Herceptin is the brand name of a medicine called trastuzumab. It’s used to treat some types of breast cancer, oesophageal cancer and stomach cancer. Herceptin (chemical name: trastuzumab) can be an effective treatment both before and after surgery for people with HER2-positive breast cancer. It has also been shown to reduce the risk of breast cancer recurrence after initial surgery.

Herceptin is approved for the treatment of early-stage breast cancer that is Human Epidermal growth factor Receptor 2-positive (HER2+) and has spread into the lymph nodes, or is HER2+ and has not spread into the lymph nodes.

If it has not spread into the lymph nodes, the cancer needs to be estrogen receptor/progesterone receptor (ER/PR)-negative or have one high risk feature.

Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer. Specifically it is used for breast cancer that is HER2 receptor positive. It may be used by itself or together with other chemotherapy medication.  Trastuzumab is given by slow injection into a vein and injection just under the skin.

Common side effects include fever, infection, cough, headache, trouble sleeping, and rash.Other severe side effects include heart failure, allergic reactions, and lung disease. Use during pregnancy may harm the baby. Trastuzumab works by binding to the HER2 receptor and slowing down cell duplication

Trastuzumab was approved for medical use in the United States in 1998.It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.The wholesale price in the developing world is between 1,800 and 1,955 USD per 440 mg vial.In the United Kingdom a 150 mg vial costs the NHS 407.00 pounds.

 Herceptin can be used in several different ways

• As part of a treatment course including the chemotherapy drugs doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. This treatment course is known as “AC→TH“
• With the chemotherapy drugs docetaxel and carboplatin. This treatment course is known as “TCH“
• Alone after treatment with multiple other therapies, including an anthracycline (doxorubicin)-based therapy (a type of chemotherapy)

*High risk is defined as ER/PR-positive with one of the following features: tumor size greater than 2 cm, age less than 35 years, or tumor Grade 2 or 3.

Indications

Adjuvant Breast Cancer

Herceptin is approved for the treatment of early-stage breast cancer that is Human Epidermal growth factor Receptor 2-positive (HER2+) and has spread into the lymph nodes, or is HER2-positive and has not spread into the lymph nodes. If it has not spread into the lymph nodes, the cancer needs to be estrogen receptor/progesterone receptor (ER/PR)-negative or have one high-risk feature.

Herceptin can be used in several different ways:

• As part of a treatment course including the chemotherapy drugs doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. This treatment course is known as “AC→TH”
• With the chemotherapy drugs docetaxel and carboplatin. This treatment course is known as “TCH”
• Alone after treatment with multiple other therapies, including an anthracycline (doxorubicin) based therapy (a type of chemotherapy)

Patients are selected for therapy based on an FDA-approved test for Herceptin

Adjuvant Breast Cancer

Herceptin is approved for the treatment of early-stage breast cancer that is Human Epidermal growth factor Receptor 2-positive (HER2+) and has spread into the lymph nodes, or is HER2-positive and has not spread into the lymph nodes. If it has not spread into the lymph nodes, the cancer needs to be estrogen receptor/progesterone receptor (ER/PR)-negative or have one high-risk feature.

Herceptin can be used in several different ways:

• As part of a treatment course including the chemotherapy drugs doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. This treatment course is known as “AC→TH“
• With the chemotherapy drugs docetaxel and carboplatin. This treatment course is known as “TCH“
• Alone after treatment with multiple other therapies, including an anthracycline (doxorubicin) based therapy (a type of chemotherapy)

Patients are selected for therapy based on an FDA-approved test for Herceptin

Metastatic Breast Cancer

Herceptin has 2 approved uses in metastatic breast cancer:

• Herceptin in combination with the chemotherapy drug paclitaxel is approved for the first line treatment of Human Epidermal growth factor Receptor 2-positive (HER2+) metastatic breast cancer
• Herceptin alone is approved for the treatment of HER2+ breast cancer in patients who have received one or more chemotherapy courses for metastatic disease

Gastric Cancer

Herceptin is approved, in combination with chemotherapy (cisplatin and either capecitabine or 5-fluorouracil), for the treatment of HER2+ metastatic cancer of the stomach or gastroesophageal junction (where the esophagus meets the stomach) in patients who have not received prior treatment for their metastatic disease.

When Herceptin is used

Herceptin can be used to treat:

• early HER2 positive breast cancer, following surgery and/or radiotherapy and chemotherapy, to reduce the risk of the cancer coming back
• advanced HER2 positive breast cancer that has spread from the breast (metastatic breast cancer), to slow the growth of the cancer and increase survival time
• advanced HER2 positive stomach cancer that has spread out of the stomach (metastatic stomach cancer)
• advanced HER2 positive gastro-oesophageal cancer, affecting the area where the oesophagus (food pipe) meets the stomach

If you have breast, oesophageal or stomach cancer, tests will be carried out to check if your cancer is HER2 positive before Herceptin is offered.

What This Drug Is Used For:

• Trastuzumab is used to treat metastatic (spread) breast cancer.  It is effective against tumors that overexpress the HER2/neu protein.
• As part of chemotherapy regimen for adjuvant treatment of lymph-node positive, HER2/neu protein positive breast cancer.
• Treatment of gastric (stomach) cancer
• It is not known whether or not trastuzumab may be effective in other cancers that may also have this HER-2/neu protein, including ovarian, colon, endometrial, lung, bladder, prostate, and salivary gland tumors.

How it works

Herceptin can help control the growth of cancer cells that contain high amounts of HER2 (human epidermal growth factor receptor 2).

HER2 is found in all human cells. It controls cell growth and repair.

But high levels of HER2 are found in some types of breast, oesophageal and stomach cancer, which helps the cancer cells grow and survive.

These are known as HER2 positive cancers. About one in five breast and stomach cancers are HER2 positive.

Herceptin works by blocking the effects of HER2 and encouraging the immune system (the body’s natural defences) to attack and kill the cancer cells.

It is a type of targeted treatment.

It is used for cancers that have large amounts of a protein called HER2 (human epidermal growth factor receptor 2).

Some breast cancers and stomach cancers have large amounts of HER2 and they are called HER2 positive cancers. HER2 makes the cancer cells grow and divide. When Herceptin attaches to HER2 it can make the cells stop growing and die.

Doctors use trastuzumab to treat some types of:

• early breast cancer in adults
• advanced breast cancer in adults
• advanced stomach cancer in adults

Side Effects

HERCEPTIN is not for everyone. Be sure to contact your doctor if you are experiencing any of the following:

Heart Problems

These include heart problems—such as congestive heart failure or reduced heart function—with or without symptoms. The risk for and seriousness of these heart problems were highest in people who received both HERCEPTIN and a certain type of chemotherapy (anthracycline). In a study of adjuvant (early) breast cancer, one patient died of significantly weakened heart muscle. Your doctor will check for signs of heart problems before, during, and after treatment with HERCEPTIN.

Infusion Reactions including:

• Fever and chills
• Feeling sick to your stomach (nausea)
• Throwing up (vomiting)
• Pain (in some cases at tumor sites)
• Headache
• Dizziness
• Shortness of breath

Herceptin often causes side effects, although many of these will become less severe over time.

Some patients receiving HERCEPTIN for breast cancer had the following side effects:

• Fever
• Feeling sick to your stomach (nausea)
• Throwing up (vomiting)
• Infusion reactions
• Diarrhea
• Infections
• Increased cough
• Headache
• Feeling tired
• Shortness of breath
• Rash
• Low white and red blood cell counts
• Muscle pain

Some patients receiving HERCEPTIN for metastatic stomach cancer had the following side effects:

• Low white blood cell counts
• Diarrhea
• Feeling tired
• Low red blood cell counts
• Swelling of the mouth lining
• Weight loss
• Upper respiratory tract infections
• Fever
• Low platelet counts
• Swelling of the mucous membranes
• Swelling of the nose and throat
• Change in taste

Interactions

Patients who receive anthracycline after stopping Herceptin may be at increased risk of cardiac dysfunction because of trastuzumab’s long washout period based on population PK analysis . If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.

Precautions

Cardiomyopathy

Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death.Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF).

There is a 4−6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline.

Withhold Herceptin for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values . The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.

Patients who receive anthracycline after stopping Herceptin may also be at increased risk of cardiac dysfunction

Cardiac Monitoring

Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan.

The following schedule is recommended:

• Baseline LVEF measurement immediately prior to initiation of Herceptin
• LVEF measurements every 3 months during and upon completion of Herceptin
• Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction.
• LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy.

In Study 1, 15% (158/1031) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH arm. In Study 3 (one-year Herceptin treatment), the number of patients who discontinued Herceptin due to cardiac toxicity at 12.6 months median duration of follow-up was2.6% (44/1678).

 In Study 4, a total of 2.9% (31/1056) of patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity.

Among 64 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology, and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.

Infusion Reactions

Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. 

In post-marketing reports, serious and fatal infusion reactions have been reported. Severe reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction.

Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.

There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre-medications.

Embryo-Fetal Toxicity

Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

Verify the pregnancy status of females of reproductive potential prior to the initiation of Herceptin. Advise pregnant women and females of reproductive potential that exposure to Herceptin during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of Herceptin.

Pulmonary Toxicity

Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.

Exacerbation Of Chemotherapy-Induced Neutropenia

In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3−4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Herceptin has not been tested for carcinogenic potential.

No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg of trastuzumab.

A fertility study was conducted in female Cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels.

Use In Specific Populations

Pregnancy

Pregnancy Exposure Registry And Pharmacovigilance Program

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Herceptin during pregnancy.

In addition, there is a pregnancy pharmacovigilance program for Herceptin. If Herceptin is administered during pregnancy, or if a patient becomes pregnant while receiving Herceptin or within 7 months following the last dose of Herceptin,

Risk Summary

Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Apprise the patient of the potential risks to a fetus. There are clinical considerations if Herceptin is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of Herceptin.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monitor women who received Herceptin during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

Data

Human Data

In post-marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received Herceptin either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin therapy resumed after amniotic index improved and oligohydramnios recurred.

Animal Data

In studies where trastuzumab was administered to pregnant Cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.

Lactation

Risk Summary

There is no information regarding the presence of trastuzumab in human milk, the effects on the breastfed infant, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts.

Trastuzumab was present in the milk of lactating Cynomolgus monkeys but not associated with neonatal toxicity Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Herceptin treatment and any potential adverse effects on the breastfed child from Herceptin or from the underlying maternal condition. This consideration should also take into account the trastuzumab wash out period of 7 months.

Data

In lactating Cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of 614 maternal serum concentrations after pre-(beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of 2 mg/kg of Herceptin). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of 618 age.

Females And Males Of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of Herceptin.

Contraception

Females

Herceptin can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Herceptin and for 7 months following the last dose of Herceptin.

Pediatric Use

The safety and effectiveness of Herceptin in pediatric patients have not been established.

Geriatric Use

Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2.

Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients < 65 years of age for metastatic disease and adjuvant treatment.

In Study 7 (metastatic gastric cancer), of the 294 patients treated with Herceptin, 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over.

No overall differences in safety or effectiveness were observed.

• Before starting trastuzumab treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.).
• Inform your health care professional if you are pregnant or may be pregnant prior to starting this treatment.  Pregnancy category B (there is no evidence of risk in humans based on negative animal studies.  Use in pregnancy only if clearly needed).
• For both men and women: It is not recommended to conceive a child (get pregnant) while taking trastuzumab. Barrier methods of contraception, such as condoms, are recommended. Discuss with your doctor when you may safely become pregnant or conceive a child after therapy.
• Do not breast feed while taking this medication.

Treatment

The optimal duration of add-on trastuzumab is currently unknown. One year of treatment is generally accepted based on current clinical trial evidence that demonstrated the superiority of one-year treatment over none. However, a small Finnish trial also showed similar improvement with nine weeks of treatment over no therapy. Because of the lack of direct head-to-head comparison in clinical trials, it is unknown whether a shorter duration of treatment may be just as effective (with fewer side effects) than the currently accepted practice of treatment for one year.

Debate about treatment duration has become a relevant issue for many public health policy makers because administering trastuzumab for a year is very expensive. Consequently, some countries with a taxpayer-funded public health system, such as New Zealand, chose to fund limited adjuvant therapy. However, subsequently New Zealand has revised its policy and now funds trastuzumab treatment for up to 12 months. Clinical trial data from Roche show that one year of therapy balances efficacy against adverse side effects.

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