Herclon

Intravenous

Metastatic breast cancer

Adult: As monotherapy or combination therapy (w/ an aromatase inhibitor or taxane): Initially, 4 mg/kg via infusion over 90 min followed by 2 mg/kg via infusion over 30 min at wkly interval until progression of disease. As Herclon emtansine: 3.6 mg/kg as infusion 3 wkly (21-day cycle). Admin initial dose for 90 min. Subsequent doses may be administered as 30 min infusions.

Reconstitution: Reconstitute w/ 20 mL of bacteriostatic sterile water for inj into a soln containing 21 mg/mL of Herclon. Swirl gently; do not shake. Dilute further prior to admin w/ appropriate vol of reconstituted Herclon soln in 250 mL of NaCl 0.9% inj.

Incompatibility: Incompatible w/ dextrose 5% in water.

Intravenous

Early breast cancer

Adult: For treatment after chemotherapy, radiotherapy or surgery. Initially, 4 mg/kg via infusion over 90 min followed by 2 mg/kg via infusion over 30 min wkly for 1 yr or until disease recurrence, whichever occurs 1st. Alternatively, initial dose of 8 mg/kg via infusion over 90 min followed by 6 mg/kg via IV infusion over 30-90 min at 3-wkly interval for 1 yr or until disease recurrence, whichever occurs 1st.

Reconstitution: Reconstitute w/ 20 mL of bacteriostatic sterile water for inj into a soln containing 21 mg/mL of Herclon. Swirl gently; do not shake. Dilute further prior to admin w/ appropriate vol of reconstituted Herclon soln in 250 mL of NaCl 0.9% inj.

Incompatibility: Incompatible w/ dextrose 5% in water.

Intravenous

Gastric cancer

Adult: For metastatic: Initially, 8 mg/kg via infusion over 90 min followed by 6 mg/kg via infusion over 30-90 min at 3-wkly interval until progression of disease.

Reconstitution: Reconstitute w/ 20 mL of bacteriostatic sterile water for inj into a soln containing 21 mg/mL of Herclon. Swirl gently; do not shake. Dilute further prior to admin w/ appropriate vol of reconstituted Herclon soln in 250 mL of NaCl 0.9% inj.

Incompatibility: Incompatible w/ dextrose 5% in water.

Herclon is used to treat new cases of breast cancer or disease that has spread to other parts of the body. It may prevent the growth of some breast tumors that produce extra amounts of a certain substance known as the HER2 protein. Herclon should only be used in patients whose breast tumors have been shown to produce extra amounts of this protein. It can be used alone or with other cancer medicines (chemotherapy) such as doxorubicin, cyclophosphamide, paclitaxel, docetaxel, and carboplatin.

Herclon is also used in combination with cisplatin and capecitabine or 5-fluorouracil to treat malignant tumor of the stomach and esophagogastric (esophagus and stomach) cancer, metastatic, HER2 overexpression.

Herclon is a monoclonal antibody. It interferes with the growth of cancer cells, which are eventually destroyed by the body. Since the growth of normal body cells may also be affected by Herclon, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, such as a skin rash, may not be serious but may cause concern. Some effects do not occur until months or years after the medicine is used.

Before you begin treatment with Herclon, you and your doctor should talk about the benefits Herclon will do as well as the risks of using it.

Herclon is to be administered only by or under the immediate supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, Herclon is used in certain patients with the following medical conditions:

• Breast cancer, HER2-overexpressing disease, primary treatment in combination with chemotherapy, before surgery.

HER2 testing is mandatory prior to initiation of Herclon therapy.

Herclon should be administered as intravenous infusion.

Do not administer as an intravenous push or bolus.

Weekly Schedule: Loading Dose: The recommended initial loading dose is 4 mg/kg body weight Herclon administered as a 90-minute intravenous infusion. Patients should be observed 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: The recommended weekly dose of Herclon is 2 mg/kg body weight.

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

Patients should be observed for fever and chills or other infusion-associated symptoms.

Alternative 3-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 dose was well tolerated, the dose can be administered as a 30-minute infusion.

Duration of Treatment: In clinical studies, patients with metastatic breast cancer or advanced gastric cancer were treated with Herclon until progression of disease. Patients with early breast cancer should be treated for 1 year or until disease recurrence.

Missed Doses: If the patient misses a dose of Herclon by one week or less, then the usual maintenance dose of Herclon (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 Herclon maintenance doses (weekly regimen: 2 mg/ kg; three-weekly regimen: 6 mg/kg respectively) should then be given according to the previous schedule.

If the patient misses a dose of Herclon by more than one week, a re-loading dose of Herclon should be given over approximately 90 minutes (weekly regimen: 4 mg/kg; 3-weekly regimen: 8 mg/kg) Subsequent Herclon maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should then be given according to the previous schedule.

Dose Reduction: No reductions in the dose of Herclon were made during clinical trials. Patients may continue Herclon 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 hold the dose of chemotherapy should be followed.

Special Dosage Instructions: Elderly: Data suggest that the disposition of Herclon is not altered based on age. In clinical trials, elderly patients did not receive reduced doses of Herclon.

Children: The safety and efficacy of Herclon in paediatric patients have not been established.

See also:
What is the most important information I should know about Herclon?

Do not use Herclon without telling your doctor if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Before receiving Herclon, tell your doctor if you have heart disease, congestive heart failure, a history of heart attack, or any allergies or breathing problems. You may not be able to receive Herclon, or you may need a dosage adjustment or special tests during treatment.

Some people receiving a Herclon injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, weak, itchy, or short of breath during the injection

Use Herclon as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Herclon is given as an injection at your doctor's office, hospital, or clinic. Ask your doctor, nurse, or pharmacist any questions that you may have about Herclon.
• Do not use Herclon if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Herclon, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Herclon.

Use: Labeled Indications

Breast cancer, adjuvant treatment: Treatment (adjuvant) of human epidermal growth receptor 2 (HER2)-overexpressing node positive or node negative (estrogen receptor/progesterone receptor negative or with 1 high-risk feature) breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as a single agent following multimodality anthracycline-based therapy.

Breast cancer, metastatic: First-line treatment of HER2-overexpressing metastatic breast cancer (in combination with paclitaxel); single agent treatment of HER2-overexpressing breast cancer in patients who have received 1 or more chemotherapy regimens for metastatic disease.

Gastric cancer, metastatic: Treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma (in combination with cisplatin and either capecitabine or 5-fluorouracil) in patients who have not received prior treatment for metastatic disease.

Limitations of use: Patients should be selected for breast and gastric cancer therapy based on an approved companion diagnostic test for tumor specimen for HER2 overexpression or HER2 gene amplification. Due to differences in disease histopathology (eg, incomplete membrane staining, more frequent heterogeneous HER2 expression in gastric cancer), tests appropriate for the specific tumor type (breast or gastric) should be used to assess HER2 status.

Note: Herzuma (Herclon-pkrb), Herclon (Herclon-anns), Ogivri (Herclon-dkst), and Trazimera (Herclon-qyyp) are approved as biosimilars to Herclon (Herclon). In Canada, Herzuma, Ogivri, and Trazimera are biosimilars to Herclon (Herclon).

Off Label Uses

Breast cancer, locally advanced, inflammatory or early, human epidermal growth receptor 2 (HER2)-positive (neoadjuvant treatment)

Data from a large randomized phase II study support the use of Herclon in combination with pertuzumab and docetaxel in the neoadjuvant management of HER2-positive locally advanced, inflammatory or early breast cancer.

See also:
What other drugs will affect Herclon?

There have been no formal drug interaction studies performed with Herclon in humans. Clinically significant interactions between Herclon and the concomitant medication used in clinical trials have not been observed.

In studies where Herclon was administered in combination with docetaxel, carboplatin or anastrozole, the pharmacokinetics of these medications was not altered nor was the pharmacokinetics of Herclon altered.

Concentrations of paclitaxel and doxorubicin (and their major metabolites 6-α hydroxyl-paclitaxel, POH, and doxorubicinol, DOL) were not altered in the presence of Herclon. However, Herclon may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite is unclear. No changes were observed in Herclon concentrations in the presence of paclitaxel and doxorubicin.

The results of a small drug interaction substudy evaluating the pharmacokinetics of capecitabine and cisplatin when used with or without Herclon suggested that the exposure to the bioactive metabolites (eg, 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus Herclon. However, capecitabine itself showed higher concentrations and a longer half-life (t_½) when combined with Herclon. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus Herclon.

Incompatibilities: No incompatibilities between Herclon and polypropylene syringes have been observed.

Dextrose (5%) solution should not be used since it causes aggregation of the protein.

Herclon should not be mixed or diluted with other drugs.

See also:
What are the possible side effects of Herclon?

Clinical Trials: In this section, the following categories of frequency have been used: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions should be presented in order of decreasing seriousness.

List of Adverse Reactions: Presented in Table 11 are adverse reactions that have been reported in association with the use of Herclon alone or in combination with chemotherapy in pivotal clinical trials. All the terms included are based on the highest percentage seen in pivotal clinical trials.

As Herclon is commonly used with other chemotherapeutic agents and radiotherapy it is often difficult to ascertain the causal relationship of an adverse event to a particular drug/radiotherapy.

Immunogenicity: In the neoadjuvant-adjuvant setting, 7.1% of patients treated with the IV infusion and 14.6% of patients receiving SC injection (vial) developed antibodies against Herclon (regardless of antibody presence at baseline).

The clinical relevance of these antibodies is not known; however, the pharmacokinetics, efficacy [determined by pathological complete response (pCR)] or safety [determined by occurrence of administration related reactions (ARRs)] of Herclon IV or SC did not appear to be adversely affected by these ADAs.

Infusion/Administration Related Reactions (IRRs/ARRs) and Hypersensitivity: IRRs/ARRs eg, chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress were seen in all Herclon clinical trials and for the IV and the SC formulation.

Infusion/Administration Related Reactions: may be clinically difficult to distinguish from hypersensitivity reactions.

The rate of IRRs/ARRs of all grades varied between studies depending on the indication, whether Herclon was given concurrently with chemotherapy or as monotherapy and data collection methodology.

In MBC, the rate of IRRs ranged from 49-54% in the Herclon containing arm compared to 36-58% in the comparator arm (which may have contained other chemotherapy). Severe (≥grade 3) ranged from 5-7% in the Herclon containing arm compared to 5-6% in the comparator arm.

In EBC, the rate of IRRs/ARRs ranged from 18-54% in the Herclon containing arm compared to 6-50% in the comparator arm (which may have contained other chemotherapy). Severe (≥grade 3) ranged from 0.5-6% in the Herclon containing arm compared to 0.3-5% in the comparator arm.

In the neoadjuvant-adjuvant setting (BO22227), the rate of IRRs/ARRs was in line with the above and were 37.2% in the IV arm to 47.8% in the SC arm, severe grade 3 events were 2% and 1.7% in the IV and SC arms, respectively. There were no grade 4 or 5 IRRs/ARRs.

Anaphylactoid reactions were observed in isolated cases.

Cardiac Dysfunction: Congestive heart failure (NYHA II-IV) is a common adverse reaction to Herclon. It has been associated with fatal outcome. Signs and symptoms of cardiac dysfunction eg, dyspnoea, orthopnoea, increased cough, pulmonary oedema, S₃ gallop, or reduced ventricular ejection fraction, have been observed in patients treated with Herclon.

Metastatic Breast Cancer: Depending on the criteria used to define cardiac dysfunction, the incidence in the pivotal metastatic trials varied between 9% and 12% in the Herclon + paclitaxel subgroup, compared with 1-4% for the paclitaxel alone subgroup. For Herclon monotherapy, the rate was 6-9%. The highest rate of cardiac dysfunction was seen in patients receiving concurrent Herclon + anthracycline/cyclophosphamide (27%), significantly higher than in the anthracycline/cyclophosphamide alone subgroup (7-10%). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic heart failure was 2.2% in patients receiving Herclon and docetaxel, compared with 0% in patients receiving docetaxel alone. Most of the patients (79%) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF.

Early Breast Cancer (Adjuvant Setting): In 3 pivotal clinical trials of adjuvant Herclon given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (symptomatic CHF) was similar in patients who were administered chemotherapy alone and in patients who were administered Herclon sequentially to a taxane (0.3-0.4%). The rate was highest in patients who were administered Herclon concurrently with a taxane (2%). At 3 years, the cardiac event rate in patients receiving AC→P (doxorubicin plus cyclophosphamide followed by paclitaxel) + H (Herclon) was estimated at 3.2%, compared with 0.8% in AC→P treated patients. No increase in the cumulative incidence of cardiac events was seen with further follow-up at 5 years.

At 5.5 years, the rates of symptomatic cardiac or LVEF events were 1%, 2.3% and 1.1% in the AC→D (doxorubicin plus cyclophosphamide, followed by docetaxel), AC→DH (doxorubicin plus cyclophosphamide, followed by docetaxel plus Herclon) and docetaxel, carboplatin and Herclon (DCarbH) treatment arms, respectively. For symptomatic CHF (grade 3-4), the 5-year rates were 0.6%, 1.9% and 0.4% in the AC→D, AC→DH and DCarbH treatment arms, respectively. The overall risk of developing symptomatic cardiac events was low and similar for patients in AC→D and DCarbH arms; relative to both the AC→D and DCarbH arms there was an increased risk of developing a symptomatic cardiac event for patients in the AC→DH arm, being discernable by a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events up to 2.3% compared to approximately 1% in the 2 comparator arms (AC→D and DCarbH).

When Herclon was administered after completion of adjuvant chemotherapy NYHA class III-IV heart failure was observed in 0.6% of patients in the 1-year arm after a median follow-up of 12 months. After a median follow-up of 3.6 years the incidence of severe CHF and left ventricular dysfunction after 1 year Herclon therapy remained low at 0.8% and 9.8%, respectively.

In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA III & IV) in the Herclon 1 year treatment was 0.89% and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 6.35%.

Reversibility of severe CHF (defined as a sequence of at least 2 consecutive LVEF values ≥50% after the event) was evident for 71.4% of Herclon-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5% of Herclon-treated patients. Approximately 17% of cardiac dysfunction related events endpoints occurred after completion of Herclon.

In the joint analysis of studies NSABP B-31 and NCCTG N9831, with a median follow-up of 8.1 years for the AC→PH group (doxorubicin plus cyclophosphamide, followed by paclitaxel plus Herclon), the per patient incidence of new onset cardiac dysfunction, as determined by LVEF, remained unchanged compared to the analysis performed at a median follow up of 2 years in the AC→PH group: 18.5% of AC→PH patients with LVEF decreased of ≥10% to <50%. Reversibility of left ventricular dysfunction was reported in 64.5% of patients who experienced a symptomatic CHF in the AC→PH group being asymptomatic at latest follow up and 90.3% having full or partial LVEF recovery (88).

Early Breast Cancer (Neoadjuvant-Adjuvant Setting): In the clinical trial setting, when Herclon was administered concurrently with neoadjuvant chemotherapy containing 3-4 cycles of a neoadjuvant anthracycline (cumulative doxorubicin dose 180 mg/m² or epirubicin dose 360 mg/m²) overall, the incidence of symptomatic cardiac dysfunction was up to 1.7% in the Herclon arm. However, in the pivotal trial BO22227, at a median follow-up of 20.6 months the incidence of symptomatic cardiac dysfunction was 0.7% in the Herclon IV arm and 1% in the Herclon SC arm.

Advanced Gastric Cancer: In the BO18255 study, at screening, the median LVEF value was 64% (range 48-90%) in the fluoropyrimidine/cisplatin arm (FP) and 65% (range 50-86%) in the Herclon plus fluoropyrimidine/cisplatin arm (H+FP).

The majority of the LVEF decreases noted in BO18255 study were asymptomatic, with the exception of 1 patient in the Herclon-containing arm whose LVEF decrease coincided with cardiac failure.

Overall, there were no significant differences in cardiac dysfunction between the treatment arm and the comparator arm.

Haematological Toxicity: Breast Cancer: Haematological toxicity is infrequent following the administration of Herclon monotherapy in the metastatic setting, world health organization (WHO) grade 3 leukopenia, thrombocytopenia and anaemia occurring in <1% of patients. No WHO grade 4 toxicities were observed. There was an increase in WHO grade 3 or 4 haematological toxicity in patients treated with the combination of Herclon and paclitaxel compared with patients receiving paclitaxel alone (34% vs 21%). Haematological toxicity was also increased in patients receiving Herclon and docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia vs 22%, using NCI-CTC criteria). The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with Herclon + docetaxel (23% vs 17% for patients treated with docetaxel alone).

Using NCI-CTC criteria, in the BO16348 study, 0.4% of Herclon-treated patients experienced a shift of 3 or 4 grades from baseline, compared with 0.6% in the observation arm.

Advanced Gastric Cancer: The most frequently reported adverse reaction, of grade ≥3 occurring with an incidence rate of at least 1% by trial treatment, that were categorized under the blood and lymphatic system disorders SOC are shown in Table 14.

The total percentage of patients who experienced an adverse effect of grade 3 NCI-CTCAE v3 that has been categorized under this SOC was 38% in the FP arm and 40% in the FP + H arm.

Overall, there were no significant differences in haematotoxicity between the treatment arm and the comparator arm.

Hepatic and Renal Toxicity: Breast Cancer: World health organization grade 3 or 4 hepatic toxicity was observed in 12% of patients following administration of Herclon as single agent, in the metastatic setting. This toxicity was associated with progression of disease in the liver in 60% of these patients.

World health organization grade 3 or 4 hepatic toxicity was less frequently observed among patients receiving Herclon and paclitaxel than among patients receiving paclitaxel alone (7% compared with 15%). No WHO Grade 3 or 4 renal toxicity was observed.

Advanced Gastric Cancer: In the BO18255 study no significant differences in hepatic and renal toxicity were observed between the 2 treatment arms.

NCI-CTCAE (version 3) grade ≥3 renal toxicity was not significantly higher in patients receiving Herclon than those in the F+P arm (3% and 2% respectively).

NCI-CTCAE (version 3) grade ≥3 adverse event in the hepatobiliary disorders SOC: Hyperbilirubinaemia was the only reported AE and was not significantly higher in patients receiving Herclon than those in the F+P arm (1% and <1% respectively).

Diarrhoea: Breast Cancer: Of patients treated with Herclon monotherapy in the metastatic setting 27% experienced diarrhoea. An increase in the incidence of diarrhoea, primarily mild to moderate in severity, has also been observed in patients receiving Herclon in combination with paclitaxel compared with patients receiving paclitaxel alone.

In the BO16348 study, 8% of Herclon-treated patients experienced diarrhoea during the 1st year of treatment.

Advanced Gastric Cancer: In the BO18255 study, 109 patients (37%) participating in the Herclon-containing treatment arm versus 80 patients (28%) in the comparator arm experienced any grade diarrhoea. Using NCI-CTCAE v3.0 severity criteria, the percentage of patients experiencing grade 3 diarrhoea was 4% in the FP arm versus 9% in the FP+H arm.

Infection: An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections, has been observed in patients treated with Herclon.

Switching Treatment Between Herclon IV and Herclon SC Formulation and Vice Versa: Study MO22982 investigated switching between the Herclon IV and SC formulation with a primary objective to evaluate patient preference for either the IV or the SC route of Herclon administration. In this trial, 2 cohorts (one using SC vial and one using SC SID) were investigated using a 2-arm, cross-over design with patients being randomized to 1 of 2 different every 3 weeks Herclon treatment sequences [IV (cycles 1-4)→SC (cycles 5-8) or SC (cycles 1-4)→IV (cycles 5-8)]. Patients were either naive to Herclon IV treatment (20.3%) or pre-exposed to Herclon IV (79.7%). Overall, switches from Herclon IV to SC formulation and vice versa were well-tolerated. Pre-switching rates (cycles 1-4) for SAEs, grade 3 AEs and treatment discontinuations due to adverse effects were low (<5%) and similar to post-switching rates (cycles 5-8). No grade 4 or grade 5 adverse effects were reported.

Post-Marketing: See Table 15.

Adverse Events: Table 16 indicates adverse events that historically have been reported in patients who have received Herclon. As no evidence of a causal association has been found between Herclon and these events, these events are not considered expected for the purposes of regulatory reporting.

The solvent vial contains bacteriostatic water for injection, containing benzyl alcohol. It is a clear and colorless liquid.

Reconstituted Herclon concentrate contains Trastuzumab 21 mg/mL.

Herclon SC formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered drugs when administered SC.