Trastuzumab

Registered South African indications:

• Metastatic breast cancer (MBC)
• Early breast cancer (EBC)
• Metastatic gastric-adenocarcinoma (MGC)

Cardiomyopathy Trastuzumab administration can result in the development of ventricular dysfunction and congestive heart failure. Left ventricular function should be evaluated in all patients prior to and during treatment with trastuzumab. Discontinuation of trastuzumab treatment should be strongly considered in patients who develop a clinically significant decrease in left ventricular function. The incidence and severity of cardiac dysfunction was particularly high in patients who received trastuzumab in combination with anthracyclines and cyclophosphamide Hypersensitivity reactions including anaphylaxis, infusion reactions, pulmonary events Trastuzumab administration can result in severe hypersensitivity reactions (including anaphylaxis), infusion reactions and pulmonary events. These may be fatal. In most cases, symptoms occurred during or within 24 hours of administration of trastuzumab. Trastuzumab infusion should be interrupted for patients experiencing dyspnoea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of trastuzumab should be strongly considered for patients who develop anaphylaxis, angioedema, or acute respiratory distress syndrome

Registered South African contraindications

• Hypersensitivity to the active ingredient or to any of its excipients
• Hypersensitivity of murine proteins
• Severe dyspnoea at rest due to complications of advanced malignancy or the requirement for supplementary oxygen therapy
• Pregnancy
• Lactation

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or to any of its excipients
• Hypersensitivity of murine proteins
• Hypersensitivity to hyaluronidase (600mg)
• Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy

Cautions

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Renal impairment
• Hepatic impairment
• Elderly (Recommendations in other jurisdictions)
• Previous exposure to trastuzumab
• History of or known cardiac disease
• Increased cardiovascular risk 
• Prior therapy with other antineoplastic agents
• Risk factors associated with interstitial lung disease
• Pneumonitis

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

HER2 testing is mandatory prior to initiation of trastuzumab therapy. Trastuzumab should be administered by a qualified healthcare professional. It is important to check the product labels to ensure that the correct formulation (trastuzumab 21mg/ml IV or trastuzumab 600mg SC) is being administered to the patient as prescribed

600mg subcutaneous injection

Metastatic breast cancer (MBC) in patients with HER2 overexpression
- As a monotherapy after at least two chemotherapy regimens for their metastatic disease
- In combination with paclitaxel or docetaxel for patients without prior chemotherapy for their metastatic disease
- In combination with an aromatase inhibitor for hormone-receptor positive metastatic breast cancer
Early breast cancer (EBC) in HER2 positive patients
- Post-surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable)
- Following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with docetaxel
- In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin
- In combination with neoadjuvant chemotherapy followed by adjuvant trastuzumab, for locally advanced (including inflammatory) breast cancer or tumours >2cm in diameter
(Trastuzumab SC is prescribed only when tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. Trastuzumab should only be used in patients whose tumours have HER2 overexpression at a 3+ level as determined by immunohistochemistry)

• SC: 600mg, given over 2-5min every 3 weeks, regardless of body weight; Injection sites should be alternated between the left and right thigh, and new injections should be given at least 2.5cm from the previous site on healthy skin; Avoid red, bruised, tender, or hard skin

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No loading dose is required for SC formulation

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Other SC medications should be injected at different sites during the trastuzumab SC 600mg treatment course

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Trastuzumab SC 600mg formulation is not to be used for intravenous administration and must be administered via subcutaneous route only

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Duration of treatment
Patients with MBC should be treated with trastuzumab SC 600mg until progression of disease or unmanageable toxicity
Patients with EBC should be treated for 1 year or until disease recurrence, or unmanageable toxicity, whichever occurs first. Extending treatment in EBC beyond one year has been shown to be not more effective than treatment for one year

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Delayed or missed doses: If one dose is missed, it is recommended to administer the next trastuzumab SC 600mg dose (i.e. the missed dose) as soon as possible. The interval between subsequent trastuzumab SC 600mg doses should not be less than three weeks

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Dose modifications: No reductions in the dose of trastuzumab SC 600mg were made during clinical trials. Patients may continue trastuzumab SC 600mg 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 withhold the dose of chemotherapy should be followed

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Limited information is currently available on switches from one formulation to the other. The three weekly dosing interval should be followed. Switching patients from SC to IV formulation was investigated in study MO22982

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21mg/ml injection

Metastatic breast cancer (MBC) in patients with HER2 overexpression
- As a monotherapy after at least two chemotherapy regimens for their metastatic disease
- In combination with paclitaxel or docetaxel for patients without prior chemotherapy for their metastatic disease
- In combination with an aromatase inhibitor for hormone-receptor positive metastatic breast cancer
Early breast cancer (EBC) in HER2 positive patients
- Post-surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable)
- In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin
- In combination with neoadjuvant chemotherapy followed by adjuvant trastuzumab, for locally advanced (including inflammatory) breast cancer or tumours >2cm in diameter
(Trastuzumab is prescribed only when tumours have HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. Trastuzumab should only be used in patients whose tumours have HER2 overexpression at a 3+ level as determined by immunohistochemistry)
Metastatic gastric-adenocarcinoma (MGC)
- In combination with capecitabine or 5-fluorouracil and cisplatin for patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who haven't undergone prior anti-cancer treatment for metastatic disease
(Trastuzumab should only be used in patients with MGC whose tumours have HER2 overexpression as defined by IHC 2+ and a confirmatory silver in situ hybridisation (SISH) or fluorescence in situ hybridisation (FISH) result, or by an IHC 3+ result. Accurate and validated assay methods should be used. In a method comparison study a high degree of concordance (> 95%) was observed for SISH and FISH techniques for the detection of HER2 gene amplification in gastric-adenocarcinoma patients)

Weekly schedule

The following loading and subsequent doses are recommended for monotherapy and in combination with paclitaxel or docetaxel

• Loading dose: IV: 4mg/kg body weight, as an infusion over 90min; Observe for fever and chills or other infusion associated symptoms; Interruption of the infusion may help control such symptoms; The infusion may be resumed when symptoms abate
• Subsequent doses: IV: 2mg/kg body weight, as an infusion over 30min, one week after loading dose (if loading dose is well tolerated); Observe for fever and chills or other infusion associated symptoms

Admin. in combination with paclitaxel or docetaxel

• Paclitaxel or docetaxel in metastatic disease may be administered the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab 21 mg/ml IV was well tolerated

Admin. in combination with an aromatase inhibitor

• In the pivotal trial trastuzumab and anastrozole were administered on day 1. There were no restrictions on the relative timing of trastuzumab and anastrozole at administration. For the anastrozole dose, refer to the anastrozole professional information

Three weekly schedule

• IV: Initial dose: 8mg/kg body weight; Followed by: 6 mg/kg body weight, 3 weeks later; Subsequent doses: Repeat dose of 6mg/kg body weight, every 3 weeks, given as infusions over approx. 90min; If the prior dose was well-tolerated, the dose can be admin. as 30min infusion

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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 1 year has been shown to be not more effective than treatment for one year

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Trastuzumab IV formulation is not intended for subcutaneous administration and should be administered via intravenous infusion only.  Trastuzumab should be administered as an intravenous infusion and should not be administered as an intravenous push or bolus

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Missed doses
If the patient misses a dose of trastuzumab by one week or less, then the usual maintenance dose of trastuzumab (weekly regimen: 2mg/kg; three-weekly regimen: 6mg/kg) should be given as soon as possible. Do not wait until the next planned cycle. Subsequent trastuzumab maintenance doses should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively
If the patient misses a dose of trastuzumab by more than one week, a re-loading dose of trastuzumab should be given over approximately 90 minutes (weekly regimen: 4mg/kg; three weekly regimen: 8mg/kg) as soon as possible
Subsequent trastuzumab maintenance doses (weekly regimen: 2mg/kg; three-weekly regimen 6mg/kg respectively) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules respectively

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Dose reductions: No reductions in trastuzumab doses were noted in clinical trials. If patients experience chemotherapy-induced myelosuppression, they may continue trastuzumab but should be closely monitored for complications of neutropenia during this time. The specific instructions to reduce or withhold the dose of chemotherapy should be followed

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Treatment with trastuzumab is contraindicated during pregnancy and in animal studies trastuzumab has been demonstrated to cross the placenta
• Contraception: In the post-marketing setting, cases of foetal renal growth, a single kidney and/or renal function impairment often in association with oligohydramnios, some of which also had fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab
• Women of childbearing potential should be advised to use effective contraception during treatment with trastuzumab and for at least 7 months after treatment has concluded. Women who become pregnant should be advised of the possibility of harm to the foetus
• Males: Based on currently available knowledge including the elimination half-life of trastuzumab in humans, male and female patients treated with trastuzumab, are recommended to use highly effective contraception, including a barrier method for at least 7 months following the last dose of trastuzumab

Recommendations in other jurisdictions

• Caution; positive evidence of risk
• Reproduction studies have been conducted in Cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2mg/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 last dose of trastuzumab, close monitoring by a multidisciplinary team is desirable
• Women of childbearing potential / Contraception: Women of childbearing potential should be advised to use effective contraception during treatment with trastuzumab and for 7 months after treatment has concluded

Breastfeeding

South African recommendations

• Contraindicated
• Mothers breastfeeding their infants should not use trastuzumab and in animal studies trastuzumab has been demonstrated to appear in breast milk

Recommendations in other jurisdictions

• Caution, not recommended 
• A study conducted in lactating Cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2mg/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 breastfeed during trastuzumab therapy and for 7 months after the last dose

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended
  Detailed pharmacokinetic studies in patients with renal impairment have not been carried out. In a population pharmacokinetic analysis, renal impairment was shown not to affect trastuzumab disposition

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available
  Dedicated pharmacokinetic studies in those with hepatic impairment have not been carried out

South African recommendations

• No dose adjustment recommended
  Age has been shown to have no effect on the disposition of trastuzumab
  In clinical trials, elderly patients did not receive reduced doses of trastuzumab

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
• Dedicated pharmacokinetic studies in the elderly have not been carried out. In a population pharmacokinetic analysis, age was not shown to affect trastuzumab disposition

Central Nervous System Disorders

• Anxiety 
• Depression 
• Insomnia
• Abnormal thinking 
• Tremor
• Dizziness
• Headache 
• Hypoaesthesia
• Peripheral neuropathy 
• Paraesthesia
• Hypertonia
• Somnolence
• Dysgeusia
• Ataxia
• Lethargy 
• Paresis
• Coma
• Paraneoplastic cerebellar degeneration
• Asthenia
• Meningitis 

Cardiovascular Disorders

• Decreased blood pressure 
• Increased blood pressure
• Irregular heart beat
• Palpitation
• Atrial flutter
• Cardiac failure 
• Supraventricular tachycardia 
• Cardiomyopathy
• Decreased ejection fraction 
• Chest discomfort 
• Pericardial effusion
• Hot flush 
• Vasodilatation 
• Worsening congestive cardiac failure
• Hypotension
• Cardiogenic shock 
• Pericarditis
• Hypertension 

Respiratory Disorders 

• Wheezing
• Dyspnoea  
• Oropharyngeal pain  
• Asthma
• Cough
• Epistaxis 
• Rhinorrhoea 
• Hiccups
• Stomatitis
• Interstitial lung disease  
• Bronchospasm
• Respiratory failure 
• Acute pulmonary oedema 
• Acute respiratory distress 
• Cheyne-Stokes breathing 
• Pneumonia
• Pneumonitis 
• Pulmonary fibrosis 
• Hypoxia
• Laryngeal oedema
• Pleural effusion
• Orthopnoea
• Nasopharyngitis 
• Sinusitis 
• Influenza 
• Bronchitis 

Gastrointestinal Disorders

• Dyspepsia
• Haemorrhoids 
• Constipation
• Dry mouth
• Gastritis
• Diarrhoea
• Nausea and vomiting

Hepatobiliary Disorders

• Hepatitis
• Hepatic tenderness
• Jaundice 
• Pancreatitis
• Hepatic failure
• Hepatocellular damage

Genitourinary Disorders

• Breast inflammation 
• Breast pain
• Dysuria
• Membranous glomerulonephritis 
• Renal failure
• Cystitis 
• Urinary tract infection

Endocrine and Metabolic Disorders 

• Increased weight
• Decreased weight 
• Anorexia 

Musculoskeletal Disorders

• Arthralgia
• Myalgia 
• Arthritis 
• Back pain
• Bone pain 
• Muscle spasms 
• Neck pain
• Pain in extremity

Skin and Subcutaneous Tissue Disorders

• Erythema
• Rash
• Facial swelling
• Palmar-plantar erythrodysaethesia syndrome 
• Acne
• Cellulitis 
• Alopecia 
• Dry skin 
• Ecchymosis 
• Hyperhidrosis 
• Maculopapular rash 
• Nail disorder
• Pruritus
• Onychorrhexis 
• Dermatitis
• Urticaria
• Stevens-Johnson syndrome
• Nail toxicity
• Contusion
• Infusion related reaction 
• Peripheral oedema
• Herpes zoster infection

Immune, Blood and Lymphatic System Disorders

• Erysipelas
• Sepsis
• Progression of malignant neoplasm
• Progression of neoplasia
• Hypoprothrombinaemia
• Leukaemia 
• Febrile neutropenic disorders
• Anaemia
• Neutropenia
• Thrombocytopenia 
• Leukopenia
• Lymphoedema 
• Rigors
• Fever 

Sensory Disorders

• Conjunctivitis
• Dry eye
• Increased lacrimation 
• Papilloedema
• Abnormal lacrimation 
• Retinal haemorrhage
• Vertigo
• Deafness

Others

• Oligohydramnios

• Antineoplastic agents
• Belimumab

• Assessment for HER-2 overexpression
• HER-2 gene amplification
• Vital signs
• ECG
• Echocardiogram
• Multigated acquisition scan
• MRI
• Full blood count

None routine. Specific cases may require

• Amniotic fluid index 
• Pregnancy test

Trastuzumab binds to the human epidermal growth factor receptor-2 (HER-2) proto-oncogene, an epidermal growth factor receptor-like protein found on 20-30% of breast cancer cells. This leads to antibody-mediated destruction of the HER-2 positive cells.

Injection 440mg

• Herceptin (Roche) originator
• Herclon (Roche)
• Ogivri 440 (Mylan)

Injection (per 5ml) 600mg

• Herceptin SC (Roche) originator