports (PSURs) on a six-monthly basis.
24
ANNEX III
LABELLING AND PACKAGE LEAFLET
25
A. LABELLING
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Herceptin 150 mg powder for concentrate for solution for infusion
Trastuzumab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
The vial contains 150 mg trastuzumab. After reconstitution 1 ml concentrate contains 21 mg of
trastuzumab
3.
LIST OF EXCIPIENTS
L-histidine hydrochloride, L-histidine, polysorbate 20, α,α-trehalose dehydrate.
4.
Powder for concentrate for solution for infusion
1 vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution and dilution
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2ºC – 8 ºC).
27
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1//00/145/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
28
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Herceptin 150 mg powder for infusion
Trastuzumab
Intravenous use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
29
B. PACKAGE LEAFLET
30
PACKAGE LEAFLET: INFORMATION FOR THE USER
Herceptin 150 mg powder for concentrate for solution for infusion
trastuzumab
Read all of this leaflet carefully before you start using this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
•
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet:
1.
What Herceptin is and what it is used for
2.
Before you use Herceptin
4.
Possible side effects
5.
How to store Herceptin
6.
Further information
1.
WHAT HERCEPTIN IS AND WHAT IT IS USED FOR
Herceptin contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal
antibodies attach to specific proteins or antigens. Trastuzumab is designed to bind selectively to an
antigen called human epidermal growth factor 2 (HER2). HER2 is found in large amounts on the
surface of some cancer cells where it stimulates their growth. When Herceptin binds to HER2 it stops
the growth of such cells and causes them to die.
Your doctor may prescribe Herceptin for the treatment of breast and gastric cancer when:
•
You have early breast cancer, with high levels of HER2 and your chemotherapy treatment is
finished.
•
You have metastatic breast cancer (i.e. breast cancer that has spread beyond the original
tumour) with high levels of HER2. Herceptin may be prescribed in combination with the
chemotherapy agents paclitaxel or docetaxel as first treatment for metastatic breast cancer or it
may be prescribed alone if other treatments have proved unsuccessful. It is also used in
combination with medicines called aromatase inhibitors with patients with high levels of HER2
and hormone receptor-positive metastatic breast cancer (i.e. cancer that is sensitive to the
presence of female sex hormones)
•
You have metastatic gastric cancer with high levels of HER2, when it is in combination with
the other cancer medicines capecitabine or 5-flououracil and cisplatin.
If you receive Herceptin with paclitaxel, docetaxel, an aromatase inhibitor, capecitabine, 5-
fluorouracil, or cisplatin you should also read the package leaflets for these products.
2.
BEFORE YOU USE HERCEPTIN
Do not use Herceptin
•
If you are allergic to trastuzumab, to murine (mouse) proteins, or to any of the other ingredients.
•
If you have severe breathing problems at rest due to your cancer or if you need oxygen
treatment.
31
3.
How to use Herceptin
Tell your doctor before you use Herceptin
•
If you have had heart failure, coronary artery disease, heart valve disease (heart murmers) or
high blood pressure. Talk to your doctor about this because Herceptin can cause heart failure.
•
If you have ever had chemotherapy with a medicine called doxorubicin or a medicine related to
doxorubicin (your doctor can advise you here). These medicinal products can damage heart
muscle and increase the risk of heart problems with Herceptin.
•
If you are breathless. Herceptin can cause breathing difficulties, especially when it is first
given. This could be more serious if you are already breathless. Very rarely, patients with
severe breathing difficulties before treatment have died when they were given Herceptin.
Your doctor will closely supervise your therapy with Herceptin
Apart from breathing difficulties, Herceptin can cause fever, chills, flu-like symptoms, swelling of the
face and lips, rash, wheezing, heart rhythm disturbances and blood pressure changes. These effects
mainly occur with the first infusion (“drip” into your vein) and during the first few hours after the start
of the infusion. Occasionally, symptoms start later than six hours after the infusion begins. Sometimes,
symptoms may improve and then get worse later. If this happens to you, contact your doctor
immediately. You will be observed by a health care professional during the infusion and for at least six
hours after the start of the first infusion and for two hours after the start of other infusions. If you
develop a reaction, they will slow down or stop the infusion and may give you treatment to counteract
the side effects.
Treatment with Herceptin may affect the heart. Therefore, your heart function will be checked before
and during the treatment with Herceptin. If you develop any signs of heart failure (i.e., inadequate
pumping of blood by the heart), you may have to stop Herceptin.
Taking other medicines:
Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
It may take up to 6 months for Herceptin to be removed from the body. Therefore you should tell your
doctor or pharmacist that you have had Herceptin if you start any new medication in the 6 months after
stopping treatment
Use in children and adolescents
At present, Herceptin is not recommended for anyone under the age of 18 years because there is not
enough information in this age group.
Pregnancy and breast-feeding
Before starting treatment, you must tell your doctor if you are pregnant, if you think you are pregnant
or if you intend to become pregnant. You should use effective contraception during treatment with
Herceptin and for at least 6 months after treatment has concluded.
In rare cases, a reduction in the
amount of (amniotic) fluid that surrounds the developing baby within the womb has been observed in
pregnant women receiving Herceptin. Your doctor will advise you of the risks and benefits of taking
Herceptin during pregnancy.
Do not breast-feed your baby during Herceptin therapy and for 6 months after the last dose of
Herceptin.
Ask your doctor or pharmacist for advice before taking any medicine
Driving and using machines
We do not know whether Herceptin could affect your ability to drive a car or operate machines.
However, if you experience symptoms, such as chills or fever, during an infusion of Herceptin (see
section 4), you should not drive or use machines until these symptoms disappear.
32
3.
HOW TO USE HERCEPTIN
Herceptin is given as an intravenous infusion (“drip”) directly into your veins. The first dose of your
treatment is given over 90 minutes and you will be observed by a health professional while it is being
given in case you have any side effects. If the first dose is well tolerated the next doses may be given
over 30 minutes (see section 2 under “Tell your doctor before you use Herceptin”).
Before starting the treatment your doctor will determine the amount of HER2 in your tumour. Only
patients with a large amount of HER2 will be treated with Herceptin. Your doctor will prescribe a dose
and treatment regimen that is right for
you
. The dose of Herceptin depends on your body weight. The
number of infusions you receive will depend on how you respond to the treatment. Your doctor will
discuss this with you.
For early breast cancer, metastatic breast cancer and metastatic gastric cancer, Herceptin is given
every 3 weeks. Herceptin may also be given once a week for metastatic breast cancer.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Herceptin can cause side effects, although not everybody gets them. Some of these
side effects may be serious and may lead to hospitalisation.
During a Herceptin infusion, chills, fever and other flu like symptoms may occur. These are very
common (affects more than 1 user in 10). They mainly occur with the first infusion and are temporary.
Other infusion-related symptoms are: feeling sick (nausea), vomiting, pain, increased muscle tension
and shaking, headache, dizziness, breathing difficulties, wheezing, high or low blood pressure, heart
rhythm disturbances (palpitations, heart fluttering or irregular heart beat), swelling of the face and lips,
rash and feeling tired. These symptoms can be serious and some patients have died (see 2. under “Tell
your doctor before you use Herceptin
”). You will be observed by a health professional during and
after each infusion. If you develop a reaction, they will slow down or stop the infusion and may give
you treatment to counteract the side effects. The infusion may be continued after the symptoms
improve.
Other side effects can occur at any time during treatment with Herceptin, not just related to an
infusion. Heart problems can sometimes occur and can be serious. They include weakening of the
heart muscle possibly leading to heart failure, inflammation (i.e. swollen, red, hot, and in pain) of the
lining around the heart and heart rhythm disturbances. Your doctor will monitor your heart regularly
during treatment but you should tell your doctor immediately if you notice:
•
breathlessness (including breathlessness at night),
•
cough,
•-
fluid retention (swelling) in the legs or arms,
•
palpitations (heart fluttering or irregular heart beat).
Very common side effects of Herceptin
(affects more than 1 user in 10)
:
•
diarrhoea,
•
weakness,
•
skin rashes,
•
chest pain,
•
abdominal pain,
•
joint pain,
•
febrile neutropenia
•
and muscle pain.
33
Other common side effects of Herceptin
(affects 1 to 10 users in 100):
•
allergic reactions
•
itchiness
•
abnormal blood counts (anaemia, low
platelet count and low white blood count)
•
dry mouth and skin
•
constipation
•
dry or watery eyes
•
heartburn (dyspepsia)
•
sweating
•
infections including bladder and skin
infections
•
feeling weak and unwell
•
shingles •
anxiety
•
inflammation of the breast •
depression
•
inflammation of the pancreas or liver •
abnormal thinking
•
kidney disorders •
dizziness
•
increased muscle tone /tension (hypertonia) •
loss of appetite
•
tremor •
weight loss
•
numbness or tingling of the fingers and toes •
altered taste
•
nail disorders
•
asthma
•
hair loss
•
lung disorders
•
inability to sleep (insomnia)
•
back pain
•
sleepiness (somnolence)
•
neck pain
•
nose bleeds
• bone pain
•
bruising
•
acne
•
haemorrhoids
•
leg cramps
Other rare side effects of Herceptin,
(affects 1 to 10 users in 10,000)
are:
•
Weakness
•
Inflammation/scarring of the lungs
•
Jaundice
Other side effects that have been reported with Herceptin use
(frequency cannot be estimated from
the available data)
:
•
Abnormally low clotting factor
•
Anaphylactic reactions
•
High potassium levels
•
Swelling of the brain
•
Swelling /bleeding at the back of the eyes
•
Shock
•
Swelling of the lining of the heart
•
Slow heart rate
•
Abnormal heart rhythm
•
Respiratory distress
•
Respiratory Failure
•
Acute accumulation of fluid in the lungs
•
Acute narrowing of the airways
•
Abnormally low oxygen levels in the blood
•
Swelling of the throat
•
Difficulty in breathing when lying flat
•
Liver damage/failure
•
Swelling of the face,lips and throat
•
rash (itchy, bumpy)
•
Kidney damage/ failure
•
Abnormally low levels of fluid around baby in womb
34
Some of the side effects you experience may be due to your underlying breast cancer. If you receive
Herceptin in combination with chemotherapy, some of them may also be due to the chemotherapy.
If you experience any of the side effects mentioned in this leaflet or notice any side effects not
mentioned in this leaflet, please inform your doctor or pharmacist.
5.
HOW TO STORE HERCEPTIN
Keep out of the reach and sight of children.
Do not use this medicine after the expiry date which is stated on the outer carton and on the vial label
after EXP.
Store in a refrigerator (2°C – 8°C).
Infusion solutions should be used immediately after dilution. Do not use Herceptin if you notice any
particulate matter or discoloration prior to administration.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Herceptin contains
•
The active substance is trastuzumab. Each vial contains 150 mg trastuzumab that has to be
dissolved in 7.2 ml of water for injection. The resulting solution contains approximately
21 mg/ml trastuzumab.
•
The other ingredient(s) are L-histidine hydrochloride, L-histidine, α,α-trehalose dihydrate,
polysorbate 20.
What Herceptin looks like and contents of the pack
Herceptin is a powder for concentrate for solution for infusion, that is supplied in a glass vial with a
rubber stopper containing 150 mg of trastuzumab. The powder is a white to pale yellow pellet. Each
carton contains 1 vial of powder..
Marketing Authorisation Holder
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
Manufacturer
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
35
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Roche Farma S.A.
Tel: +34 - 91 324 81 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
France
Roche
Tél: +33 (0) 1 46 40 50 00
România
Roche România S.R.L.
Tel: +40 21 206 47 01
Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700
Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00
Ísland
Roche a/s
c/o Icepharma hf
Sími: +354 540 8000
Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201
Italia
Roche S.p.A.
Tel: +39 - 039 2471
Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500
Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76
Sverige
Roche AB
Tel: +46 (0) 8 726 1200
36
Latvija
Roche Latvija SIA
Tel: +371 - 67 039831
United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
The following information is intended for medical or healthcare professionals only
Always keep this medicine in the closed original pack at a temperature of 2ºC – 8 ºC in a refrigerator.
A vial of Herceptin reconstituted with water for injections (not supplied) is stable for 48 hours at 2ºC –
8 ºC after reconstitution and must not be frozen.
Appropriate aseptic technique should be used. Each vial of Herceptin is reconstituted with 7.2 ml of
water for injections (not supplied). Use of other reconstitution solvents should be avoided. This yields
a 7.4 ml solution for single-dose use, containing approximately 21 mg/ml trastuzumab. A volume
overage of 4 % ensures that the labelled dose of 150 mg can be withdrawn from each vial.
Herceptin should be carefully handled during reconstitution. Causing excessive foaming during
reconstitution or shaking the reconstituted Herceptin may result in problems with the amount of
Herceptin that can be withdrawn from the vial.
Instructions for Reconstitution:
1) Using a sterile syringe, slowly inject 7.2 ml of water for injections in the vial containing the
lyophilised Herceptin, directing the stream into the lyophilised cake.
2) Swirl vial gently to aid reconstitution. DO NOT SHAKE!
Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed
for approximately 5 minutes. The reconstituted Herceptin results in a colourless to pale yellow
transparent solution and should be essentially free of visible particulates.
Determine the volume of the solution required:
•
based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose
of 2 mg trastuzumab/kg body weight:
Volume
(ml) =
Body weight
(kg) x
dose
(
4
mg/kg for loading or
2
mg/kg for maintenance)
21
(mg/ml, concentration of reconstituted solution)
•
based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3-weekly dose
of 6 mg trastuzumab/kg body weight:
Volume
(ml) =
Body weight
(kg) x
dose
(
8
mg/kg for loading or 6 mg/kg for maintenance)
21
(mg/ml, concentration of reconstituted solution)
The appropriate amount of solution should be withdrawn from the vial and added to a
polyvinylchloride, polyethylene or polypropylene infusion bag containing 250 ml of 0.9 % sodium
chloride solution. Do not use with glucose-containing solutions. The bag should be gently inverted to
mix the solution in order to avoid foaming. Parenteral solutions should be inspected visually for
particulates and discoloration prior to administration. Once the infusion is prepared it should be
37
administered immediately. If diluted aseptically, it may be stored for 24 hours (do not store above
30°C).
38
Source: European Medicines Agency
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