Trastuzumab

Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in 20–30% of primary breast cancers, and breast cancer patients whose tumours overexpress it have a shorter disease-free survival than those whose tumours do not. HER2 positivity in gastric cancer varies widely, from about 7% to 43% depending on the test.

Mechanism of Action

• Binding: trastuzumab binds with high affinity and specificity to sub-domain IV, a region of HER2’s extracellular domain close to the cell membrane.
• Signalling: binding inhibits ligand-independent HER2 signalling and prevents cleavage of the extracellular domain, an activation mechanism of HER2. Downstream pathways such as MAPK and PI3K/Akt are dampened, leading to cell-cycle arrest and slower growth.
• Proliferation: in laboratory assays and in animals it inhibits the proliferation of human tumour cells that overexpress HER2.
• Immune action: trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity, which in vitro acts preferentially on HER2-overexpressing cells.
• Resistance: intrinsic resistance has been noted in some patients with HER2-positive breast cancer.
• Cardiac electrophysiology: no clinically significant effect on the QTc interval was seen in patients with HER2-positive solid tumours.

Pharmacokinetics

• Model: a population analysis of 1,582 subjects in 18 trials fitted a two-compartment model with parallel linear and non-linear elimination. Because clearance rises as concentrations fall, trastuzumab has no constant half-life; at steady state it ranges from about 13 to 27 days, depending on concentration, regimen and tumour type.
• Distribution and clearance: central compartment volume about 2.6 L in metastatic and early breast cancer and 3.6 L in gastric cancer. Linear clearance was 0.136, 0.112 and 0.176 L/day in metastatic breast, early breast and gastric cancer. Steady state is reached after about 9 to 15 weeks, depending on regimen and tumour type.
• Metabolism and excretion: after binding to HER2, the antibody is broken down inside cells to peptides and amino acids; renal excretion is very low.
• Washout: at least 95% of patients fall below 1 µg/mL by about 7 months after stopping.
• Special populations: body weight, aspartate aminotransferase and albumin affect exposure, but not enough to matter clinically. Age and renal impairment did not affect disposition. No dedicated studies were done in the elderly or in renal or hepatic impairment.

Herceptin is authorised in the EU for adults with HER2-positive disease. Tuznue has the same indications as Herceptin.

• Metastatic breast cancer: as monotherapy in patients who have had at least two chemotherapy regimens for metastatic disease (including at least an anthracycline and a taxane unless unsuitable, and hormonal therapy in hormone receptor-positive disease unless unsuitable); with paclitaxel in patients not previously given chemotherapy for metastatic disease and for whom an anthracycline is not suitable; with docetaxel in patients not previously given chemotherapy for metastatic disease; with an aromatase inhibitor in postmenopausal patients with hormone receptor-positive disease not previously treated with trastuzumab.
• Early breast cancer: after surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy if applicable; after adjuvant doxorubicin and cyclophosphamide, with paclitaxel or docetaxel; with adjuvant docetaxel and carboplatin; with neoadjuvant chemotherapy followed by adjuvant trastuzumab, for locally advanced (including inflammatory) disease or tumours over 2 cm in diameter.
• Metastatic gastric cancer: with capecitabine or 5-fluorouracil and cisplatin, for adenocarcinoma of the stomach or gastro-oesophageal junction in patients with no prior anti-cancer treatment for metastatic disease.

Tumours must show HER2 overexpression or HER2 gene amplification on an accurate and validated assay. In gastric cancer this means IHC 2+ with a confirmatory SISH or FISH result, or IHC 3+.

The subcutaneous Herceptin 600 mg solution for injection is authorised for breast cancer only (metastatic and early, with the same wording as above) and has no gastric cancer indication.

• Hypersensitivity to trastuzumab, to murine proteins or to any of the excipients (for the subcutaneous solution, also to hyaluronidase).
• Severe dyspnoea at rest due to complications of advanced malignancy, or requiring supplementary oxygen therapy.

The most serious or common reactions are cardiac dysfunction, infusion-related reactions, haematotoxicity (especially neutropenia), infections and pulmonary reactions. Frequencies below are from pivotal trials of intravenous Herceptin (N = 8,386) and post-marketing reports.

Very common (≥1/10): infection, nasopharyngitis, febrile neutropenia, anaemia, neutropenia, leukopenia, thrombocytopenia, weight loss, anorexia, insomnia, tremor, dizziness, headache, paraesthesia, dysgeusia, conjunctivitis, increased lacrimation, decreased or increased blood pressure, irregular heartbeat, cardiac flutter, decreased ejection fraction, hot flush, dyspnoea, cough, epistaxis, rhinorrhoea, diarrhoea, vomiting, nausea, lip swelling, abdominal pain, dyspepsia, constipation, stomatitis, erythema, rash, swollen face, alopecia, nail disorder, palmar-plantar erythrodysaesthesia syndrome, arthralgia, muscle tightness, myalgia, asthenia, chest pain, chills, fatigue, influenza-like symptoms, infusion-related reaction, pain, pyrexia, mucosal inflammation, peripheral oedema.

Common (≥1/100 to <1/10): neutropenic sepsis, cystitis, influenza, sinusitis, skin infection, rhinitis, upper respiratory tract infection, urinary tract infection, pharyngitis, hypersensitivity, anxiety, depression, peripheral neuropathy, hypertonia, somnolence, dry eye, congestive cardiac failure, supraventricular tachyarrhythmia, cardiomyopathy, palpitation, hypotension, vasodilatation, pneumonia, asthma, lung disorder, pleural effusion, haemorrhoids, dry mouth, hepatocellular injury, hepatitis, liver tenderness, acne, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, pruritus, onychoclasis, dermatitis, arthritis, back pain, bone pain, muscle spasms, neck pain, pain in extremity, renal disorder, breast inflammation or mastitis, malaise, oedema, contusion.

Uncommon (≥1/1,000 to <1/100): deafness, pericardial effusion, wheezing, pneumonitis, urticaria.

Rare (≥1/10,000 to <1/1,000): anaphylactic reaction, anaphylactic shock, jaundice.

Not known: neoplasm progression, hypoprothrombinaemia, immune thrombocytopenia, tumour lysis syndrome, hyperkalaemia, papilloedema, retinal haemorrhage, cardiogenic shock, gallop rhythm, pulmonary fibrosis, respiratory distress, respiratory failure, lung infiltration, acute pulmonary oedema, acute respiratory distress syndrome, bronchospasm, hypoxia, decreased oxygen saturation, laryngeal oedema, orthopnoea, pulmonary oedema, interstitial lung disease, angioedema, membranous glomerulonephritis, glomerulonephropathy, renal failure, oligohydramnios, renal hypoplasia, pulmonary hypoplasia.

Congestive heart failure (NYHA class II–IV) is a common reaction and has been fatal. About 40% of patients have some infusion-related reaction, mostly mild to moderate and most often during the first three infusions; severe anaphylactic reactions usually occur during the first or second infusion and have been fatal. Severe pulmonary reactions have also been fatal. In one study 10.1% of patients developed antibodies against trastuzumab, of unknown clinical relevance.

No formal drug interaction studies have been done, and no clinically significant interactions were seen with the medicines used in clinical trials.

• Anthracyclines: trastuzumab and anthracyclines should not be given concurrently in metastatic or adjuvant treatment, because of the risk of cardiac dysfunction. Trastuzumab can persist for up to 7 months, so anthracycline-based therapy should if possible be avoided for up to 7 months after stopping it, and cardiac function monitored carefully if anthracyclines are used.
• Paclitaxel and doxorubicin: their exposure was not altered, but trastuzumab may raise the exposure of one doxorubicin metabolite (D7D), whose activity and clinical impact are unclear.
• Docetaxel, cisplatin and carboplatin: no effect on their pharmacokinetics.
• Capecitabine: its active metabolite (5-FU) was not affected, but capecitabine itself reached higher concentrations and had a longer half-life with trastuzumab.
• Effect of other medicines on trastuzumab: docetaxel, paclitaxel, doxorubicin, carboplatin and anastrozole did not appear to change trastuzumab pharmacokinetics.
• Glucose solutions: trastuzumab must not be diluted with glucose solutions, which cause the protein to aggregate.

HER2 testing is mandatory before treatment. Treatment must be started by a physician experienced in giving cytotoxic chemotherapy and given by a healthcare professional only. The intravenous formulation is for intravenous infusion only, never subcutaneously, and must not be given as an intravenous push or bolus. Product and vial labels must be checked so that the right formulation (intravenous or subcutaneous) and the right product are given, and not another trastuzumab-containing medicine such as trastuzumab emtansine or trastuzumab deruxtecan.

Recommended Dose

• Metastatic breast cancer, three-weekly: loading dose 8 mg/kg, then 6 mg/kg every three weeks starting three weeks after the loading dose.
• Metastatic breast cancer, weekly: loading dose 4 mg/kg, then 2 mg/kg weekly starting one week after the loading dose.
• With a taxane or aromatase inhibitor: in the pivotal trials paclitaxel or docetaxel was given the day after the first trastuzumab dose and immediately after later doses if the previous dose was well tolerated; anastrozole was given from day 1 with no restriction on timing. Their doses are in their own SmPCs.
• Early breast cancer: the same three-weekly schedule, or a weekly schedule (4 mg/kg, then 2 mg/kg weekly) together with paclitaxel after doxorubicin and cyclophosphamide. See the SmPC for chemotherapy combination dosing.
• Metastatic gastric cancer: three-weekly, 8 mg/kg then 6 mg/kg.
• Duration: metastatic breast or gastric cancer until disease progression; early breast cancer for 1 year or until recurrence, whichever comes first. Extending beyond one year is not recommended.

Infusion

The loading dose is infused over 90 minutes; if it was well tolerated, later doses can be given over 30 minutes. Patients are observed for at least six hours after the start of the first infusion and for two hours after later ones, for fever, chills or other infusion-related symptoms. Interrupting or slowing the infusion may help, and it can be resumed when symptoms abate. An emergency kit must be available and staff prepared to manage anaphylaxis. Each 150 mg vial is reconstituted with 7.2 mL of sterile water for injection, swirled gently and never shaken, then diluted in 250 mL of 0.9% sodium chloride using aseptic technique.

Dose Adjustments

No dose reductions were made in clinical trials, and treatment can continue through reversible chemotherapy-induced myelosuppression with careful monitoring for neutropenic complications. If the left ventricular ejection fraction (LVEF) falls by 10 points or more from baseline and to below 50%, treatment is suspended and LVEF repeated within about 3 weeks. If it has not improved, has fallen further, or symptomatic heart failure has developed, discontinuation should be strongly considered unless the benefit outweighs the risk, and the patient is referred to a cardiologist.

Missed Dose

If a dose is missed by one week or less, give the usual maintenance dose (2 mg/kg weekly or 6 mg/kg three-weekly) as soon as possible, without waiting for the next cycle; later doses follow 7 or 21 days afterwards. If a dose is missed by more than one week, give a re-loading dose over about 90 minutes (4 mg/kg weekly or 8 mg/kg three-weekly) as soon as possible, then maintenance doses 7 or 21 days later.

Subcutaneous Herceptin 600 mg

Herceptin 600 mg solution for injection (5 mL vial) is for subcutaneous injection only, never for intravenous use, and is given by a healthcare professional only. As for the intravenous form, HER2 testing is mandatory and treatment is started by a physician experienced in cytotoxic chemotherapy.

• Dose: 600 mg every three weeks, irrespective of body weight. No loading dose is needed. The dose is injected over 2–5 minutes.
• Duration: metastatic breast cancer until disease progression; early breast cancer for 1 year or until recurrence, whichever comes first.
• Injection site: alternate between the left and right thigh. Each new injection is given at least 2.5 cm from the old site, never into an area where the skin is red, bruised, tender or hard. Other subcutaneous medicines should preferably be injected at different sites.
• Observation: patients are observed for 30 minutes after the first injection and for 15 minutes after later ones, for signs or symptoms of administration-related reactions.
• Missed dose: the next 600 mg dose is given as soon as possible, and the interval between two consecutive doses must not be less than three weeks.
• Switching: switching between the intravenous and subcutaneous forms on the three-weekly schedule has been studied (study MO22982). The vial labels are checked so that the prescribed formulation is given.
• Dose adjustments and special populations: as for the intravenous form, including the ejection fraction rule under Dose Adjustments; there is no relevant use in children.

Special Populations

• Elderly, renal and hepatic impairment: no dedicated studies; age and renal impairment did not affect disposition. Clinical experience in early breast cancer above 65 years is limited.
• Children: there is no relevant use in the paediatric population.

Traceability and HER2 Testing

The trade name and batch number of the product given must be clearly recorded. HER2 testing must be done in a specialised laboratory with validated procedures. In breast cancer, patients are eligible with a 3+ score on immunohistochemistry or a positive FISH or CISH result. There are no clinical-trial data on re-treatment after adjuvant exposure.

Cardiac Dysfunction

Trastuzumab increases the risk of congestive heart failure (NYHA class II–IV) and of asymptomatic cardiac dysfunction, especially after anthracycline chemotherapy; events can be moderate to severe and have been fatal. Caution is needed with hypertension, coronary artery disease, heart failure, LVEF below 55% and older age. All candidates, especially after anthracycline and cyclophosphamide, need a baseline cardiac assessment (history and examination, ECG, echocardiogram or MUGA scan, or magnetic resonance imaging), repeated every 3 months during treatment and every 6 months after stopping until 24 months from the last dose. In early breast cancer after anthracyclines, monitoring continues yearly for up to 5 years. Symptomatic heart failure is treated with standard medicines, typically an ACE inhibitor or angiotensin receptor blocker plus a beta-blocker. In the neoadjuvant setting, concurrent use with anthracyclines is limited to chemotherapy-naive patients on low-dose regimens (maximum cumulative doxorubicin 180 mg/m² or epirubicin 360 mg/m²).

Infusion-Related Reactions and Hypersensitivity

Serious reactions to the infusion have been reported, including dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema. Most occur during or within 2.5 hours of the start of the first infusion. The infusion should be stopped or slowed and the patient monitored until symptoms resolve; pre-medication may be used. Delayed deterioration has occurred, with fatalities within hours up to a week after an infusion, so patients should know to contact their doctor if symptoms appear late.

Pulmonary Events

Severe pulmonary events, occasionally fatal, have been reported, including interstitial lung disease, acute respiratory distress syndrome, pneumonitis, pleural effusion and acute pulmonary oedema. Risk factors include taxanes, gemcitabine, vinorelbine and radiotherapy. Caution is needed for pneumonitis, particularly with taxanes. Patients with dyspnoea at rest should not be treated.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for 7 months afterwards.
• Pregnancy: trastuzumab should be avoided unless the benefit to the mother outweighs the risk to the foetus. After marketing, impaired foetal kidney growth and function with oligohydramnios, sometimes with fatal pulmonary hypoplasia, has been reported. A pregnancy during treatment or within 7 months of the last dose calls for close monitoring by a multidisciplinary team.
• Breastfeeding: women should not breastfeed during treatment or for 7 months after the last dose.
• Fertility: no data are available.

Polysorbate 20

Each 150 mg vial contains 0.6 mg of polysorbate 20, and each 5 mL vial of the subcutaneous 600 mg solution contains 2.0 mg; polysorbate 20 may cause allergic reactions.

Effect on Driving

Trastuzumab has a minor influence on driving. Dizziness and somnolence may occur, and patients with infusion-related symptoms should not drive or use machines until these have gone.

Store vials in a refrigerator at 2–8 °C and keep the cold chain unbroken during transport. Do not freeze the reconstituted solution. Herceptin is supplied as one 15 mL glass vial per carton. The subcutaneous 600 mg solution is also stored in a refrigerator at 2–8 °C and not frozen, with the vial kept in the outer carton to protect it from light; once taken out of the refrigerator it must be given within 6 hours and must not be kept above 30 °C.

• Unopened Herceptin vial: 4 years.
• Reconstituted solution: stable for 48 hours at 2–8 °C.
• Diluted solution: in polyvinylchloride, polyethylene or polypropylene bags of 0.9% sodium chloride, stable for up to 30 days at 2–8 °C and 24 hours at not more than 30 °C.
• Use: from a microbiological point of view the prepared solution should be used immediately; otherwise storage is the user’s responsibility and should not normally exceed 24 hours at 2–8 °C, unless preparation took place under controlled and validated aseptic conditions.
• Subcutaneous 600 mg solution, unopened vial: 21 months.
• Subcutaneous 600 mg solution, once transferred from the vial to the syringe: stable for 28 days at 2–8 °C and for 6 hours (cumulative time in the vial and the syringe) at up to 30 °C in diffused daylight. It contains no antimicrobial preservative, so from a microbiological point of view it should be used immediately.

Prescription only (Rx), on the prescription of a physician experienced in the administration of cytotoxic chemotherapy. The intravenous infusion is prepared and given, and the subcutaneous 600 mg solution is injected, by healthcare professionals, so both are supplied to the hospital or clinic that administers them, under cold-chain conditions (2–8 °C).