Herceptin 21 mg Solution

Metastatic breast cancer (MBC) Herceptin is indicated for the treatment of patients with metastatic breast cancer whose tumours over-express HER2: u00b7 As monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease. u00b7 In combination with paclitaxel or docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease. u00b7 In combination with an aromatase inhibitor for the treatment of patients with hormone-receptor positive metastatic breast cancer. Early breast cancer (EBC) Herceptin is indicated for the treatment of patients with HER2 positive early breast cancer: u00b7 Following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable). u00b7 In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin. u00b7 In combination with neoadjuvant chemotherapy followed by adjuvant Herceptin, for locally advanced (including inflammatory) breast cancer or tumours > 2 cm in diameter. 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. Herceptin should only be used in patients whose tumours have HER2 overexpression at a 3+ level as determined by immunohistochemistry.

Metastatic gastric-adenocarcinoma (MGC) Herceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anti-cancer treatment for their metastatic disease. Herceptin should only be used in patients with metastatic gastric-adenocarcinoma 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 (see section 4.4). 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.

HER2 testing is mandatory prior to initiation of Herceptin therapy. Herceptin should be administered by a qualified healthcare professional. It is important to check the product labels to ensure that the correct formulation (Herceptin 21 mg/mL IV or Herceptin 600 mg SC) is being administered to the patient as prescribed. Herceptin IV formulation is not intended for subcutaneous administration and should be administered via intravenous infusion only. Herceptin should be administered as an intravenous infusion. Do not administer as an intravenous push or bolus.

Early breast cancer (EBC), Metastatic breast cancer (MBC) and Metastatic gastric-adenocarcinoma (MGC): Weekly schedule The following loading and subsequent doses are recommended for monotherapy and in combination with paclitaxel or docetaxel. Loading dose: The recommended initial loading dose is 4 mg/kg body weight Herceptin administered as a 90-minute intravenous infusion. Patients should be observed for fever and chills or other infusion-associated symptoms (see sections 4.4 and 4.8). Interruption of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate. Subsequent doses: The recommended weekly dose of Herceptin is 2 mg/kg body weight, beginning one week after the loading dose. If the loading dose was well tolerated, the subsequent dose can be administered as a 30-minute infusion. Patients should be observed for fever and chills or other infusion-associated symptoms (see sections 4.4 and 4.8).

Administration in combination with paclitaxel or docetaxel Paclitaxel or docetaxel in metastatic disease may be administered the day following the first dose of Herceptin or immediately after the subsequent doses of Herceptin if the preceding dose of Herceptin 21 mg/mL IV was well tolerated. Administration in combination with an aromatase inhibitor In the pivotal trial Herceptin and anastrozole were administered on day 1. There were no restrictions on the relative timing of Herceptin and anastrozole at administration. For the anastrozole dose, refer to the anastrozole professional information.

Three weekly schedule 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. If the prior dosage was well tolerated, the dose can be administered as a 30-minute infusion.

Duration of treatment Patients with MBC or MGC should be treated with Herceptin until progression of disease. Patients with EBC should be treated with Herceptin 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.

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

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 withhold the dose of chemotherapy should be followed.

Special populations Elderly : Data suggests that the disposition of Herceptin is not altered based on age (see section 5.2). In clinical trials, elderly patients did not receive reduced doses of Herceptin. Children : Herceptin is not recommended for use in children below 18 years of age because the safety and efficacy in paediatric patients have not been established.

u00b7 Patients with known hypersensitivity to trastuzumab, murine proteins, or to any of the excipients in Herceptin. u00b7 Patients with severe dyspnoea at rest due to complications of advanced malignancy or the requirement for supplementary oxygen therapy. u00b7 Pregnancy and lactation (see section 4.6).

General HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 4.1). Herceptin 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 in the adjuvant or neoadjuvant setting.

Cardiotoxicity General considerations Patients treated with Herceptin 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 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 section 4.8). 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 treatment (see section 5.2). Patients who receive anthracycline after stopping Herceptin 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. If anthracyclines are used, the patientu2019s cardiac function should be monitored carefully. Candidates for treatment with Herceptin, 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. If LVEF percentage drops 10 points from baseline and to below 50 %, Herceptin 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 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 if no clinical benefit of Herceptin therapy has been seen. The safety of continuation or resumption of Herceptin in patients who experience cardiac dysfunction has not been prospectively studied. If symptomatic cardiac failure develops during Herceptin therapy, Herceptin should be stopped and patients treated with standard medicines 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 treatment continued with Herceptin without additional clinical cardiac events.

Metastatic breast cancer (MBC) Herceptin 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. 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, 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 - IV), 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.

Adjuvant treatment Herceptin 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 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 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/m 2 ).

Neoadjuvant-adjuvant treatment In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin 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/m 2 (doxorubicin) or 360 mg/m 2 (epirubicin). If patients have been treated concurrently with low-dose anthracyclines and Herceptin in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery.

There have been no formal medicine interaction studies performed with Herceptin in humans. The results of an interaction substudy evaluating the pharmacokinetics of capecitabine and cisplatin when used with or without Herceptin suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus Herceptin. However, capecitabine itself showed higher concentrations and a longer half-life when combined with Herceptin. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus Herceptin.

Pregnancy Treatment with Herceptin is contraindicated during pregnancy. Breastfeeding Herceptin crosses the placenta and appears in the breast milk (see section 4.2). Mothers breastfeeding their infants should not use Herceptin (see section 4.2). 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 Herceptin. Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin 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 in humans, male and female patients treated with Herceptin, are recommended to use highly effective contraception, including a barrier method for at least 7 months following the last dose of Herceptin.

No studies on the effects on the ability to drive and use machines have been performed. Patients experiencing infusion-related symptoms should be advised not to drive or use machines until symptoms resolved completely.

a. Summary of the safety profile Amongst the most serious and/or common adverse reactions reported with Herceptin usage are cardiotoxicity, infusion-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.

b. Tabulated list of adverse reactions Clinical trials Presented in the following table are adverse reactions that have been reported in association with the use of Herceptin alone or in combination with chemotherapy in pivotal clinical trials for EBC, MBC and MGC. All the frequency terms included are based on the highest percentage seen in pivotal clinical trials.

Symptoms of overdose may be exacerbated and/or exaggerated to those reported in side effects. There is no experience with overdosage in human clinical trials. Single doses higher than 10 mg/kg have not been tested.