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Drug Details

HERCEPTIN

• Drug Class Description
  Monoclonal antibodies (antineoplastic agents).
• Generic Name
  Trastuzumab
• Presentation
  Powder for concentrate for solution for infusion. Herceptin is a white to pale yellow lyophilised powder.
• Description
  1 vial contains 150 mg of trastuzumab, a humanised IgG1 monoclonal antibody manufactured from a mammalian cell line (Chinese hamster ovary, CHO) by continuous perfusion. Reconstituted Herceptin solution contains 21 mg/ml of trastuzumab.
• Indications
  

  Metastatic Breast Cancer (MBC) Herceptin is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2:

  a) 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.

  b) 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.

  c) in combination with docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.

  d) in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive metastatic breast cancer, not previously treated with trastuzumab. Early Breast Cancer (EBC) Herceptin is indicated for the treatment of patients with HER2 positive early breast cancer following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable). Herceptin should only be used in patients whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay.

• Adult Dosage
  

  HER2 testing is mandatory prior to initiation of Herceptin therapy. Herceptin treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy.

  MBC Weekly schedule:

  The following loading and subsequent doses are recommended for monotherapy and in combination with paclitaxel, docetaxel or an aromatase inhibitor.

  Loading dose

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

  Subsequent doses

  The recommended weekly dose of Herceptin is 2 mg/kg body weight, beginning one week after the loading dose.

  Method of administration

  Herceptin is administered as a 90-minute intravenous infusion. 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. Interruption 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. Emergency equipment must be available.

  Administration in combination with paclitaxel or docetaxel

  In the pivotal trials, paclitaxel or docetaxel was administered the day following the first dose of Herceptin (for dose, see the Summary of Product Characteristics for paclitaxel or docetaxel) and immediately after the subsequent doses of Herceptin if the preceding dose of Herceptin was well tolerated.

  Administration in combination with an aromatase inhibitor

  In the pivotal trial Herceptin and anastrozole were administered from day 1. There were no restrictions on the relative timing of Herceptin and anastrozole at administration (for dose, see the Summary of Product Characteristics for anastrozole or other aromatase inhibitors).

  Duration of treatment

  Herceptin should be administered until progression of disease.

  MBC 3-weekly schedule:

  Alternatively the following loading and subsequent doses are recommended for monotherapy and in combination with paclitaxel, docetaxel or an aromatase inhibitor.

  Initial loading dose of 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as infusions over approximately 90 minutes.

  Duration of treatment

  Herceptin should be administered until progression of disease.

  EBC 3-weekly schedule:

  In the HERA trial, Herceptin was initiated after completions of standard chemotherapy (most commonly, anthracycline-containing regimens or anthracyclines plus a taxane).

  Initial loading dose of 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as infusions over approximately 90 minutes.

  Patients with early breast cancer should be treated for 1 year or until disease recurrence.

  EBC weekly schedule:

  In the adjuvant setting, Herceptin has also been investigated as a weekly regimen (an initial loading dose of 4 mg/kg followed by 2 mg/kg every week for one year) concomitantly with paclitaxel (administered weekly (80 mg/m²) or every 3 weeks (175 mg/m²) for a total of 12 weeks) following 4 cycles of AC (doxorubicin 60 mg/m² IV push concurrently with cyclophosphamide 600 mg/m² over 20–30 minutes).

  MBC and EBC:

  Do not administer as an intravenous push or bolus.

  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. Refer to the Summary of Product Characteristics for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.

  Missed doses during 3-weekly schedule

  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 3 weeks, according to the previous schedule.

  If the patient misses a dose of Herceptin by more than one week, a re-loading dose of Herceptin should be given (8 mg/kg over approximately 90 minutes). Subsequent maintenance Herceptin doses of 6 mg/kg should then be given every 3 weeks from that point.

  Special patient populations

  Clinical data show that the disposition of Herceptin is not altered based on age or serum creatinine. In clinical trials, elderly patients did not receive reduced doses of Herceptin. Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. However in a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.

  Paediatric use

  Herceptin is not recommended for use in children below 18 due to insufficient data on safety and efficacy.

• Child Dosage
  Not recommended.
• Contra Indications
  

  Patients with known hypersensitivity to trastuzumab, murine proteins, or to any of the excipients.

  Patients with severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.

• Special Precautions
  

  HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures.

  Currently no data from clinical trials are available on Herceptin re-treatment of patients with previous exposure to Herceptin in the adjuvant setting.

  The use of Herceptin is associated with cardiotoxicity. All candidates for treatment should undergo careful cardiac monitoring .The risk of cardiotoxicity is greatest when Herceptin is used in combination with anthracyclines. Therefore Herceptin and anthracyclines should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines. Because the half-life of Herceptin is approximately 28.5 days (95 % confidence interval, 25.5 – 32.8 days), Herceptin may persist in the circulation for up to 24 weeks after stopping Herceptin treatment. Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 24 weeks after stopping Herceptin. If anthracyclines are used, the patient's cardiac function should be monitored carefully. Serious adverse reactions including infusion reactions, hypersensitivity, allergic-like reactions and pulmonary events have been observed in patients receiving Herceptin therapy. Patients who are experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction. These severe reactions were usually associated with the first infusion of Herceptin and generally occurred during or immediately following the infusion. For some patients, symptoms progressively worsened and led to further pulmonary complications. 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 or pulmonary symptoms more than six hours after the start of the Herceptin infusion. Patients should be warned of the possibility of such a late onset and should be instructed to contact their physician if these symptoms occur.

  Infusion reactions, allergic-like reactions and hypersensitivity

  Serious adverse reactions to Herceptin infusion that have been reported infrequently include dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema (see 4.8). The majority of these events occur during or within 2.5 hours of the start of the first infusion. Should an infusion reaction occur the Herceptin infusion should be discontinued and the patient monitored until resolution of any observed symptoms (see 4.2). The majority of patients experienced resolution of symptoms and subsequently received further infusions of Herceptin. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. Patients who are experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction. Therefore, these patients should not be treated with Herceptin (see 4.3).

  Pulmonary events

  Severe pulmonary events have been reported rarely with the use of Herceptin in the post-marketing setting (see 4.8). These rare events have occasionally been fatal. 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 who are experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Herceptin (see 4.3). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.

  Cardiotoxicity

  Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. This may be moderate to severe and has been associated with death (see 4.8).

  All candidates for treatment with Herceptin, but especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, ECG, echocardiogram, or MUGA scan or magnetic resonance imaging. A careful risk-benefit assessment should be made before deciding to treat with Herceptin.

  In EBC, the following patients were excluded from the HERA trial, there are no data about the benefit:risk balance, and therefore treatment can not be recommended in such patients:

  • History of documented CHF

  • High-risk uncontrolled arrhythmias

  • Angina pectoris requiring medication

  • Clinically significant valvular disease

  • Evidence of transmural infarction on ECG

  • Poorly controlled hypertension

  Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. Cardiac function should be further monitored during treatment (e.g. every three months). Monitoring may help to identify patients who develop cardiac dysfunction. For early breast cancer patients, cardiac assessment, as performed at baseline, should be repeated every 3 months during treatment and at 6, 12 and 24 months following cessation of treatment. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6-8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been seen. Caution should be exercised in treating patients with symptomatic heart failure, a history of hypertension or documented coronary artery disease, and in early breast cancer, in those patients with an LVEF of 55 % or less.

  If LVEF drops 10 ejection points from baseline AND to below 50 %, Herceptin should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.

  If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with the standard medications for this purpose. Discontinuation of Herceptin therapy should be strongly considered in patients who develop clinically significant heart failure unless the benefits for an individual patient are deemed to outweigh the risks.

  The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has not been prospectively studied. However, most patients who developed heart failure in the pivotal trials improved with standard medical treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensinconverting 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.

• Interactions
  

  No interaction studies have been performed. A risk for interactions with concomitant medication cannot be excluded.

• Adverse Drug Reactions
  

  MBC

  The adverse event data reflect the clinical trial and post marketing experience of using Herceptin at the recommended dose regimen, either alone or in combination with paclitaxel.

  Patients received Herceptin as monotherapy or in combination with paclitaxel in the two pivotal clinical trials. 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:	influenza-like illness, back pain, infection, neck pain, malaise, hypersensitivity reaction, mastitis, weight loss
  Cardiovascular:	vasodilation, supraventricular tachyarrythmia, hypotension, heart failure, cardiomyopathy, palpitation
  Digestive:	anorexia, constipation, dyspepsia, liver tenderness, dry mouth, rectal disorder (haemorrhoids)
  Blood and lymphatic:	leucopenia, ecchymosis
  Metabolic:	peripheral oedema, oedema
  Musculoskeletal:	bone pain, leg cramps, arthritis
  Nervous:	dizziness, paraesthesia, somnolence, hypertonia, peripheral neuropathy, tremor
  Psychiatric disorders	anxiety, depression, insomnia,
  Respiratory:	asthma, cough increased, dyspnoea, epistaxis, lung disorders, pharyngitis, rhinitis, sinusitis
  Urogenital:	urinary tract infection
  Skin and appendages:	pruritus, sweating, nail disorder, dry skin, alopecia, acne, maculopapular rash
  Special senses:	taste perversion

  In a further randomised clinical trial (M77001), patients with metastatic breast cancer received docetaxel, with or without Herceptin. The following table displays 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
  Blood and lymphatic system disorders	febrile neutropenia1 / neutropenic sepsis	23	17
  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
  [1] These numbers include patients with preferred terms of 'febrile neutropenia', 'neutropenic sepsis' or 'neutropenia' that was associated with fever (and antibiotic use).

   

  There was an increased incidence of SAEs (40 % vs. 31%) and Grade 4 AEs (34 % vs. 23 %) in the combination arm compared to docetaxel monotherapy.

  In a further randomised clinical trial (BO16216), patients with HER2 positive and hormone receptor positive metastatic breast cancer received anastrozole with or without Herceptin. In this trial, there was no change in the safety profile compared with previous trials in the metastatic population. The following table displays adverse events which were reported in 10% of patients, by study treatment:

  Table 2 Summary of Adverse Events with an Incidence Rate of at Least 10 % by Trial Treatment

  Adverse Event	Arimidex Plus Herceptin N=103 No. (%)	Arimidex Alone N=104 No. (%)
  Fatigue	22 (21)	10 (10)
  Diarrhoea	21 (20)	8 (8)
  Vomiting	22 (21)	5 (5)
  Arthralgia	15 (15)	10 (10)
  Pyrexia	18 (17)	7 (7)
  Back pain	15 (15)	7 (7)
  Dyspnoea	13 (13)	9 (9)
  Nausea	17 (17)	5 (5)
  Cough	14 (14)	6 (6)
  Headache	14 (14)	6 (6)
  Nasopharyngitis	17 (17)	2 (2)
  Bone pain	11 (11)	6 (6)
  Constipation	12 (12)	5 (5)
  Chills	15 (15)	-
  Percentages are based on N. Multiple occurrences of the same adverse event in one individual counted only once. Note: For patients from the Arimidex Alone arm who switched to Herceptin, only AEs before the 1st Herceptin administration are displayed

   

  There was an increased incidence of SAEs (23% vs. 6%) and Grade 3/4 AEs (25% vs. 15%) in the combination arm compared to anastrozole monotherapy.

  EBC

  The HERA trial is a randomised, open label study in patients with HER2-positive early breast cancer. Table 3 displays adverse events which were reported at 1 year in 1% of patients, by study treatment.

  Table 3 Adverse Events Reported at 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.

  The following information is relevant to all indications:

   

  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 or has been reported during post marketing experience:

  Body System	Adverse Event
  Body as a Whole	hypersensitivity reaction, anaphylaxis and anaphylactic shock, angioedema, ataxia, sepsis, chills and fever, asthenia, fever, rigor, headache, paresis, chest pain, fatigue, infusion-related symptoms, peripheral oedema, bone pain, coma, meningitis, cerebral oedema, thinking abnormal, progression of neoplasia
  Cardiovascular	cardiomyopathy, congestive heart failure, increased congestive heart failure, decreased ejection fraction, hypotension, pericardial effusion, bradycardia, cerebrovascular disorder, cardiac failure, cardiogenic shock, pericarditis
  Digestive	hepat   Back Home News View EPGOnline.org (not optimised for mobile devices)