Data Sheet
Herceptin®
Trastuzumab 150 mg and 440 mg powder for concentrate for solution for infusion
Antineoplastic agent
Pharmaceutical Form
Type of dosage form
Powder for concentrate for solution for infusion.
Route of administration
Intravenous infusion.
Sterile/radioactive statement
Sterile product.
Qualitative and Quantitative Composition
Active ingredient
Trastuzumab.
Dosage Preparations: 150 mg single-dose vial and 440 mg multi-dose vial containing powder for concentrate for solution for infusion. Reconstituted Herceptin concentrate contains 21 mg/mL of trastuzumab.
Excipients
Herceptin 150 mg and 440 mg vials:
L-histidine hydrochloride, L-histidine, α,α-trehalose dihydrate, polysorbate 20.
Solvent vial (for use with the 440 mg vial only):
Water for Injection containing 1.1% benzyl alcohol (Bacteriostatic Water for Injection).
Appearance
Herceptin is a white to pale yellow lyophilised powder. The solvent is a clear to slightly opalescent liquid.
Indications
Metastatic breast cancer
Herceptin is indicated for the treatment of patients with metastatic breast cancer who have tumours that overexpress HER2:
a) as monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease; or
b) in combination with taxanes for the treatment of those patients who have not received chemotherapy for their metastatic disease
Early breast cancer
Herceptin is also indicated for the treatment of HER2-positive early breast cancer in women with a normal Left Ventricular Ejection Fraction following surgery, sequentially or concurrently with chemotherapy and, if applicable, radiotherapy.
Dosage and Administration
HER2 testing by an accredited laboratory using a validated immunohistochemistry test, such as Herceptest, or FISH, is mandatory prior to initiation of Herceptin therapy.
Herceptin should be administered as an intravenous infusion.
DO NOT ADMINISTER HERCEPTIN AS AN INTRAVENOUS PUSH OR BOLUS.
Herceptin may be used in metastatic breast cancer with the originally proven once weekly dose schedule, or the newer, alternative three-weekly schedule. The alternative schedule has been tested in clinical trials but has not been compared directly with the standard weekly regimen. In clinical studies, patients with metastatic breast cancer were treated with Herceptin until progression of disease.
For treatment of early breast cancer, either the once weekly schedule or the three weekly schedule, with loading and subsequent doses, may be used. Patients should be treated for a maximum of 12 months or until disease recurrence.
Once Weekly Dose Schedule
Loading dose
The recommended initial loading dose of Herceptin is 4 mg/kg body weight administered as a 90-minute intravenous infusion. Patients should be observed for fever and chills or other infusion-associated symptoms (see Undesirable Effects). Interruption of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.
Subsequent doses
The recommended weekly maintenance dose of Herceptin is 2 mg/kg body weight. If the prior dose was well tolerated, the dose can be administered as a 30-minute infusion. Patients should be observed for fever and chills or other infusion-associated symptoms (see Undesirable Effects).
Three-Weekly Dose Schedule
Loading dose
The recommended initial loading dose of Herceptin is 8 mg/kg body weight administered as a 90-minute intravenous infusion. Patients should be observed for fever and chills or other infusion-associated symptoms (see Undesirable Effects). Interruption of the infusion and/or medication may help to control such symptoms. The infusion may be resumed when symptoms abate.
Subsequent doses
The recommended three-weekly maintenance dose of Herceptin is 6 mg/kg body weight administered as a 90-minute intravenous infusion. Patients should be observed for fevers and chills or other infusion-associated symptoms (see Undesirable Effects).
Switching patients from established weekly schedule to three-weekly doses
The first 6 mg/kg dose should be given a week after the last 2 mg/kg dose. As a precaution, all 6 mg/kg doses should be administered as a 90-minute intravenous infusion. Patients should be observed for fever and chills or other infusion-associated symptoms (see Undesirable Effects). Interruption of the infusion and/or medication may help to control such symptoms. The infusion may be resumed when symptoms abate. Subsequent maintenance doses of 6 mg/kg are given three-weekly.
Missed doses
If the patient misses a dose of Herceptin by one week or less, then the usual dose of Herceptin (6 mg/kg) should be given as soon as possible (do not wait until the next planned cycle). Subsequent maintenance Herceptin doses of 6 mg/kg should then be given every three weeks, according to the previous schedule.
If the patient misses a dose of trastuzumab by more than one week, a re-loading dose of trastuzumab should be given (8 mg/kg over approximately 90 minutes). Subsequent maintenance trastuzumab doses of 6 mg/kg should then be given every three weeks from that point.
Dose reduction
No reductions in the dose of Herceptin were made during clinical trials. Patients may continue Herceptin therapy during periods of reversible, chemotherapy-induced myelosuppression, but they should be monitored carefully for complications of neutropenia during this time. The specific instructions to reduce or hold the dose of chemotherapy should be followed.
Special Dosage Instructions
Elderly
Data suggest that the disposition of Herceptin is not altered based on age (see Pharmacokinetics in Special Populations). In clinical trials, elderly patients did not receive reduced doses of Herceptin.
Children
The safety and efficacy of Herceptin in paediatric patients have not been established.
Contraindications
Herceptin is contraindicated in patients with known hypersensitivity to trastuzumab or to any other component of the product.
Warnings and Precautions
General
Herceptin therapy should only be initiated under supervision of a physician experienced in the treatment of cancer patients.
Infusion related reactions
Serious adverse reactions to Herceptin infusion including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress have been reported infrequently. The Herceptin infusion should be discontinued and the patient monitored until resolution of any observed symptoms. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists and corticosteroids (see Undesirable Effects). In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. Patients who are experiencing dyspnoea at rest due to complications of advanced malignancy or comorbidities may be at increased risk of a fatal infusion reaction. Therefore, these patients should be treated with extreme caution and the risk versus the benefit considered for each patient (see Undesirable Effects).
Pulmonary toxicity
Severe pulmonary events have been reported rarely with the use of Herceptin in the post-marketing setting. These rare events have occasionally resulted in a fatal outcome. In addition, rare cases of pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. These events may occur as part of an infusion-related reaction or with a delayed onset. Patients with symptomatic intrinsic lung disease or with extensive tumour involvement of the lungs, resulting in dyspnoea at rest, may be at greater risk of severe reactions (see Undesirable Effects).
Cardiac toxicity
Heart failure (New York Heart Association [NYHA] class II - IV) has been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be moderate to severe and has been associated with death (see Undesirable Effects).
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 an LVEF of 55% or less (and patients 50 years and above should Herceptin be used concurrently with chemotherapy). All candidates for treatment with Herceptin, (especially those with prior anthracycline and cyclophosphamide (AC) exposure), should undergo baseline cardiac assessment including history and physical examination, ECG, echocardiogram, and/or MUGA scan. A careful risk-benefit assessment should be made before deciding to treat with Herceptin.
In early breast cancer, there are insufficient clinical data available about the benefit:risk balance in the following patients and consequently treatment cannot be recommended in such patients:
- History of documented congestive heart failure
- High-risk uncontrolled arrhythmias
- Angina pectoris requiring medication
- Clinically significant valvular disease
- Evidence of transmural infarction on ECG
- Poorly controlled hypertension
Cardiac function should be further monitored every three months while on treatment. Assessment of Left Ventricular Ejection Fraction (LVEF) should be monitored by an echocardiogram or a MUGA scan. The same method used for baseline assessment should be used throughout treatment. Monitoring may help to identify patients who develop cardiac dysfunction.
Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6 - 8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been seen.
If LVEF drops 10 ejection points from baseline and to below 50%, Herceptin should be withheld and a repeat LVEF assessment performed within approximately three 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.
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 trials improved with standard medical treatment. This included diuretics, cardiac glycosides, and/or angiotensin-converting enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on weekly therapy with Herceptin without additional clinical cardiac events.
Benzyl alcohol, used as a preservative in Bacteriostatic Water for Injection in the 440 mg multidose vial, has been associated with toxicity in neonates and children up to 3 years old. When administering Herceptin to a patient with a known sensitivity to benzyl alcohol, Herceptin should be reconstituted with water for injection, and only one dose per Herceptin vial should be used. Any unused portion must be discarded. Sterile water for injection, used to reconstitute the 150 mg single dose vials, does not contain benzyl alcohol.
Interactions
There have been no formal interaction studies performed with Herceptin in humans. Clinically significant interactions with the concomitant medication used in clinical trials have not been observed (see Pharmacokinetic Properties).
Paclitaxel pharmacokinetics determined during the fourth cycle of the alternative 3-weekly Herceptin regimen (n = 25) were not altered appreciably, relative to parameters determined during the initiation of paclitaxel, prior to introduction of Herceptin. Similarly, docetaxel pharmacokinetics determined during the first dose of Herceptin in the standard weekly regimen (n = 10) were not altered appreciably relative to those determined 2 weeks earlier for docetaxel-alone.
Use in Special Populations
Pregnancy
Pregnancy Category: B2
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 have been reported in pregnant women receiving Herceptin.
It is not known whether Herceptin can cause foetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. Animal reproduction studies revealed no evidence of impaired fertility or harm to the foetus (See Preclinical Safety, Teratogenicity).
Nursing mothers
It is not known whether trastuzumab is secreted in human milk. As human IgG is secreted into human milk, and the potential for harm to the infant is unknown, breast-feeding should be avoided during Herceptin therapy (See Preclinical Safety, Other).
Undesirable Effects
Clinical Trials
Metastatic breast cancer
Experience from clinical trials
Patients received Herceptin as monotherapy or in combination with paclitaxel in the two pivotal clinical trials. Approximately 50% of patients can be expected to experience adverse reactions. The most common adverse reactions are infusion-related symptoms, such as fever and chills, usually following the first infusion of Herceptin.
Adverse reactions attributed to Herceptin in ≥ 10% of patients in the two pivotal clinical trials were the following:
| Body as a whole: | abdominal pain, asthenia, chest pain, chills, fever, headache, pain |
|---|---|
| Digestive: | diarrhoea, nausea, vomiting |
| Musculoskeletal: | arthralgia, myalgia |
| Skin and appendages: | rash |
Adverse reactions attributed to Herceptin in > 1% and < 10% of patients in the two pivotal clinical trials were the following:
| Body as a whole: | back pain, influenza-like illness, infection, neck pain, malaise, hypersensitivity reaction |
|---|---|
| Cardiovascular: | vasodilation, supraventricular tachyarrhythmia, hypotension, heart failure, cardiomyopathy, palpitation |
| Digestive: | anorexia, constipation, dyspepsia |
| Haeme and lymphatic | leucopenia |
| Metabolic: | peripheral oedema, oedema |
| Musculoskeletal: | bone pain |
| Nervous: | anxiety, depression, dizziness, insomnia, paraesthesia, somnolence, hypertonia, peripheral neuropathy |
| Respiratory: | asthma, cough increased, dyspnoea, epistaxis, lung disorders, pleural effusion, pharyngitis, rhinitis, sinusitis |
| Urogenital: | urinary tract infection |
| Skin and appendages: | pruritus, sweating, nail disorders, dry skin, alopecia, acne, maculopapular rash |
In another randomised clinical trial, patients with metastatic breast cancer received docetaxel, with or without Herceptin. The following table displays common non-haematological adverse events which were reported in
≥ 10% of patients, by study treatment:
Table 1 Common Non-haematological Adverse Events Reported in ≥ 10% of Patients, by Study Treatment
| Body System | Adverse Event | Herceptin plus docetaxel n = 92 (%) |
Docetaxel n = 94 (%) |
|---|---|---|---|
| General disorders and administration site conditions | asthenia | 45 | 41 |
| oedema peripheral | 40 | 35 | |
| fatigue | 24 | 21 | |
| mucosal inflammation | 23 | 22 | |
| pyrexia | 29 | 15 | |
| pain | 12 | 9 | |
| lethargy | 7 | 11 | |
| chest pain | 11 | 5 | |
| influenza-like illness | 12 | 2 | |
| rigors | 11 | 1 | |
| Skin and subcutaneous tissue disorders | alopecia | 67 | 54 |
| nail disorder | 17 | 21 | |
| rash | 24 | 12 | |
| erythema | 23 | 11 | |
| Gastrointestinal disorders | nausea | 43 | 41 |
| diarrhoea | 43 | 36 | |
| vomiting | 29 | 22 | |
| constipation | 27 | 23 | |
| stomatitis | 20 | 14 | |
| abdominal pain | 12 | 12 | |
| dyspepsia | 14 | 5 | |
| Nervous system disorders | paraesthesia | 32 | 21 |
| headache | 21 | 18 | |
| dysgeusia | 14 | 12 | |
| hypoaesthesia | 11 | 5 | |
| Musculoskeletal and connective tissue disorders | myalgia | 27 | 26 |
| arthralgia | 27 | 20 | |
| pain in extremity | 16 | 16 | |
| back pain | 10 | 14 | |
| bone pain | 14 | 6 | |
| Respiratory, thoracic and mediastinal disorders | cough | 13 | 16 |
| dyspnoea | 14 | 15 | |
| pharyngolaryngeal pain | 16 | 9 | |
| epistaxis | 18 | 5 | |
| rhinorrhoea | 12 | 1 | |
| Infections and infestations | nasopharyngitis | 15 | 6 |
| Eye disorders | lacrimation increased | 21 | 10 |
| conjunctivitis | 12 | 7 | |
| Vascular disorders | lymphoedema | 11 | 6 |
| Metabolism and nutrition disorders | anorexia | 22 | 13 |
| Investigations | weight increased | 15 | 6 |
| Psychiatric disorders | insomnia | 11 | 4 |
| Injury, poisoning and procedural complications | nail toxicity | 11 | 7 |
Early breast cancer
The HERA trial was a randomised, open label study in patients with HER2-positive early breast cancer (see Clinical efficacy studies). Table 2 displays adverse events which were reported at a median follow-up of 1 year in ≥ 1% of patients, by study treatment.
Table 2 Adverse Events Reported at a median follow-up of 1 year in ≥ 1% of Patients, by Study Treatment
|
Body System |
Adverse Event | Observation Only n = 1708 No. (%) |
Herceptin 1 year n = 1678 No. (%) |
|---|---|---|---|
| Total Pts with at least one AE Total number of AEs |
792 (46) 2251 |
1179 (70) 5248 |
|
| Musculoskeletal and connective tissue disorders |
arthralgia* | 98 (6) | 137 (8) |
| back pain* | 59 (3) | 91 (5) | |
| pain in extremity | 45 (3) | 60 (4) | |
| myalgia* | 17 (<1) | 63 (4) | |
| bone pain | 26 (2) | 49 (3) | |
| shoulder pain | 29 (2) | 30 (2) | |
| chest wall pain | 24 (1) | 26 (2) | |
| muscle spasms* | 3 (<1) | 45 (3) | |
| musculoskeletal pain | 11 (<1) | 17 (1) | |
| Infections and infestations | nasopharyngitis* | 43 (3) | 135 (8) |
| influenza* | 9 (<1) | 69 (4) | |
| upper respiratory tract infection* | 20 (1) | 46 (3) | |
| urinary tract infection | 13 (<1) | 39 (2) | |
| rhinitis | 6 (<1) | 36 (2) | |
| sinusitis | 5 (<1) | 26 (2) | |
| cystitis | 11 (<1) | 19 (1) | |
| pharyngitis | 9 (<1) | 20 (1) | |
| bronchitis | 9 (<1) | 18 (1) | |
| herpes zoster | 9 (<1) | 17 (1) | |
| General disorders and administration site conditions |
fatigue* | 44 (3) | 128 (8) |
| oedema peripheral | 38 (2) | 79 (5) | |
| pyrexia* | 6 (<1) | 100 (6) | |
| asthenia* | 30 (2) | 75 (4) | |
| chills* | - | 85 (5) | |
| chest pain* | 22 (1) | 45 (3) | |
| influenza illness | 3 (<1) | 40 (2) | |
| oedema | 7 (<1) | 18 (1) | |
| chest discomfort | 2 (<1) | 20 (1) | |
| Gastrointestinal disorders | diarrhoea* | 16 (<1) | 123 (7) |
| nausea* | 19 (1) | 108 (6) | |
| vomiting* | 10 (<1) | 58 (3) | |
| abdominal pain | 16 (<1) | 40 (2) | |
| constipation | 17 (<1) | 33 (2) | |
| abdominal pain upper | 15 (<1) | 29 (2) | |
| dyspepsia | 9 (<1) | 30 (2) | |
| gastritis | 11 (<1) | 20 (1) | |
| stomatitis | 1 (<1) | 26 (2) | |
| Nervous system disorders | headache* | 49 (3) | 161 (10) |
| dizziness* | 29 (2) | 60 (4) | |
| paraesthesia | 11 (<1) | 29 (2) | |
| vertigo | 7 (<1) | 25 (1) | |
| Vascular disorders | hot flush | 84 (5) | 98 (6) |
| hypertension* | 35 (2) | 64 (4) | |
| lymphoedema | 40 (2) | 42 (3) | |
| Skin and subcutaneous tissue | rash* | 10 (<1) | 70 (4) |
| pruritus | 10 (<1) | 40 (2) | |
| nail disorder* | - | 43 (3) | |
| onychorrhexis | 1 (<1) | 36 (2) | |
| erythema | 7 (<1) | 24 (1) | |
| Respiratory, thoracic and mediastinal disorders |
cough* | 34 (2) | 81 (5) |
| dyspnoea | 26 (2) | 56 (3) | |
| pharyngolaryngeal pain | 8 (<1) | 32 (2) | |
| dyspnoea exertional | 15 (<1) | 21 (1) | |
| rhinorrhoea | 5 (<1) | 24 (1) | |
| epistaxis | 1 (<1) | 24 (1) | |
| Reproductive system and breast disorders | breast pain | 19 (1) | 24 (1) |
| Psychiatric | insomnia | 31 (2) | 58 (3) |
| depression | 34 (2) | 51 (3) | |
| anxiety | 19 (1) | 39 (2) | |
| Cardiac disorders | palpitations* | 12 (<1) | 48 (3) |
| cardiac failure congestive | 5 (<1) | 30 (2) | |
| tachycardia | 5 (<1) | 20 (1) | |
| Investigations | ejection fraction decreased* | 11 (<1) | 58 (3) |
| weight increased | 17 (<1) | 29 (2) | |
| Renal and urinary disorders | dysuria | 2 (<1) | 17 (1) |
* Adverse Events that were reported at higher incidence (≥ 2% difference) in the Herceptin group compared with the observation group and therefore may be attributable to Herceptin.
At a median follow-up of two-years in the HERA trial, there were more episodes of at least one Grade 3-4 adverse event and of serious adverse events with Herceptin than in the observation group (p < 0.0001). The only Grade 3-4 adverse event experienced by five or more patients in the observation group (n = 1,698) was hypertension (5). The Grade 3-4 adverse events experienced by five or more patients in the Herceptin group (n = 1,703) were: hypertension (12), depression (8), diarrhoea (7), congestive cardiac failure (7), vomiting (6), arthralgia (6), cardiac failure (5), hot flush (5), headache (5), and back pain (5).
The B-31 and N9831 trials were phase III, randomised, open-label trials in patients with HER2-positive early breast cancer (see Clinical efficacy studies). The following non-cardiac adverse reactions of Grade 2-5 occurred in at least one of these trials at an incidence of at least 2% greater among patients randomised to Herceptin-plus-chemotherapy as compared to chemotherapy-alone: arthralgia, myalgia, fatigue, infection, hot flashes, anaemia, dyspnoea, rash/desquamation, neutropenia, headache, insomnia and nail changes. The majority of these events were Grade 2 in severity.
The following information is relevant to all indications:
Infusion-related symptoms
During the first infusion of Herceptin, chills and/or fever are observed commonly in patients. Other signs and/or symptoms may include nausea, vomiting, pain, rigors, headache, cough, dizziness, rash, asthenia and hypertension. These symptoms are usually mild to moderate in severity, and occur infrequently with subsequent Herceptin infusions. These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine (see Dosage and Administration). Some adverse reactions to Herceptin infusion including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress can be serious and potentially fatal (see Warnings and Precautions).
Hypersensitivity reaction
Anaphylactoid reactions were observed in isolated cases.
Cardiac toxicity
Signs and symptoms of cardiac dysfunction, such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ejection fraction, have been observed in patients treated with Herceptin (see Warnings and Precautions). Depending on the criteria used to define cardiac dysfunction, the incidence in the pivotal metastatic trials varied between 9% and 12% in the Herceptin + paclitaxel subgroup, compared with 1% - 4% for the paclitaxel-alone subgroup. For Herceptin monotherapy, the rate was 6% - 9%. The highest rate of cardiac dysfunction was seen in patients receiving Herceptin + anthracycline/cyclophosphamide (27% - 28%), which was significantly higher than the rate reported for patients in the anthracycline/cyclophosphamide-alone subgroup (7% - 10%). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic heart failure was 2.2% in patients receiving Herceptin and docetaxel, compared with 0% in patients receiving docetaxel-alone.
In the early breast cancer HERA trial, 2.1% of women developed symptomatic heart failure with 0.6% developing severe heart failure (NYHA class III-IV) in the one year Herceptin arm. In the B-31 and N9831 early breast cancer trials, at a median follow-up of two years, the three-year cumulative incidences of severe heart failure or death from cardiac causes were 4.1% and 2.9% respectively in the Herceptin groups versus 0.8% and 0% respectively in the control groups.
As the mean terminal half-life of Herceptin is 28.5 days (95% confidence interval, 25.5 - 32.8 days), trastuzumab may persist in the circulation for up to 20 weeks (95% confidence interval, 18 - 24 weeks) after stopping treatment. Since the use of an anthracycline during this period could possibly be associated with an increased risk of cardiac dysfunction, a thorough assessment of the risks versus the potential benefits is recommended in addition to careful cardiac monitoring.
Haematological toxicity
Haematological toxicity is infrequent following the administration of Herceptin monotherapy in the metastatic setting, WHO Grade 3 leucopenia, thrombocytopenia and anaemia occurring in < 1% of patients. No WHO Grade 4 toxicities were observed.
There was an increase in WHO Grade 3 or 4 haematological toxicity in patients treated with the combination of Herceptin and paclitaxel compared with patients receiving paclitaxel-alone (34% vs. 21%). Haematological toxicity was also increased in patients receiving Herceptin and docetaxel, compared with docetaxel-alone (32% grade 3/4 neutropenia versus 22%, using HCl-CTC criteria). The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel-alone).
Using NCI-CTC criteria, in the HERA trial (median follow-up 1 year), 0.4% of Herceptin-treated patients experienced a shift of 3 or 4 grades from baseline, compared with 0.6% in the observation arm.
Hepatic and renal toxicity
WHO Grade 3 or 4 hepatic toxicity was observed in 12% of patients following administration of Herceptin as single agent, in the metastatic setting. This toxicity was associated with progression of disease in the liver in 60% of these patients.
WHO Grade 3 or 4 hepatic toxicity was less frequently observed among patients receiving Herceptin and paclitaxel than among patients receiving paclitaxel (7% compared with 15%). No WHO Grade 3 or 4 renal toxicity was observed.
Diarrhoea
Of patients treated with Herceptin monotherapy in the metastatic setting, 27% experienced diarrhoea. An increase in the incidence of diarrhoea, primarily mild to moderate in severity, has also been observed in patients receiving Herceptin in combination with paclitaxel compared with patients receiving paclitaxel-alone.
In the HERA trial (median follow-up 1 year), 7% of Herceptin-treated patients had diarrhoea.
Infection
An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections, has been observed primarily in patients treated with Herceptin-plus-paclitaxel compared with patients receiving paclitaxel-alone.
Serious adverse reactions
At least one case of the following serious adverse reactions has occurred in at least one patient treated with Herceptin-alone or in combination with chemotherapy in clinical trials.
| Body as a whole: | hypersensitivity reaction, anaphylaxis and anaphylactic shock, ataxia, sepsis, chills and fever, asthenia, fever, rigor, headache, paresis, chest pain, fatigue |
|---|---|
| Cardiovascular: | cardiomyopathy, congestive heart failure, increased congestive heart failure, decreased ejection fraction, hypotension, pericardial effusion, bradycardia, cerebrovascular disorder |
| Digestive: | hepatocellular damage, diarrhoea, nausea and vomiting |
| Haeme and lymphatic: | leukaemia, febrile neutropenia, neutropenia, thrombocytopenia |
| Infections: | cellulitis, erysipelas |
| Respiratory: | bronchospasm, respiratory distress, acute pulmonary oedema, respiratory insufficiency, pneumonitis |
| Skin and appendages: | rash |
Post-Marketing Experience
The following additional serious adverse reactions have been reported in at least one patient during post-marketing experience:
| Body as a whole: | infusion-related symptoms, peripheral oedema, bone pain, coma, meningitis, cerebral oedema, abnormal thinking |
| Cardiovascular: | cardiac failure, cardiogenic shock, pericarditis, hypertension |
| Digestive: | pancreatitis, hepatic failure, jaundice |
| Haeme and lymphatic: | anaemia, hypoprothrombinaemia |
| Musculoskeletal | myalgia |
| Respiratory: | dyspnoea, hypoxia, laryngeal oedema, acute respiratory distress, adult respiratory distress syndrome, pleural effusion, pulmonary infiltrates, pneumonia, pneumonitis, pulmonary fibrosis |
| Renal: | glomerulonephropathy, renal failure |
| Skin and appendages: | dermatitis, urticaria |
| Special senses | deafness |
Overdosage
There is no experience with overdosage in human clinical trials. Single doses higher than 10 mg/kg have not been tested.
Pharmacological Properties and Effects
Pharmacodynamic Properties
Mechanism of action
Trastuzumab is a recombinant DNA-derived humanised monoclonal antibody that selectively targets the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). The antibody is an IgG1 that contains human framework regions with the complementarity-determining regions of a murine anti-p185 HER2 antibody that binds to HER2.
The HER2 proto-oncogene or c-erbB2 encodes for a single transmembrane spanning, receptor-like protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Overexpression of HER2 is observed in 25% - 30% of primary breast cancers. A consequence of HER2 gene amplification is an increase in HER2 protein expression on the surface of these tumour cells, which results in a constitutively activated HER2 receptor.
Studies indicate that patients whose tumours have amplification or overexpression of HER2 have a shortened disease-free survival compared to patients whose tumours do not have amplification or overexpression of HER2.
Trastuzumab has been shown, both in in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. In vitro, trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
Clinical efficacy studies
Efficacy
Metastatic breast cancer
Herceptin monotherapy has been used in clinical trials 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 has also been used in clinical trials in combination with paclitaxel or an anthracycline (doxorubicin or epirubicin) plus cyclophosphamide (AC) as first line therapy for patients with metastatic breast cancer who have tumours that overexpress HER2.
Patients who had previously received anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m2 infused over 3 hours) with or without Herceptin. Patients could be treated with Herceptin until progression of disease.
Herceptin monotherapy, when used as second- or third-line treatment of women with metastatic breast cancer which overexpresses HER2, results in an overall tumour response rate of 15% and a median survival of 13 months.
The use of Herceptin in combination with paclitaxel as first-line treatment of women with metastatic breast cancer that overexpresses HER2 significantly prolongs the median time to disease progression, compared with patients treated with paclitaxel-alone. The increase in median time to disease progression for patients treated with paclitaxel is 3.9 months (6.9 months vs. 3.0 months). Tumour response and one year survival rate are also increased for Herceptin in combination with paclitaxel versus paclitaxel-alone.
Herceptin has also been studied in a randomised, controlled trial, in combination with docetaxel, as first-line treatment of women with metastatic breast cancer. The combination of Herceptin and docetaxel significantly increased response rate (61% vs. 34%) and prolonged the median time to disease progression, (by 5.6 months) compared with patients treated with docetaxel-alone. Median survival was also significantly increased in patients receiving the combination, compared with those receiving docetaxel-alone (31.2 months vs. 22.7 months).
Early breast cancer
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 summarised in the following table:
Table 3 Efficacy Results from the HERA Trial (median follow-up of 2 years; intention-to-treat analysis)
| Parameter | Observation n = 1698 |
Herceptin 1 Year n = 1703 |
p-value vs. Observation (log rank test) |
Hazard Ratio vs. Observation (95% CI) |
|---|---|---|---|---|
| Disease-free survival | ||||
| - No. patients with event | 321 (18.9%) | 218 (12.8%) | < 0.0001 | 0.64 |
| - No. patients without event | 1377 (81.1%) | 1485 (87.2%) | (0.54 - 0.76) | |
| Distant disease-free survival | ||||
| - No. patients with event | 233 (13.7%) | 152 (8.9%) | < 0.0001 | 0.60 |
| - No. patients without event | 1465 (86.3%) | 1551 (91.1%) | (0.49 - 0.73) | |
| Overall survival (death) | ||||
| - No. patients with event | 90 (5.3%) | 59 (3.5 %) | = 0.0115 | 0.66 |
| - No. patients without event | 1608 (94.7%) | 1644 (96.5%) | (0.47 - 0.91) |
The hazard ratios translate into absolute benefits, in favour of the Herceptin arm, of a 3-year disease-free survival rate of 6.3 percentage points (80.6% vs. 74.3%) and a 3-year overall survival rate of 2.7 percentage points (92.4% vs. 89.7%).
Herceptin has also been investigated in the adjuvant setting in two phase III, multi-centre, randomised, open-label trials (NSABP B-31 and NCCTG N9831). The trials were designed to compare the efficacy and safety of adjuvant chemotherapy with or without Herceptin. Patients assigned to receive Herceptin were given an initial loading dose of 4 mg/kg, followed by 2 mg/kg once a week for a total of 52 weeks.
The US Food and Drug Administration (FDA) approved a joint-analysis plan to combine data from B-31 and N9831. In the combined analysis, the two concurrent chemotherapy-plus-Herceptin arms (trastuzumab group) were compared with the two chemotherapy-alone arms (control group).
Efficacy results from the combined analysis of the B-31 and N9831 trials are summarised in the following table:
Table 4 Efficacy Results from the B-31/N9831 Combined Analysis (median follow-up of 2 years; intention-to-treat analysis)
| Number of patients | |||||
| End point | Trastuzumab Group n = 1672 |
Control Group n = 1679 | Total n = 3351 |
Hazard Ratio (95% CI) | p-value* by log-rank test |
|---|---|---|---|---|---|
| Disease-free survival | 133 | 261 | 394 | 0.48 (0.39 - 0.59) |
< 0.0001 |
| Time to recurrence | 117 | 235 | 352 | 0.47 (0.38 - 0.59) |
< 0.0001 |
| Time to distant recurrence | 96 | 193 | 289 | 0.47 (0.37 - 0.61) |
< 0.0001 |
| Overall survival | 62 | 92 | 154 | 0.67 (0.48 - 0.93) |
0.015 |
* All p-values are two-sided.
Immunogenicity
Human anti-trastuzumab antibodies were detected in 1 of 903 patients, who had no allergic manifestations.
Pharmacokinetic Properties
The pharmacokinetics of trastuzumab has been studied in patients with metastatic breast cancer and early breast cancer. In Phase I studies, short duration intravenous infusions of 10, 50, 100, 250 and 500 mg trastuzumab once weekly in patients demonstrated dose-dependent pharmacokinetics. Mean half-lives increased and clearance decreased with increased dose level.
Steady state pharmacokinetics
A population pharmacokinetic method, using data from Phase I, Phase II and pivotal Phase III studies, was used to estimate the steady state pharmacokinetics in patients with metastatic breast cancer administered trastuzumab at a loading dose of 4 mg/kg followed by a weekly maintenance dose of 2 mg/kg. In this assessment, the typical clearance of trastuzumab was 0.225 L/day and the typical volume of distribution was 2.95 L, with a corresponding terminal half-life of 28.5 days (95% confidence interval, 25.5 - 32.8 days). Steady state weekly AUC of 578 mg*day/L, peak concentrations of 110 mg/L and trough concentrations of 66 mg/L should be reached by 143 days, or approximately 20 weeks. The same time interval would be predicted for trastuzumab elimination after discontinuation of Herceptin therapy.
An assessment in early breast cancer patients administered Herceptin at an initial loading dose of 8 mg/kg followed by a three weekly maintenance dose of 6 mg/kg achieved steady state trough concentrations of 63 mg/L, by cycle 13. The concentrations were comparable to those reported previously in patients with metastatic breast cancer.
The administration of concomitant chemotherapy (either anthracycline/cyclophosphamide, paclitaxel or docetaxel) did not appear to influence the pharmacokinetics of trastuzumab.
Pharmacokinetics in Special Populations
Detailed pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out.
Elderly
Age has been shown to have no effect on the disposition of trastuzumab (see Dosage and Administration).
Preclinical Safety
Teratogenicity
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. However, when assessing the risk of reproductive toxicity to humans, it is also important to consider the significance of the rodent form of the HER2 receptor in normal embryonic development and the embryonic death in mutant mice lacking this receptor. Placental transfer of trastuzumab during the early (days 20 - 50 of gestation) and late (days 120 - 150 of gestation) foetal development period was observed.
Other
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.
Pharmaceutical Particulars
Storage
Vials
Store vials at 2 °C - 8 °C.
This medicine should not be used after the expiry date shown on the pack.
Shelf-life of the reconstituted solution
Herceptin 440 mg vial
Reconstituted solutions made with Bacteriostatic Water for Injection for the 440 mg vial of Herceptin, as supplied, are stable for 28 days when stored refrigerated at 2 °C - 8 °C. The reconstituted solution contains preservative and is therefore suitable for multiple use. Any remaining reconstituted solution should be discarded after 28 days. If sterile water is used to reconstitute the 440 mg vial, the solution is stable for only 24 hours, and must be discarded thereafter.
Do not freeze the reconstituted solution.
Herceptin 150 mg vial
The 150 mg vials are reconstituted with sterile water for injection and are for single use only.
The reconstituted product is physically and chemically stable for 48 hours at 2 oC - 8 oC (refrigerate, do not freeze) after dissolving with water for injections.
From a microbiological point of view, the reconstituted solution should be further diluted immediately. If not further diluted immediately, in-use storage times and conditions prior to dilution are the responsibility of the user. The shelf-life of the reconstituted solution is 24 hours at 2 oC - 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions in which case the shelf-life is 48 hours at 2 oC - 8 °C.
Shelf-life of the solution for infusion containing the reconstituted product
The infusion solution (0.9% sodium chloride infusion solution) containing the reconstituted product is physically and chemically stable for 24 hours (do not store above 30 °C).
From a microbiological point of view, the Herceptin infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.
Special Instructions for Use, Handling and Disposal
Appropriate aseptic technique should be used.
The 440 mg vial of Herceptin is reconstituted with 20 mL of Bacteriostatic Water for Injection, containing 1.1% benzyl alcohol, as supplied. This yields a solution for multiple use, containing 21 mg/mL trastuzumab, at a pH of approximately 6.0. Use of other reconstitution solvents should be avoided.
The 150 mg vial of Herceptin is reconstituted with 7.2 mL of sterile water for injection.
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 - 440 mg vial:
- Using a sterile syringe, slowly inject 20 mL of sterile Bacteriostatic Water for Injection into the vial containing the lyophilised Herceptin, directing the stream into the lyophilised cake.
- Swirl vial gently to aid reconstitution. DO NOT SHAKE!
Instructions for reconstitution - 150 mg vial:
- Using a sterile syringe, slowly inject 7.2 mL of sterile water for injection into the vial containing the lyophilised Herceptin, directing the stream into the lyophilised cake.
- 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 particles.
Instructions for dilution
Weekly schedule
Determine the volume of the reconstituted solution required based on a loading dose of 4 mg trastuzumab/kg body weight, or a maintenance 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)
Three-weekly schedule
Determine the volume of the reconstituted solution required based on a loading dose of 8 mg trastuzumab/kg body weight, or a maintenance 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)
Preparation and Stability of the Admixture
The appropriate amount of reconstituted solution should be withdrawn from the vial and added to an infusion bag containing 250 mL of 0.9% sodium chloride. Dextrose (5%) solution should not be used (see Incompatibilities). The bag should be gently inverted to mix the solution in order to avoid foaming. Parenteral medicines should be inspected visually for particulates and discoloration prior to administration. Once the infusion is prepared it should be administered immediately (see Storage).
Incompatibilities
No incompatibilities between Herceptin and polyvinylchloride, polyethylene or polypropylene bags have been observed.
Dextrose (5%) solution should not be used since it causes aggregation of the protein.
Herceptin should not be mixed or diluted with other medicines.
Medicine Classification
Prescription medicine.
Packs
Herceptin 150 mg single-dose vials: each pack contains one vial of Herceptin (150 mg trastuzumab).
Herceptin 440 mg multi-dose vials: each pack contains one vial of Herceptin (440 mg trastuzumab) and one 20 mL vial of Bacteriostatic Water for Injection.
Further Information
Provisional consent has been granted for distribution of Herceptin 150 mg and 440 mg vials under Section 23 of the Medicines Act 1981.
Name and Address
Roche Products (New Zealand) Limited
P O Box 12492
Penrose
AUCKLAND 1642
Ph: (09) 635 1500
Fax: (09) 635 1522
Toll Free: 0800 656 464
Date of Preparation
19 February 2009
Reference: Herceptin Core Data Sheet V7.0, 06 November 2008.