Herceptin Sc 600 mg Concentrate for solution for infusion

Metastatic Breast Cancer (MBC) Herceptin SC 600 mg is indicated for the treatment of patients with metastatic adenocarcinoma of the breast whose tumours over-express HER2:

• As monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease.
• In combination with paclitaxel or docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.
• In combination with an aromatase inhibitor for the treatment of patients with hormone-receptor positive metastatic breast cancer.

Early Breast Cancer (EBC) Herceptin SC 600 mg is indicated for the treatment of patients with HER2 positive early adenocarcinoma of the breast:

• Following 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 Herceptin SC 600 mg, for locally advanced (including inflammatory) breast cancer or tumours > 2 cm in diameter.

Herceptin SC 600 mg should only be used in patients whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. Herceptin SC 600 mg should only be used in patients whose tumours have HER2 overexpression at a 3+ level as determined by immunohistochemistry.

HER2 testing is mandatory prior to initiation of Herceptin SC 600 mg therapy. Herceptin SC 600 mg should be administered by a qualified healthcare professional. It is important to check the product labels to ensure that the correct formulation, SC is being administered to the patient as prescribed. 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.

Herceptin SC 600 mg formulation is not to be used for intravenous administration and must be administered via subcutaneous route only. No loading dose is required. The recommended fixed dose of Herceptin SC 600 mg is 600 mg irrespective of the patientu2019s body weight. This dose should be administered subcutaneously over 2 - 5 minutes every three weeks. The injection site should be alternated between the left and right thigh. New injections should be given at least 2,5 cm from the previous site on healthy skin and never into areas where the skin is red, bruised, tender or hard. During the treatment course with Herceptin SC 600 mg other medications for SC administration should preferably be injected at different sites.

Duration of treatment Patients with MBC should be treated with Herceptin SC 600 mg 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.

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

Dose modifications No reductions in the dose of Herceptin SC 600 mg were made during clinical trials. Patients may continue Herceptin SC 600 mg 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.

Special dosing instructions Elderly: Data suggests that the disposition of Herceptin SC 600 mg is not altered based on age. (See Pharmacokinetics in special populations.) In clinical trials, elderly patients u2265 65 years of age did not receive reduced doses of Herceptin SC 600 mg. Children: Herceptin SC 600 mg is not recommended for use in children below 18 years of age because the safety and efficacy in paediatric patients have not been established.

Patients with known hypersensitivity to trastuzumab, murine proteins, or to any of the excipients in Herceptin SC 600 mg. Patients with severe dyspnoea at rest due to complications of advanced malignancy or the requirement for supplementary oxygen therapy. (see Pregnancy and Lactation (see section 4.6).

General In order to improve traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file. HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see INDICATIONS section 4.1). Herceptin SC 600 mg therapy should only be initiated under supervision of a medical practitioner experienced in the treatment of cancer patients. Refer to boxed warning. No data are available on re-treatment of patients with previous exposure to Herceptin SC 600 mg in the adjuvant or neo-adjuvant setting.

Cardiotoxicity General considerations Patients treated with Herceptin SC 600 mg are at increased risk of developing congestive heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving Herceptin SC 600 mg therapy alone or in combination with taxane following anthracycline (doxorubicin or epirubicin)u2013containing chemotherapy. This may be moderate to severe and has been associated with death (see SIDE EFFECTS). In addition, extreme caution should be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary artery disease, CHF, LVEF of < 55 %, older age. Population pharmacokinetic model simulations indicate that trastuzumab may persist in the circulation for up to 7 months after stopping Herceptin SC 600 mg treatment (see Pharmacokinetic properties). Patients who receive anthracycline after stopping Herceptin SC 600 mg are also at increased risk of cardiac dysfunction. If possible, medical practitioners should avoid anthracycline-based therapy for up to 7 months after stopping Herceptin SC 600 mg. If anthracyclines are used, the patientu2019s cardiac function should be monitored carefully. Candidates for treatment with Herceptin SC 600 mg, especially those with prior exposure to an anthracycline, should undergo baseline cardiac assessment including history and physical examination, electrocardiogram (ECG) and echocardiogram, or multigated acquisition scanning (MUGA) scan. Monitoring may help to identify patients who develop cardiac dysfunction, including signs and symptoms of CHF. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin SC 600 mg.

If LVEF percentage drops 10 points from baseline and to below 50 %, Herceptin SC 600 mg should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, or if clinically significant CHF has developed, discontinuation of Herceptin SC 600 mg should be strongly considered. 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 medical practitioner should consider discontinuing therapy unless the benefits for the individual patient are deemed to outweigh the risks. The safety of continuation or resumption of Herceptin SC 600 mg in patients who experience cardiac dysfunction has not been prospectively studied. If symptomatic cardiac failure develops during Herceptin SC 600 mg therapy, it should be stopped and the patient treated with standard medications for heart failure (HF). In the pivotal trials, most patients who developed HF or asymptomatic cardiac dysfunction improved with standard HF treatment consisting of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a u03b2- blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin SC 600 mg treatment continued with Herceptin SC 600 mg without additional clinical cardiac events.

Metastatic breast cancer (MBC) Herceptin SC 600 mg and anthracyclines should not be given concurrently in the metastatic breast cancer setting.

Early breast cancer (EBC) For patients with EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of Herceptin SC 600 mg. In patients who receive anthracycline-containing chemotherapy, further monitoring is recommended and should occur yearly up to 5 years from the last administration of Herceptin SC 600 mg, or longer if a continuous decrease of LVEF is observed. Patients with history of myocardial infarction (MI), angina pectoris requiring medication, history of or present CHF (NYHA Class II u2013IV), other cardiomyopathy, cardiac dysrhythmia requiring medication, clinically significant cardiac valvular disease, uncontrolled hypertension, and haemodynamic significant pericardial effusion were excluded from adjuvant breast cancer clinical trials with Herceptin SC 600 mg.

Adjuvant treatment Herceptin SC 600 mg and anthracyclines should not be given concurrently in the adjuvant treatment setting. In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when Herceptin IV was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin. The incidence was more marked when Herceptin IV was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months. Risk factors for a cardiac event identified in four large adjuvant studies included advanced age (> 50 years), low level of baseline and declining LVEF (25 kg/m2).

Neoadjuvant-adjuvant treatment In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin SC 600 mg concurrently with anthracyclines should be used with caution and only in chemotherapy-nau00efve patients. The maximum cumulative doses of the low-dose anthracycline regimens should not exceed 180 mg/m2 (doxorubicin) or 360 mg/m2 (epirubicin). If patients have been treated concurrently with low-dose anthracyclines and in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery.

Administration-related reactions (ARRs), and hypersensitivity Serious adverse reactions to Herceptin SC 600 mg administration that have been reported include dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachydysrythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria, angioedema, chills, fever, rash, nausea and vomiting and headache (see SIDE EFFECTS). These symptoms can be treated with an analgesic/antipyretic such as pethidine or paracetamol, or an antihistamine such as diphenhydramine. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists, and corticosteroids. However, these reactions may have a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal administration reaction. Therefore, these patients should not be treated with Herceptin SC 600 mg, (see Section 4.2 Special warnings and precautions).

Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical deterioration may occur. Fatalities have occurred within hours and up to one week following infusion. Patients have experienced the onset of infusion symptoms or pulmonary symptoms more than six hours after the start of the Herceptin SC 600 mg administration. Patients should be warned of the possibility of such a late onset and should be instructed to contact their medical practitioner if these symptoms occur. Administration related adverse events (ARRs) may be clinically difficult to distinguish from hypersensitivity reactions. The rate of ARRs of all grades varied between studies depending on the indication, whether Herceptin SC 600 mg was given concurrently with chemotherapy or as monotherapy and data collection methodology. In MBC, the rate ranged from 49 % to 54 % in the Herceptin-containing arm compared to 36 % to 58 % in the comparator arm (which may have contained other chemotherapy). Severe (grade 3 and above) ranged from 5 % to 7 % in the Herceptin-containing arm compared to 5 to 6 % in the comparator arm. In EBC, the rate of ARRs ranged from 18 % to 54 % in the Herceptin-containing arm compared to 6 % to 50 % in the comparator arm (which may have contained other chemotherapy). Severe (grade 3 and above) ranged from 0,5 % to 6 % in the Herceptin-containing arm compared to 0,3 to 5 % in the comparator arm. In the neoadjuvant-adjuvant setting, the rate of ARRs was in line with the above and was 47,8 % and severe grade 3 events was 1,7 % in the Herceptin SC 600 mg arm. There were no grade 4 or 5 ARRs.

Pulmonary events Caution is advised with Herceptin SC 600 mg formulation, as severe pulmonary events leading to death have been reported with the use of Herceptin SC 600 mg, (see SIDE EFFECTS). These events may result in fatal outcome and may occur as part of an ARR or with delayed onset. In addition, cases of interstitial lung disease (ILD), including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Therefore, these patients should not be treated with Herceptin SC 600 mg, (see CONTRAINDICATIONS). Risk factors associated with interstitial lung disease (ILD) include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with ILD such as taxanes, gemcitabine, vinorelbine and radiation therapy. Patients with dyspnoea at rest due to complications of advanced malignancy and co-morbidities may be at risk of pulmonary events.

There have been no formal medicine interaction studies performed with Herceptin SC 600 mg in humans.

Pregnancy Treatment with Herceptin SC 600 mg is contraindicated during pregnancy. Herceptin SC 600 mg crosses the placenta and appears in the breast milk. (See CONTRAINDICATIONS.)

Breastfeeding Mothers breastfeeding their infants should not use Herceptin SC 600 mg. (See CONTRAINDICATIONS.)

In the post-marketing setting, cases of foetal renal growth 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 Herceptin. Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin SC 600 mg 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 Herceptin SC 600 mg in humans, male and female patients treated with Herceptin SC 600 mg, are recommended to use highly effective contraception, including a barrier method for at least 7 months following the last dose of Herceptin SC 600 mg.

Herceptin has a minor influence on the ability to drive and use machines. (see section 4.8). Dizziness and somnolence may occur during treatment with Herceptin (see section 4.8). Patients experiencing infusion-related symptoms reactions (see section 4.4) should be advised not to drive and use machines until symptoms abate.

Amongst the most serious and/or common adverse reactions (ADRs) reported with Herceptin SC 600 mg usage are cardiotoxicity, administration-related reactions, haematotoxicity (in particular neutropenia) and pulmonary adverse events. In this section, the following categories of frequency have been used: very common ( u00b3 1/10), common ( u00b3 1/100 to <1/10), uncommon (u22651/1 000 to <1/100), rare (u22651/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Clinical trials Presented in the following table, Table 1 are adverse reactions that have been reported in association with the use of Herceptin alone or in combination with chemotherapy. All the frequency terms included are based on the highest percentage seen in pivotal clinical trials.

Table 1 : Clinical trial ADRs System organ class Frequency Adverse reaction Infections and infestations Very common Nasopharanygitis, infection Common Neutropenic sepsis, cystitis, herpes zoster, influenza, sinusitis, skin infection, rhinitis, upper respiratory tract infection, urinary tract infection. Blood and lymphatic system disorders Very common Anaemia, thrombocytopenia, febrile neutropenia, leukopenia Common neutropenia, Immune system disorders Common Hypersensitivity, e.g. allergic- like reactions, (itching, lacrimation, skin rash, urticaria), Rare analphalytic shock Metabolism and nutrition disorders Very common Increased weight, decreased weight, decreased appetite, anorexia Psychiatric disorders Very common Insomnia Common Anxiety, depression, Nervous system disorders Very common Tremor, dizziness, headache, hypoaesthesia, paraesthesia, dysgeusia Common Peripheral neuropathy, hypertonia, somnolence Eye disorders Very common Conjunctivitis, increased lacrimation Common Dry eye Uncommon Deafness Cardiac disorders Very common Decreased blood pressure, increased blood pressure, irregular heart beat, palpitation, atrial flutter, decreased left ventricular ejection fraction Common Cardiac failure (congestive), supraventricular tachydysrhythmia, cardiomyopathy, chest discomfort Uncommon Pericardial effusion Vascular disorders Very common Hot flushes, lymphoedema Common Hypotension, vasodilatation, hypertension Respiratory, thoracic and mediastinal disorders Very common Wheezing, dyspnoea, oropharyngeal pain, epistaxis, cough, rhinorrhoea Common Asthma, cough, lung disorder, pharyngitis, hiccups, exertional dyspnoea, pleural effusion, pneumonia Uncommon Interstitial pneumonitis Gastrointestinal disorders Very common Diarrhoea, vomiting, nausea, lip swelling, abdominal pain, stomatitis, dyspepsia, constipation Common Pancreatitis, haemorrhoids, dry mouth, gastritis, Hepatocellular injury Hepatobiliary disorders Common Hepatitis, liver tenderness Rare Jaundice Very common Erythema Skin and subcutaneous tissue disorders Very common rash, swelling face, palmar- plantar erythrodysaethesia syndrome (hand-foot syndrome), alopecia, nail disorder Common Acne, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, pruritus, onychoclasis, injection site pain, dermatitis Uncommon Urticaria Musculoskeletal and connective tissue disorders Very common Arthralgia, rigor, myalgia Common Arthritis, back pain, bone pain, muscle spasms, neck pain, pain in extremity, musculoskeletal pain Renal and urinary conditions Common Renal disorder, dysuria Reproductive system and breast disorders Common Breast inflammation/mastitis, breast pain General disorders and administration site conditions Very common Asthenia, chest pain, chills, fatigue, influenza-like symptoms, administration related reaction, pain, pyrexia, peripheral oedema, mucosal inflammation Common Malaise, oedema, injection site pain** Injury, poisoning and procedural complications Very common Nail changes including brittle nail, nail loss, splitting nails ** Injection site pain was identified as an ADR in the SC arm in the phase 3 study. ADRs were added to the appropriate system organ class (SOC) category and are presented in a single table according to the highest incidence seen in any of the major clinical trials.

Symptoms of overdose may be exacerbated and, or exaggerated to those reported in side effects. Single doses of up to 960 mg have been administered with no reported untoward effects.