4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Breast cancer

Metastatic breast cancer

Ogivri is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer

(MBC):

- 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 MBC, not previously treated with trastuzumab.

 

Early breast cancer

Ogivri is indicated for the treatment of adult patients with HER2 positive early breast cancer (EBC):

- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see

section 5.1)

- following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with

paclitaxel or docetaxel

- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

- in combination with neoadjuvant chemotherapy followed by adjuvant Ogivri therapy, for locally

advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 4.4 and

5.1).

Ogivri should only be used in patients with metastatic or EBC 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).

Metastatic gastric cancer

Ogivri in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of

adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal

junction who have not received prior anti-cancer treatment for their metastatic disease.

Ogivri should only be used in patients with metastatic gastric cancer (MGC) 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).

 

4.2 Posology and method of administration

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Trastuzumab

treatment should only be initiated by a physician experienced in the administration of cytotoxic

chemotherapy (see section 4.4), and should be administered by a healthcare professional only.

Ogivri intravenous formulation is not intended for subcutaneous administration and should be

administered via an intravenous infusion only.

If an alternate route of administration is required, other trastuzumab products offering such an option

should be used.

In order to prevent medication errors it is important to check the vial labels to ensure that the

medicinal product being prepared and administered is trastuzumab and not trastuzumab emtansine.

 

Posology

Metastatic breast cancer

Three-weekly schedule

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose

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

 

Weekly schedule

The recommended initial loading dose of trastuzumab is 4 mg/kg body weight. The recommended

weekly maintenance dose of trastuzumab 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 trastuzumab (for dose, see the Summary of Product Characteristics (SmPC) for paclitaxel

or docetaxel) and immediately after the subsequent doses of trastuzumab if the preceding dose of

trastuzumab was well tolerated.

 

Administration in combination with an aromatase inhibitor

In the pivotal trial (BO16216) trastuzumab and anastrozole were administered from day 1. There were

no restrictions on the relative timing of trastuzumab and anastrozole at administration (for dose, see

the SmPC for anastrozole or other aromatase inhibitors).

 

Early breast cancer

Three-weekly and weekly schedule

As a three-weekly regimen the recommended initial loading dose of trastuzumab is 8 mg/kg body

weight. The recommended maintenance dose of trastuzumab at three-weekly intervals is 6 mg/kg body

weight, beginning three weeks after the loading dose.

As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly

with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide.

See section 5.1 for chemotherapy combination dosing.

 

Metastatic gastric cancer

Three-weekly schedule

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose

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

Breast cancer and gastric cancer

 

Duration of treatment

Patients with MBC or MGC should be treated with trastuzumab until progression of disease.

Patients with EBC should be treated with trastuzumab for 1 year or until disease recurrence, whichever

occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).

 

Dose reduction

No reductions in the dose of trastuzumab 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 SmPC for

paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.

 

If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 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 trastuzumab should be strongly considered, unless the

benefits for the individual patient are deemed to outweigh the risks. All such patients should be

referred for assessment by a cardiologist and followed up.

 

Missed doses

If the patient has missed a dose of trastuzumab by one week or less, then the usual maintenance dose

(weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as

possible. Do not wait until the next planned cycle. Subsequent maintenance doses should be

administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

If the patient has missed a dose of trastuzumab by more than one week, a re-loading dose of

trastuzumab should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; threeweekly regimen: 8 mg/kg) as soon as possible. Subsequent trastuzumab maintenance doses (weekly

regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should be administered 7 days or 21

days later according to the weekly or three-weekly schedules respectively.

 

Special populations

Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not

been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown

to affect trastuzumab disposition.

 

Paediatric population

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

Method of administration

Trastuzumab loading dose should be administered as a 90-minute intravenous infusion. Do not

administer as an intravenous push or bolus. Trastuzumab intravenous infusion should be administered

by a healthcare 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 reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications • Hypersensitivity to the active substance, murine proteins, or to any of the excipients listed in section 6.1. • Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number

of the administered product should be clearly recorded.

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 trastuzumab in the adjuvant setting.

 

Cardiac dysfunction

General considerations

Patients treated with trastuzumab are at increased risk for developing CHF (New York Heart

Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been

observed in patients receiving trastuzumab therapy alone or in combination with paclitaxel or

docetaxel, particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy.

These may be moderate to severe and have been associated with death (see section 4.8). In addition,

caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension,

documented coronary artery disease, CHF, LVEF of < 55%, older age.

All candidates for treatment with trastuzumab, but especially those with prior anthracycline and

cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and

physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition

(MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop

cardiac dysfunction. Cardiac assessments, as performed at baseline, should be repeated every 3 months

during treatment and every 6 months following discontinuation of treatment until 24 months from the

last administration of trastuzumab. A careful risk-benefit assessment should be made before deciding

to treat with trastuzumab.

Trastuzumab may persist in the circulation for up to 7 months after stopping Ogivri treatment based on

population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive

anthracyclines after stopping trastuzumab may possibly be at increased risk of cardiac dysfunction. If

possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping

trastuzumab. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.

Formal cardiological assessment should be considered in patients in whom there are cardiovascular

concerns following baseline screening. In all patients cardiac function should be monitored during

treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac

dysfunction. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent

monitoring (e.g. every 6 - 8 weeks). If patients have a continued decrease in left ventricular function,

but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of

trastuzumab therapy has been seen.

The safety of continuation or resumption of trastuzumab in patients who experience cardiac

dysfunction has not been prospectively studied. If LVEF percentage drops ≥ 10 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 trastuzumab 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 trastuzumab therapy, it should be treated with standard

medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction

in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting

enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of

patients with cardiac symptoms and evidence of a clinical benefit of trastuzumab treatment continued

on therapy without additional clinical cardiac events.

 

Metastatic breast cancer

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

Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction

with trastuzumab treatment, although the risk is lower than with concurrent use of trastuzumab and

anthracyclines.

 

Early breast cancer

For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3

months during treatment and every 6 months following discontinuation of treatment until 24 months

from the last administration of trastuzumab. In patients who receive anthracycline-containing

chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last

administration of trastuzumab, or longer if a continuous decrease of LVEF is observed.

Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment,

history of or existing CHF (NYHA Class II –IV), LVEF of < 55%, other cardiomyopathy, cardiac

arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly

controlled hypertension (hypertension controlled by standard medical treatment eligible), and

hemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC

pivotal trials with trastuzumab and therefore treatment cannot be recommended in such patients.

 

Adjuvant treatment

Trastuzumab and anthracyclines should not be given concurrently in combination in the adjuvant

treatment setting.

In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events

was observed when trastuzumab was administered after anthracycline-containing chemotherapy

compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was

more marked when trastuzumab was administered concurrently with taxanes than when administered

sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred

within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of

5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic

cardiac or LVEF events was observed in patients who were administered trastuzumab concurrently

with a taxane following anthracycline therapy up to 2.37 % compared to approximately 1 % in the two

comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin

and trastuzumab).

Risk factors for a cardiac event identified in four large adjuvant studies included advanced age

(> 50 years), low LVEF (< 55 %) at baseline, prior to or following the initiation of paclitaxel

treatment, decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive

medicinal products.

In patients receiving trastuzumab after completion of adjuvant chemotherapy, the risk of cardiac

dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of

trastuzumab and a body mass index (BMI) > 25 kg/m2.

 

Neoadjuvant-adjuvant treatment

In patients with EBC eligible for neoadjuvant-adjuvant treatment, trastuzumab should be used

concurrently with anthracyclines only in chemotherapy-naive patients and only with low-dose

anthracycline regimens i.e. maximum cumulative doses of doxorubicin 180 mg/m2 or epirubicin

360 mg/m2.

If patients have been treated concurrently with a full course of low-dose anthracyclines and

trastuzumab in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after

surgery. In other situations, the decision on the need for additional cytotoxic chemotherapy is

determined based on individual factors.

Experience of concurrent administration of trastuzumab with low dose anthracycline regimens is

currently limited to the trial MO16432.

In the pivotal trial MO16432, trastuzumab was administered concurrently with neoadjuvant

chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2).

The incidence of symptomatic cardiac dysfunction was 1.7 % in the trastuzumab arm.

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

Infusion-related reactions (IRRs) and hypersensitivity

Serious IRRs to trastuzumab infusion including 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

trastuzumab. 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 trastuzumab (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 trastuzumab 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 trastuzumab in the post-marketing setting

(see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lung

disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis,

pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been

reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy

with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine,

vinorelbine and radiation therapy. 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 trastuzumab (see section 4.3). Caution should be exercised for pneumonitis,

especially in patients being treated concomitantly with taxanes.

Sorbitol content

Ogivri 420 mg contains 322.6 mg sorbitol in each vial.

Patients with hereditary fructose intolerance (HFI) must not be given this medicine unless strictly

necessary.

A detailed history with regards to HFI symptoms has to be taken of each patient prior to being given

this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Clinically significant interactions between trastuzumab

and the concomitant medicinal products used in clinical trials have not been observed.

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 hydroxylpaclitaxel,

POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or

4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous,

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 were unclear.

Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg intravenous loading dose and

2 mg/kg intravenous weekly) and docetaxel (60 mg/m2 intravenous) in Japanese women with HER2-

positive MBC, suggested that concomitant administration of trastuzumab had no effect on the single

dose pharmacokinetics of docetaxel. Study JP19959 was a sub study of BO18255 (ToGA) performed

in male and female Japanese patients with advanced gastric cancer (AGC) to study the

pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The results of

this sub study suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was

not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab.

However, capecitabine itself showed higher concentrations and a longer half-life when combined with

trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by

concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced

inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.

 

Effect of antineoplastic agents on trastuzumab pharmacokinetics

By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy

(4 mg/kg loading/2 mg/kg q1w intravenous) 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 trastuzumab and paclitaxel and two phase

II studies in which trastuzumab was administered as monotherapy (W016229 and MO16982), in

women with HER2-positive MBC indicates that individual and mean trastuzumab 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

trastuzumab, paclitaxel and doxorubicin to trastuzumab PK data in studies where trastuzumab was

administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide

or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the

pharmacokinetics of trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the

PK of trastuzumab.

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

trastuzumab.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception during treatment

with trastuzumab and for 7 months after treatment has concluded (see section 5.2).

 

Pregnancy

Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the

weekly human maintenance dose of 2 mg/kg trastuzumab intravenous formulation 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 trastuzumab can affect reproductive capacity. As animal

reproduction studies are not always predictive of human response, trastuzumab 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 foetal renal growth and/or function impairment in association

with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been

reported in pregnant women receiving trastuzumab. Women who become pregnant should be advised

of the possibility of harm to the foetus. If a pregnant woman is treated with trastuzumab, or if a patient

becomes pregnant while receiving trastuzumab or within 7 months following the last dose of

trastuzumab, close monitoring by a multidisciplinary team is desirable.

 

Breast-feeding

A study conducted in lactating Cynomolgus monkeys at doses 25 times that of the weekly human

maintenance dose of 2 mg/kg trastuzumab intravenous formulation 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 trastuzumab therapy

and for 7 months after the last dose.

 

Fertility

There is no fertility data available.

4.7 Effects on ability to drive and use machines

Ogivri may have a minor influence on the ability to drive and use machines (see section 4.8). Patients

experiencing infusion-related symptoms (see section 4.4) should be advised not to drive and use

machines until symptoms abate.

4.8 Undesirable effects

Summary of the safety profile

Amongst the most serious and/or common adverse reactions reported in trastuzumab usage

(intravenous and subcutaneous formulations) to date are cardiac dysfunction, infusion-related

reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions.

Tabulated list of adverse reactions

In this section, the following categories of frequency have been used: very common (≥ 1/10), common

(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare

(< 1/10,000), not known (cannot be estimated from the available data). Within each frequency

grouping, adverse reactions are presented in order of decreasing seriousness.

Presented in Table 1 are adverse reactions that have been reported in association with the use of

intravenous trastuzumab alone or in combination with chemotherapy in pivotal clinical trials and in the

post-marketing setting.

 

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

terms reported in the post marketing setting are included in Table 1.

Table 1 Undesirable effects reported with intravenous trastuzumab monotherapy or in combination

with chemotherapy in pivotal clinical trials (N = 8386) and in post-marketing

 

System organ class

Neoplasms benign, malignant and unspecified

(incl. cysts and polyps)

Blood and lymphatic system disorders

Immune system disorders

Metabolism and nutrition disorders

Psychiatric disorders

Nervous system disorders

Eye disorders

Ear and labyrinth disorders

Cardiac disorders

System organ class

Vascular disorders

Respiratory, thoracic and mediastinal disorders

Gastrointestinal disorders

Hepatobiliary disorders

Skin and subcutaneous tissue disorders

System organ class

Musculoskeletal and connective tissue disorders

Renal and urinary disorders

Pregnancy, puerperium and perinatal conditions

Reproductive system and breast disorders

General disorders and administration site conditions

Injury, poisoning and procedural complications

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
	Adverse reaction	Frequency
	Sepsis	Uncommon
	Malignant neoplasm progression	Not known
	Neoplasm progression	Not known
	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
	Hypersensitivity	Common
	+Anaphylactic reaction	Not known
	+Anaphylactic shock	Not known
	Weight decreased/Weight loss	Very common
	Anorexia	Very common
	Tumour lysis syndrome	Not known
	Hyperkalaemia	Not known
	Insomnia	Very common
	Anxiety	Common
	Depression	Common
	Thinking abnormal	Common
	1Tremor	Very common
	Dizziness	Very common
	Headache	Very common
	Paraesthesia	Very common
	Dysgeusia	Very common
	Peripheral neuropathy	Common
	Hypertonia	Common
	Somnolence	Common
	Ataxia	Common
	Paresis	Rare
	Brain oedema	Not known
	Conjunctivitis	Very common
	Lacrimation increased	Very common
	Dry eye	Common
	Papilloedema	Not known
	Retinal haemorrhage	Not known
	Deafness	Uncommon
	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
Adverse reaction	Frequency
Pericarditis	Not known
Bradycardia	Not known
Gallop rhythm present	Not known
Hot flush	Very common
+1 Hypotension	Common
Vasodilatation	Common
+1Wheezing	Very common
+Dyspnoea	Very common
Cough	Very common
Epistaxis	Very common
Rhinorrhoea	Very common
+Pneumonia	Common
Asthma	Common
Lung disorder	Common
+Pleural effusion	Common
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
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
Haemorrhoids	Common
Dry mouth	Common
Hepatocellular injury	Common
Hepatitis	Common
Liver tenderness	Common
Jaundice	Rare
Hepatic failure	Not known
Erythema	Very common
Rash	Very common
1 Swelling face	Very common
Alopecia	Very common
Nail disorder	Very common
Palmar-plantar erythrodysaesthesia syndrome	Very common
Adverse reaction	Frequency
Acne	Common
Dry skin	Common
Ecchymosis	Common
Hyperhydrosis	Common
Maculopapular rash	Common
Pruritus	Common
Onychoclasis	Common
Dermatitis	Common
Urticaria	Uncommon
Angioedema	Not known
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 disorder	Common
Glomerulonephritis membranous	Not known
Glomerulonephropathy	Not known
Renal failure	Not known
Oligohydramnios	Not known
Renal hypoplasia	Not known
Pulmonary hypoplasia	Not known
Breast inflammation/mastitis	Common
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	Very common
Malaise	Common
Oedema	Common
Contusion	Common

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

1 Denotes adverse reactions that are reported largely in association with Infusion-related reactions. Specific

percentages for these are not available.

* Observed with combination therapy following anthracyclines and combined with taxanes

Description of selected adverse reactions

 

Cardiac dysfunction

Congestive heart failure (NYHA Class II – IV) is a common adverse reaction associated with the use

of trastuzumab and has been associated with a fatal outcome (see section 4.4). 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 trastuzumab (see

section 4.4).

In 3 pivotal clinical trials of adjuvant trastuzumab 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 (i.e. did not receive trastuzumab) and

in patients who were administered trastuzumab sequentially after a taxane (0.3-0.4 %). The rate was

highest in patients who were administered trastuzumab concurrently with a taxane (2.0 %). In the

neoadjuvant setting, the experience of concurrent administration of trastuzumab and low dose

anthracycline regimen is limited (see section 4.4).

When trastuzumab 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, after a median follow-up of 8 years the incidence of severe CHF (NYHA

Class III & IV) in the trastuzumab 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 trastuzumab-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 trastuzumab.

In the pivotal metastatic trials of intravenous trastuzumab, 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 trastuzumab 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 trastuzumab 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.

 

Infusion reactions, allergic-like reactions and hypersensitivity

It is estimated that approximately 40 % of patients who are treated with trastuzumab 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 chills,

fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation,

respiratory distress, rash, nausea, vomiting and headache (see section 4.4). The rate of infusion-related

reactions of all grades varied between studies depending on the indication, the data collection

methodology, and whether trastuzumab was given concurrently with chemotherapy or as

monotherapy.

Severe anaphylactic reactions requiring immediate additional intervention can occur usually during

either the first or second infusion of trastuzumab (see section 4.4) and have been associated with a

fatal outcome.

Anaphylactoid reactions have been observed in isolated cases.

 

Haematotoxicity

Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred very

commonly. The frequency of occurrence of hypoprothrombinemia is not known. The risk of

neutropenia may be slightly increased when trastuzumab is administered with docetaxel following

anthracycline therapy.

 

Pulmonary events

Severe pulmonary adverse reactions occur in association with the use of trastuzumab 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.

 

Immunogenicity

In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months,

10.1 % (30/296) of patients treated with trastuzumab intravenous developed antibodies against

trastuzumab.

Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in

the trastuzumab intravenous arm.

The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodies

had no impact on pharmacokinetics, efficacy (determined by pathological Complete Response [pCR]

and event free survival [EFS]) and safety determined by occurrence of administration related reactions

(ARRs) of trastuzumab intravenous.

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

Switching treatment between trastuzumab intravenous and trastuzumab subcutaneous formulation and

vice versa.

Study MO22982 investigated switching between the trastuzumab intravenous and trastuzumab

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 Trastuzumab treatment sequences (intravenous [Cycles 1-4]→ subcutaneous

[Cycles 5-8], or subcutaneous [Cycles 1-4]→ intravenous [Cycles 5-8]). Patients were either naïve to

trastuzumab intravenous treatment (20.3 %) or pre-exposed to trastuzumab intravenous (79.7 %). For

the sequence intravenous → subcutaneous (subcutaneous vial and subcutaneous formulation in

administration system cohorts combined), adverse event rates (all grades) were described preswitching

(Cycles 1-4) and post-switching (Cycles 5-8) as 53.8 % vs. 56.4 %, respectively; for the

sequence subcutaneous → intravenous (subcutaneous vial and subcutaneous formulation in

administration system cohorts combined), adverse event 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via

Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

 

Other GCC States:

Please contact the relevant competent authority.

4.9 Overdose

There is no experience with overdose in human clinical trials. Single doses of trastuzumab alone

greater than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of

10 mg/kg q3w following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic

gastric cancer patients. Doses up to this level were well tolerated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Ogivri is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu.

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

Trastuzumab 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

Ogivri treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a

positive FISH or CISH result.

 

To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory,

which can ensure validation of the testing procedures.

 

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

Table 2 Recommended scoring system to evaluate the IHC staining patterns in breast cancer

 

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.

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 tumour 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.

 

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3:

Table 3 Recommended scoring system to evaluate the IHC staining patterns in gastric cancer

 

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
2+	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	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

 

Metastatic breast cancer

Trastuzumab has been used in clinical trials as monotherapy for patients with MBC who have tumours

that overexpress HER2 and who have failed one or more chemotherapy regimens for their metastatic

disease (trastuzumab alone).

Trastuzumab 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/m2 infused

over 3 hours) with or without trastuzumab. In the pivotal trial of docetaxel (100 mg/m2 infused over

1 hour) with or without trastuzumab, 60 % of the patients had received prior anthracycline-based

adjuvant chemotherapy. Patients were treated with trastuzumab until progression of disease.

The efficacy of trastuzumab in combination with paclitaxel in patients who did not receive prior

adjuvant anthracyclines has not been studied. However, trastuzumab 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

trastuzumab monotherapy and trastuzumab 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+).

The main test method used to determine HER2 positivity in the pivotal trial of docetaxel, with or

without trastuzumab, 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 metastatic breast cancer

The efficacy results from the monotherapy and combination therapy studies are summarised in

Table 4:

 

Table 4 Efficacy results from the monotherapy and combination therapy studies

 

Parameter	Monotherapy	Combination Therapy
	Trastuzumab1 N = 172	Trastuzumab plus paclitaxel2 N = 68	Paclitaxel2 N = 77	Trastuzumab plus docetaxel3 N = 92	Docetaxel3 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)
Median Survival (months) (95 %CI)	16.4 (12.3-ne)	24.8 (18.6-33.7)	17.9 (11.2-23.8)	31.2 (27.3-40.8)	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. Study H0649g: IHC3+ patient subset

2. Study H0648g: IHC3+ patient subset

3. Study M77001: Full analysis set (intent-to-treat), 24 months results

 

Combination treatment with Trastuzumab and anastrozole

Trastuzumab has been studied in combination with anastrozole for first line treatment of MBC 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 trastuzumab 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 trastuzumab containing regimen after progression of disease.

 

Three -weekly dosing in metastatic breast cancer

The efficacy results from the non-comparative monotherapy and combination therapy studies are

summarised in Table 5:

Table 5 Efficacy results from the non-comparative monotherapy and combination therapy studies

 

Parameter	Monotherapy		Combination Therapy
	Trastuzumab1 N = 105	Trastuzumab2 N = 72	Trastuzumab plus paclitaxel3 N = 32	Trastuzumab plus docetaxel4 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)
Median Survival (months) (95 %CI)	ne	ne	ne	47.3 (32-ne)

 

TTP = time to progression; "ne" indicates that it could not be estimated or it was not yet reached.

1. 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 BO15935

4. Study MO16419

 

Sites of progression

The frequency of progression in the liver was significantly reduced in patients treated with the

combination of trastuzumab and paclitaxel, compared to paclitaxel alone (21.8 % versus 45.7 %;

p = 0.004). More patients treated with trastuzumab and paclitaxel progressed in the central nervous

system than those treated with paclitaxel alone (12.6 % versus 6.5 %; p = 0.377).

 

Early breast cancer (adjuvant setting)

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

In the adjuvant treatment setting, trastuzumab was investigated in 4 large multicentre, randomised,

trials.

- Study BO16348 was designed to compare one and two years of three-weekly trastuzumab

treatment versus observation in patients with HER2 positive EBC following surgery, established

chemotherapy and radiotherapy (if applicable). In addition, comparison of two years of

trastuzumab treatment versus one year of trastuzumab treatment was performed. Patients

assigned to receive trastuzumab were given an initial loading dose of 8 mg/kg, followed by

6 mg/kg every three weeks for either one or two years.

- The NSABP B-31 and NCCTG N9831 studies that comprise the joint analysis were designed to

investigate the clinical utility of combining trastuzumab treatment with paclitaxel following AC

chemotherapy; additionally, the NCCTG N9831 study also investigated adding trastuzumab

sequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery.

- The BCIRG 006 study was designed to investigate combining trastuzumab treatment with

docetaxel either following AC chemotherapy or in combination with docetaxel and carboplatin

in patients with HER2 positive EBC following surgery.

 

EBC 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 joint analysis of the NSABP B-31 and NCCTG N9831 studies, EBC was limited to women with

operable breast cancer at high risk, defined as HER2-positive and axillary lymph node positive or

HER2 positive and lymph node negative with high risk features (tumour size > 1 cm and ER negative

or tumour size > 2 cm, regardless of hormonal status).

In the BCIRG 006 study HER2 positive, EBC was defined as either lymph node positive or high risk

node negative patients with no (pN0) lymph node involvement, and at least 1 of the following factors:

tumour size greater than 2 cm, estrogen receptor and progesterone receptor negative, histological

and/or nuclear grade 2-3, or age < 35 years).

 

The efficacy results from the BO16348 trial following 12 months* and 8 years** median follow-up

are summarized in Table 6:

Table 6 Efficacy results from study BO16348

 

	Median follow-up 12 months*		Median follow-up 8 years**
Parameter	Observation N = 1693	Trastuzumab 1 Year N = 1693	Observation N = 1697***	Trastuzumab 1 Year N = 1702***
Disease-free survival -  No. patients with event -   No. patients without event P-value versus Observation Hazard Ratio versus Observation	219 (12.9 %) 127 (7.5 %) 1474 (87.1 %) 1566 (92.5 %) < 0.0001 0.54		570 (33.6 %) 471 (27.7 %) 1127 (66.4 %) 1231 (72.3 %) < 0.0001 0.76
Recurrence-free survival -  No. patients with event -   No. patients without event P-value versus Observation Hazard Ratio versus Observation	208 (12.3 %) 113 (6.7 %) 1485 (87.7 %) 1580 (93.3 %) < 0.0001 0.51		506 (29.8 %) 399 (23.4 %) 1191 (70.2 %) 1303 (76.6 %) < 0.0001 0.73
Distant disease-free survival -  No. patients with event -   No. patients without event P-value versus Observation Hazard Ratio versus Observation	184 (10.9 %) 99 (5.8 %) 1508 (89.1 %) 1594 (94.6 %) < 0.0001 0.50		488 (28.8 %) 399 (23.4 %) 1209 (71.2 %) 1303 (76.6 %) < 0.0001 0.76
Overall survival (death) -  No. patients with event -   No. patients without event P-value versus Observation Hazard Ratio versus Observation	40 (2.4 %) 31 (1.8 %) 1653 (97.6 %) 1662 (98.2 %) 0.24 0.75		350 (20.6 %) 278 (16.3 %) 1347 (79.4 %) 1424 (83.7 %) 0.0005 0.76

*Co-primary endpoint of DFS of 1 year versus observation met the pre-defined statistical boundary

**Final analysis (including crossover of 52 % of patients from the observation arm to trastuzumab)

*** There is a discrepancy in the overall sample size due to a small number of patients who were randomised

after the cut-off date for the 12-month median follow-up analysis

 

The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical

boundary for the comparison of 1-year of trastuzumab versus observation. After a median follow-up of

12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54 (95 % CI 0.44, 0.67) which

translates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentage

points (85.8 % versus 78.2 %) in favour of the trastuzumab arm.

A final analysis was performed after a median follow-up of 8 years, which showed that 1 year

trastuzumab treatment is associated with a 24 % risk reduction compared to observation only

(HR = 0.76, 95 % CI 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year disease

free survival rate of 6.4 percentage points in favour of 1 year trastuzumab treatment.

In this final analysis, extending trastuzumab treatment for a duration of two years did not show

additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years

versus 1 yea r= 0.99 (95 % CI: 0.87, 1.13), p-value = 0.90 and OS HR = 0.98 (0.83, 1.15); pvalue

= 0.78]. The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm

(8.1 % versus 4.6 % in the 1-year treatment arm). More patients experienced at least one grade 3 or 4

adverse event in the 2-year treatment arm (20.4 %) compared with the 1-year treatment arm (16.3 %).

In the NSABP B-31 and NCCTG N9831 studies trastuzumab was administered in combination with

paclitaxel, following AC chemotherapy.

Doxorubicin and cyclophosphamide were administered concurrently as follows:

- intravenous push doxorubicin, at 60 mg/ m2, given every 3 weeks for 4 cycles.

- intravenous cyclophosphamide, at 600 mg/ m2 over 30 minutes, given every 3 weeks for 4

cycles

Paclitaxel, in combination with trastuzumab, was administered as follows:

- intravenous paclitaxel – 80 mg/ m2 as a continuous intravenous infusion, given every week for

12 weeks.

or

- intravenous paclitaxel – 175 mg/ m2 as a continuous intravenous infusion, given every 3 weeks

for 4 cycles (day 1 of each cycle).

The efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831 trials at the time

of the definitive analysis of DFS* are summarized in Table 7. The median duration of follow up was

1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm.

Table 7 Summary of efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831

trials at the time of the definitive DFS analysis*

 

Parameter	AC→P (n = 1679)	AC→PH (n = 1672)	Hazard Ratio vs AC→P (95% CI) p-value
Disease-free survival	261 (15.5)	133 (8.0)	0.48 (0.39, 0.59)
No. patients with event (%)			p < 0.0001
Distant Recurrence	193 (11.5)	96 (5.7)	0.47 (0.37, 0.60)
No. patients with event			p < 0.0001
Death (OS event):	92 (5.5)	62 (3.7)	0.67 (0.48, 0.92)
No. patients with event			p = 0.014**

 

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

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

AC→PH arm

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

 

For the primary endpoint, DFS, the addition of trastuzumab to paclitaxel chemotherapy resulted in a

52 % decrease in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, in

terms of 3-year disease-free survival rate estimates of 11.8 percentage points (87.2 % versus 75.4 %)

in favour of the AC→PH (trastuzumab) arm.

At the time of a safety update after a median of 3.5-3.8 years follow up, an analysis of DFS reconfirms

the magnitude of the benefit shown in the definitive analysis of DFS. Despite the cross-over to

trastuzumab in the control arm, the addition of trastuzumab to paclitaxel chemotherapy resulted in a

52 % decrease in the risk of disease recurrence. The addition of trastuzumab to paclitaxel

chemotherapy also resulted in a 37 % decrease in the risk of death.

The pre-planned final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG

N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC→P H

group). Treatment with AC→PH resulted in a statistically significant improvement in OS compared

with AC→P (stratified HR = 0.64; 95% CI [0.55, 0.74]; log-rank p-value < 0.0001). At 8 years, the

survival rate was estimated to be 86.9 % in the AC→PH arm and 79.4 % in the AC→P arm, an

absolute benefit of 7.4 % (95 % CI 4.9 %, 10.0 %).

 

The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are

summarized in Table 8 below:

Table 8 Final overall survival analysis from the joint analysis of trials NSABP B-31 and NCCTG

N9831

 

Parameter	AC→P (N = 2032)	AC→PH (N = 2031)	p-value versus AC→P	Hazard Ratio versus AC→P (95 % CI)
Death (OS event):
No. patients with event (%)	418 (20.6 %)	289 (14.2 %)	< 0.0001	0.64 (0.55, 0.74)

 

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

 

DFS analysis was also performed at the final analysis of OS from the joint analysis of studies NSABP

B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95% CI [0.54,

0.69]) showed a similar DFS benefit compared to the definitive primary DFS analysis, despite 24.8 %

patients in the AC→P arm who crossed over to receive trastuzumab. At 8 years, the disease-free

survival rate was estimated to be 77.2 % (95 % CI: 75.4, 79.1) in the AC→PH arm, an absolute benefit

of 11.8% compared with the AC→P arm.

In the BCIRG 006 study trastuzumab was administered either in combination with docetaxel,

following AC chemotherapy (AC→DH) or in combination with docetaxel and carboplatin (DCarbH).

Docetaxel was administered as follows:

- intravenous docetaxel – 100 mg/m2 as an intravenous infusion over 1 hour, given every 3 weeks

for 4 cycles (day 2 of first docetaxel cycle, then day 1 of each subsequent cycle).

or

- intravenous docetaxel – 75 mg/m2 as an intravenous infusion over 1 hour, given every 3 weeks

for 6 cycles (day 2 of cycle 1, then day 1 of each subsequent cycle).

which was followed by:

- carboplatin – at target AUC = 6 mg/mL/min administered by intravenous infusion over 30-

60 minutes repeated every 3 weeks for a total of six cycles.

Trastuzumab was administered weekly with chemotherapy and 3 weekly thereafter for a total of 52

weeks.

25

The efficacy results from the BCIRG 006 are summarized in Tables 9 and 10. The median duration of

follow up was 2.9 years in the AC→D arm and 3.0 years in each of the AC→DH and DCarbH arms.

Table 9 Overview of efficacy analyses BCIRG 006 AC→D versus AC→DH

 

Parameter	AC→D (n = 1073)	AC→DH (n = 1074)	Hazard Ratio vs AC→D (95 % CI) p-value
Disease-free survival No. patients with event	195	134	0.61 (0.49, 0.77) p < 0.0001
Distant recurrence No. patients with event	144	95	0.59 (0.46, 0.77) p < 0.0001
Death (OS event) No. patients with event	80	49	0.58 (0.40, 0.83) p = 0.0024

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

 

Table 10 Overview of efficacy analyses BCIRG 006 AC→D versus DCarbH

 

Parameter	AC→D (n = 1073)	DCarbH (n = 1074)	Hazard Ratio vs AC→D (95 % CI) p-value
Disease-free survival No. patients with event	195	145	0.67 (0.54, 0.83) p = 0.0003
Distant recurrence No. patients with event	144	103	0.65 (0.50, 0.84) p = 0.0008
Death (OS event) No. patients with event	80	56	0.66 (0.47, 0.93) p = 0.0182

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

 

In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolute

benefit, in terms of 3-year disease-free survival rate estimates of 5.8 percentage points (86.7 % versus

80.9 %) in favour of the AC→DH (trastuzumab) arm and 4.6 percentage points (85.5 % versus

80.9 %) in favour of the DCarbH (trastuzumab) arm compared to AC→D.

In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the AC→DH

(AC→TH) arm, and 217/1073 in the AC→D (AC→T) arm had a Karnofsky performance status ≤ 90

(either 80 or 90). No disease-free survival (DFS) benefit was noticed in this subgroup of patients

(hazard ratio = 1.16, 95 % CI [0.73, 1.83] for DCarbH (TCH) versus AC→D (AC→T); hazard ratio

0.97, 95 % CI [0.60, 1.55] for AC→DH (AC→TH) versus AC→D).

In addition, a post-hoc exploratory analysis was performed on the data sets from the joint analysis (JA)

NSABP B-31/NCCTG N9831* and BCIRG006 clinical studies combining DFS events and

symptomatic cardiac events and summarised in Table 11:

Table 11 Post-Hoc exploratory analysis results from the joint analysis NSABP B-31/NCCTG N9831 and BCIRG006 clinical studies combining DFS events and symptomatic cardiac events

 

	AC→PH (vs. AC→P) (NSABP B-31 and NCCTG N9831)*	AC→DH (vs. AC→D) (BCIRG 006)	DCarbH (vs. AC→D) (BCIRG 006)
Primary efficacy analysis DFS Hazard ratios (95 % CI) p-value	0.48 (0.39, 0.59) p < 0.0001	0.61 (0.49, 0.77) p < 0.0001	0.67 (0.54, 0.83) p = 0.0003
Long term follow-up efficacy analysis** DFS Hazard ratios (95 % CI) p-value	0.61 (0.54, 0.69) p < 0.0001	0.72 (0.61, 0.85) p < 0.0001	0.77 (0.65, 0.90) p = 0.0011
Post-hoc exploratory analysis with DFS and symptomatic cardiac events Long term follow-up** Hazard ratios (95 % CI)	0.67 (0.60, 0.75)	0.77 (0.66, 0.90)	0.77 (0.66, 0.90)

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 arm and 7.9 years (range: 0.0 to 12.2) for the AC→P arm; 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) arm and the DCarbH arm (range: 0.0 to 13.1), and was 10.4 years (range: 0.0 to 12.7) in the AC→DH arm

 

Early breast cancer (neoadjuvant-adjuvant setting)

So far, no results are available which compare the efficacy of trastuzumab administered with

chemotherapy in the adjuvant setting with that obtained in the neo-adjuvant/adjuvant setting.

In the neoadjuvant-adjuvant treatment setting, study MO16432, a multicentre randomised trial, was

designed to investigate the clinical efficacy of concurrent administration of trastuzumab with

neoadjuvant chemotherapy including both an anthracycline and a taxane, followed by adjuvant

trastuzumab, up to a total treatment duration of 1 year. The study recruited patients with newly

diagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours were

randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant

trastuzumab, or neoadjuvant chemotherapy alone.

In study MO16432, trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance every 3

weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapy as follows:

- Doxorubicin 60 mg/m2 and paclitaxel 150 mg/m2, administered 3-weekly for 3 cycles,

which was followed by

- Paclitaxel 175 mg/m2 administered 3-weekly for 4 cycles,

which was followed by

- CMF on day 1 and 8 every 4 weeks for 3 cycles

which was followed after surgery by

- additional cycles of adjuvant trastuzumab (to complete 1 year of treatment)

 

The efficacy results from Study MO16432 are summarized in Table 12. The median duration of

follow-up in the trastuzumab arm was 3.8 years.

Table 12 Efficacy results from MO16432

 

* defined as absence of any invasive cancer both in the breast and axillary nodes

An absolute benefit of 13 percentage points in favour of the trastuzumab arm was estimated in terms

of 3-year event-free survival rate (65 % versus 52 %).

 

Metastatic gastric cancer

Trastuzumab 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/m2 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/m2/day as a continuous intravenous 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/m2 every 3 weeks for 6 cycles on day 1 of each cycle.

 

The efficacy results from study BO18225 are summarised in Table 13:

Table 13 Efficacy results from BO18225

 

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 %	1.70a (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 + Trastuzumab 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 randomisation to the date of death from any cause. At the time of

the analysis a total of 349 randomised 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 trastuzumab 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)].

 

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with the

reference medicinal product containing trastuzumab in all subsets of the paediatric population for

breast and gastric cancer (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis

using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or

other tumour types, and healthy volunteers, in 18 Phase I, II and III trials receiving trastuzumab IV. A

two-compartment model with parallel linear and non-linear elimination from the central compartment

described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance

increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can

be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 16).

MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment

volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance

was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The non-linear elimination

parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 mcg/mL for the

Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central compartment

volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC. In the final

population PK model, in addition to primary tumour type, body-weight, serum aspartate

aminotransferase and albumin were identified as a statistically significant covariates affecting the

exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab

exposure suggests that these covariates are unlikely to have a clinically meaningful effect on

trastuzumab concentrations.

 

The population predicted PK exposure values (median with 5th - 95th Percentiles) and PK parameter

values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated

with the approved q1w and q3w dosing regimens are shown in Table 14 (cycle 1), Table 15 (steadystate),

and Table 16 (PK parameters).

 

Table 14 Population predicted cycle 1 PK exposure values (median with 5th - 95th percentiles)

fortrastuzumab intravenous dosing regimens in MBC, EBC and AGC patients

 

Regimen	Primary tumour type	N	Cmin (mcg/mL)	Cmax (mcg/mL)	AUC0-21days (mcg.day/mL)
8 mg/kg + 6 mg/kg q3w	MBC	805	28.7 (2.9 - 46.3)	182 (134 - 280)	1376 (728 - 1998)
	EBC	390	30.9 (18.7 - 45.5)	176 (127 - 227)	1390 (1039 - 1895)
	AGC	274	23.1 (6.1 - 50.3)	132 (84.2 – 225)	1109 (588 – 1938)
4 mg/kg + 2 mg/kg qw	MBC	805	37.4 (8.7 - 58.9)	76.5 (49.4 - 114)	1073 (597 – 1584)
	EBC	390	38.9 (25.3 - 58.8)	76.0 (54.7 - 104)	1074 (783 - 1502)

 

Table 15 Population predicted steady state PK exposure values (median with 5th - 95th percentiles)for trastuzumab intravenous dosing regimens in MBC, EBC and AGC patients

 

Regimen	Primary tumour type	N	Cmin,ss* (mcg/mL)	Cmax,ss** (mcg/mL)	AUCss, 0-21days (mcg.day/mL)	Time to steady- state*** (week)
			44.2	179	1736
8 mg/kg +	MBC	805	(1.8 - 85.4)	(123 - 266)	(618 - 2756)	12
6 mg/kg q3w
			53.8	184	1927
	EBC	390	(28.7 - 85.8)	(134 - 247)	(1332 -2771)	15
			32.9	131	1338
	AGC	274	(6.1 – 88.9)	(72.5 -251)	(557 - 2875)	9
			63.1	107	1710
4 mg/kg +	MBC	805	(11.7 - 107)	(54.2 - 164)	(581 - 2715)	12
2 mg/kg qw
			72.6	115	1893
	EBC	390	(46 - 109)	(82.6 - 160)	(1309 -2734)	14

*C_min,ss – C_min at steady state

**C_max,ss = C_max at steady state

*** time to 90% of steady-state

 

Table 16 Population predicted PK parameter values at steady state for trastuzumab intravenous dosing regimens in MBC, EBC and AGC patients

Regimen	Primary tumour type	N	Total CL range from Cmax,ss to Cmin,ss (L/day)	t1/2 range from Cmax,ss to Cmin,ss (day)
8 mg/kg + 6 mg/kg q3w	MBC	805	0.183 - 0.302	15.1 - 23.3
	EBC	390	0.158 - 0.253	17.5 – 26.6
	AGC	274	0.189 - 0.337	12.6 - 20.6
4 mg/kg + 2 mg/kg qw	MBC	805	0.213 - 0.259	17.2 - 20.4
	EBC	390	0.184 - 0.221	19.7 - 23.2

 

Trastuzumab washout

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

97 % washout) by 7 months.

 

Circulating shed HER2-ECD

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

Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBC

and EBC patients and no apparent impact on trastuzumab clearance was observed.

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. Trastuzumab is not genotoxic.

No long-term animal studies have been performed to establish the carcinogenic potential of

trastuzumab, or to determine its effects on fertility in males.

6.1 List of excipients

L-histidine hydrochloride

L-histidine

Sorbitol (E420)

Macrogol 3350

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed or diluted with other medicinal products except those

mentioned in section 6.6.

Glucose solutions must not be used for dilution since these cause aggregation of the protein.

6.3 Shelf life 4 years. After reconstitution with sterile water for injections, the reconstituted solution is physically and chemically stable for 10 days at 2°C – 8°C. Any remaining reconstituted solution should be discarded. Solutions of Ogivri for intravenous infusion are physically and chemically stable in polyvinylchloride, polyethylene or polypropylene bags containing sodium chloride 9 mg/mL (0.9 %) solution for injection for up to 90 days at 2°C – 8°C and 24 hours at temperatures not exceeding 30°C. From a microbiological point of view, the reconstituted solution and Ogivri 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).

For storage conditions after reconstitution of the medicinal product, see sections 6.3 and 6.6.

 

6.5 Nature and contents of container

Ogivri 420 mg powder for concentrate for solution for infusion

50 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film containing

420 mg of trastuzumab.

Each carton contains one vial.

6.6 Special precautions for disposal and other handling

Ogivri should be carefully handled during reconstitution. Causing excessive foaming during

reconstitution or shaking the reconstituted solution may result in problems with the amount of Ogivri

that can be withdrawn from the vial.

The reconstituted solution should not be frozen.

Ogivri 420 mg powder for concentrate for solution for infusion

Each 420 mg vial of Ogivri is reconstituted with 20 mL of sterile water for injections (not supplied).

Use of other reconstitution solvents should be avoided. This yields a 21 mL solution for single-dose

use, containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. A volume

overage of 4.8 % ensures that the labelled dose of 420 mg can be withdrawn from each vial.

 

Ogivri vial		Volume of sterile water for injections		Final concentration
420 mg vial	+	20 mL	=	21 mg/mL

 

Instructions for reconstitution

-         Using a sterile syringe, slowly inject the appropriate volume (as noted above) of sterile water for injections in the vial containing the lyophilised Ogivri, directing the stream into the lyophilised cake.

-         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 Ogivri 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 an infusion bag containing 250 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection. 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. Once the infusion is prepared it should be administered immediately. If diluted aseptically, it may be stored for up to 90 days at 2°C – 8°C and 24 hours at temperatures not exceeding 30°C

Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration.

Ogivri is for single-use only, as the product contains no preservatives.

No incompatibilities between Ogivri and polyvinylchloride, polyethylene or polypropylene bags have been observed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.