KADCYLA 100

Indications

• Breast cancer
• Non-small cell lung cancer
• Other malignancies as determined by oncologist

Dosage

Children: Dosing in pediatric populations should be determined by a healthcare professional experienced in pediatric oncology, following established clinical guidelines.

Adults: Dosing should be based on the specific clinical scenario and the guidance provided in the prescribing information or clinical guidelines.

Mechanism of action

Emitansine works by binding to specific antigens expressed on the surface of cancer cells. Once the drug is internalized, it releases the cytotoxic agent DM1, which disrupts microtubule dynamics, leading to cell cycle arrest and apoptosis in malignant cells. This mechanism is reliant on both the specificity of the antibody and the potency of the cytotoxic agent.

Pharmacodynamics

The pharmacodynamics of emitansine involve its ability to selectively target and destroy cancer cells, which contributes to its therapeutic efficacy. The drug's action leads to the disruption of cellular functions critical for cancer cell survival and proliferation, with a focus on tumor cells that express the target antigen, thus sparing normal cells and reducing side effects.

Pharmacokinetics

Emitansine has a complex pharmacokinetic profile characterized by its distribution, metabolism, and elimination. After administration, it is distributed primarily to tissues with high antigen expression. The drug is metabolized in the liver, and its elimination half-life can vary based on patient factors and the specific formulation used. The drug's pharmacokinetics are influenced by the characteristics of both the antibody and the cytotoxic component.

Contra-indications

• Hypersensitivity to emitansine or any component of the formulation
• Severe hepatic impairment
• Pregnancy

Adverse effects

• Nausea
• Vomiting
• Fatigue
• Bone marrow suppression
• Neurotoxicity
• Cardiotoxicity
• Peripheral neuropathy

Interactions

• CYP3A4 inhibitors may increase levels of emitansine
• CYP3A4 inducers may decrease levels of emitansine
• Concomitant use with other myelosuppressive agents may exacerbate bone marrow suppression

Precautions

• Monitor complete blood counts regularly due to risk of myelosuppression
• Assess cardiac function before and during treatment due to potential cardiotoxicity
• Use caution in patients with a history of neuropathy

Pregnancy

Emitansine is contraindicated during pregnancy due to potential for teratogenic effects.

Breast-feeding

It is not known if emitansine is excreted in human milk. Caution is advised when administering to nursing mothers.

Storage

Store at 20-25°C (68-77°F). Protect from light and moisture.

Formulations

• Injectable solution

Indications

• Metastatic breast cancer in patients with HER2 overexpression who have received at least two prior chemotherapy regimens, including an anthracycline and a taxane.
• Metastatic gastric cancer in patients with HER2-positive tumors who have not received prior treatment for this condition.

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients, as specific doses are not provided in the BNF.

Adults: The recommended dosage for adults is typically 8 mg/kg as a loading dose, followed by 6 mg/kg every three weeks, administered via intravenous infusion or subcutaneous injection.

Mechanism of action

Trastuzumab binds specifically to the extracellular domain of the human epidermal growth factor receptor 2 (HER2), leading to inhibition of HER2-mediated signaling pathways, including the PI3K/AKT and MAPK pathways. This blockade reduces cell proliferation and induces apoptosis in HER2-overexpressing cells. Additionally, trastuzumab enhances antibody-dependent cellular cytotoxicity (ADCC) through immune effector cells.

Pharmacodynamics

Trastuzumab demonstrates a dose-dependent effect on inhibiting the growth of HER2-positive cancer cells. Its clinical efficacy is primarily associated with its ability to target HER2 overexpression, leading to decreased tumor growth and improved survival rates in patients with HER2-positive breast and gastric cancers. Common side effects include infusion-related reactions, gastrointestinal disturbances, and increased risk of infections.

Pharmacokinetics

Trastuzumab has a terminal half-life of approximately 5 to 8 days after the initial intravenous administration. It is distributed widely, with a volume of distribution typically around 2-3 L/kg. Metabolism occurs via proteolytic degradation, primarily in the reticuloendothelial system. The clearance is affected by the patient's body size and HER2 expression levels, and it is excreted mainly through the lymphatic system.

Contra-indications

• Severe dyspnoea at rest
• Symptomatic heart failure
• Uncontrolled arrhythmias

Adverse effects

• Abdominal pain
• Alopecia
• Anaemia
• Appetite decreased
• Arthralgia
• Asthenia
• Constipation
• Cough exacerbated
• Decreased leucocytes
• Diarrhoea
• Dyspnoea
• Electrolyte imbalance
• Fever
• Headache
• Hyperbilirubinaemia
• Hyperhidrosis
• Hypogammaglobulinaemia
• Increased risk of infection
• Infusion related reaction
• Malaise
• Mucositis
• Muscle spasms
• Nasal congestion
• Nausea
• Neutropenia
• Pain
• Paresthesia
• Peripheral oedema
• Sepsis
• Skin reactions
• Taste altered
• Thrombocytopenia
• Vomiting
• Weight decreased

Interactions

• Anthracyclines: Severe (increases risk of cardiotoxicity)
• Anthracyclines + trastuzumab-emtansine: Severe (increases risk of cardiotoxicity)
• Cobicistat + trastuzumab-emtansine: Severe (increases exposure)
• Idelalisib + trastuzumab-emtansine: Severe (increases exposure)
• Clarithromycin + trastuzumab-emtansine: Severe (increases exposure)
• Anthracyclines + trastuzumab-deruxtecan: Unknown (increases risk of cardiotoxicity)

Precautions

• Monitor for cardiac function before each treatment cycle and throughout therapy
• Females of childbearing potential should use effective contraception during treatment and for at least 3 months after last treatment

Pregnancy

Use is not recommended during pregnancy. If exposed, monitor the infant for B-cell depletion.

Breast-feeding

It is not known if trastuzumab is excreted in human milk. Caution should be exercised.