Pertuzumab

Registered South African indications:

• Metastatic breast cancer
  - HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease
• Early breast cancer
  - Neoadjuvant treatment of patients with HER2 positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node positive)
  - Adjuvant treatment of patients with HER-2 positive breast cancer at high risk of recurrence

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl <30ml/min)
• Hepatic impairment
• Elderly (>75 years)
• Prior use of anthracycline-based chemotherapy
• Prior radiotherapy to the chest area
• Pre-treatment left ventricular ejection fraction (LVEF) of <50%
• History of congestive heart failure
• History of LVEF decrease to <50% during prior trastuzumab adjuvant therapy
• Conditions that could impair left ventricular function
  - Uncontrolled hypertension
  - Recent myocardial infarction
  - Serious cardiac arrhythmia requiring treatment
  - Cumulative prior anthracycline exposure to >360mg/m² of doxorubicin or its equivalent
• May impair ability to drive and operate machinery

South African manufacturer recommendations

• Severe renal impairment (CrCl <30ml/min)
• Hepatic impairment
• Elderly
• Prior use of anthracycline-based chemotherapy
• Prior radiotherapy to the chest area
• Pre-treatment LVEF of ≤50%
• History of congestive heart failure
• History of LVEF decrease to <50% during prior trastuzumab adjuvant therapy
• Conditions that could impair left ventricular function
  - Uncontrolled hypertension
  - Recent myocardial infarction
  - Serious cardiac dysrhythmia requiring treatment
  - Cumulative prior anthracycline exposure to >360mg/m² of doxorubicin or its equivalent
• Diabetes mellitus
• Fructose intolerance
• Glucose-galactose malabsorption
• Sucrase-isomaltase insufficiency
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used for the treatment of

• Metastatic breast cancer (Additional agents required)
  - In combination with trastuzumab and docetaxel for patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease
• Early breast cancer (Additional agents required)
  - Neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence
  - Adjuvant treatment of HER2-positive early breast cancer at high risk of recurrence

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Consult specialist for dosages and regimens

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South African manufacturer recommendations

Used for the treatment of

• Metastatic breast cancer (Additional agents required)  
  - In combination with trastuzumab and docetaxel for patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease
• Early breast cancer (Additional agents required)  
  - Neoadjuvant treatment of patients with HER2 positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node positive) as part of a complete regimen for early breast cancer 
  - Adjuvant treatment of patients with HER-2 positive breast cancer at high risk of recurrence

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

International manufacturer recommendations

• Caution; positive evidence of risk
• There is limited amount of data from the use of pertuzumab in pregnant women. Studies in animals have shown reproductive toxicity
• Pertuzumab is not recommended during pregnancy and in women of childbearing potential not using contraception
• Women of childbearing potential should use effective contraception while receiving pertuzumab and for 6 months following the last dose of pertuzumab

South African manufacturer recommendations

• Contraindicated 
• Pertuzumab should not be used during pregnancy
• Women of childbearing potential and female partners of male patients of childbearing potential should use effective contraception while receiving pertuzumab and for 6 months following the last dose of pertuzumab. Combined hormonal and barrier methods are recommended
  In animal studies, pertuzumab administered to cynomolgus monkeys during organogenesis led to oligohydramnios, delayed renal development and embryo foetal death

Breastfeeding

International manufacturer recommendations

• Caution
• Because human IgG is secreted in human milk and the potential for absorption and harm to the infant is unknown, a decision should be made to discontinue breastfeeding or to discontinue treatment, taking into account the benefit of breastfeeding for the child and the benefit of pertuzumab therapy for the woman

South African manufacturer recommendations

• Contraindicated
• Because human IgG is secreted in human milk and animal data that indicate pertuzumab is foetotoxic, women receiving pertuzumab must not breastfeed their infants 

Fertility

International manufacturer recommendations

• No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab
• In repeated dose toxicity studies in cynomolgus monkeys, no definitive conclusions could be drawn on the adverse effect on male reproductive organs. No adverse reactions were observed in sexually mature female cynomolgus monkeys exposed to pertuzumab

South African manufacturer recommendations

• No information available

Renal Impairment

• Mild to moderate (CrCl ≥30ml/min): No dose adjustment recommended
• Severe (CrCl <30ml/min): Caution; no information available
  No dose recommendations can be made for severe renal impairment due to the limited pharmacokinetic data available ,

Hepatic Impairment

• Caution; no information available
  No specific dose recommendations can be made as the safety and efficacy of pertuzumab has not been studied in hepatic impairment

Elderly

• Caution; no dose adjustment recommended
  Limited data is available in patients >75 years of age

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Peripheral neuropathy
  - Peripheral sensory neuropathy
• Headache
• Dizziness
• Paraesthesia
• Insomnia
• Fatigue

Cardiovascular Disorders

• Left ventricular dysfunction
• Congestive cardiac failure

Respiratory Disorders

• Cough
• Epistaxis
• Dyspnoea
• Interstitial lung disease
• Pleural effusion
• Nasopharyngitis
• Upper respiratory tract infection

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Stomatitis
• Constipation
• Dyspepsia
• Abdominal pain

Endocrine and Metabolic Disorders

• Decreased appetite
• Tumour lysis syndrome
• Hot flush

Musculoskeletal Disorders

• Myalgia
• Arthralgia
• Pain in extremity

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Rash
• Nail disorder
• Pruritus
• Dry skin
• Mucosal inflammation
• Paronychia

Immune, Blood and Lymphatic System Disorders

• Infusion reaction
  - Fever
  - Chills
  - Fatigue
  - Headache
  - Vomiting
  - Dysgeusia
  - Myalgia
• Hypersensitivity (including fatal outcome)
  - Drug hypersensitivity (including fatal outcome)
• Anaphylactic reaction (including fatal outcome)
• Cytokine release syndrome
• Febrile neutropenia (including fatal outcome)
• Neutropenia
• Leucopenia
• Anaemia
• Oedema
  - Peripheral oedema
• Fever
• Chills

Sensory Disorders

• Dysgeusia
• Increased lacrimation

Others

• Pain

None known

• HER2 expression

Specific cases may require

• Pregnancy test
• Left ventricular ejection fraction (LVEF)

Additional observations

• Infusion reactions 
• Diarrhoea
• Hypersensitivity

Traceability

• In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded

Method of administration

• Pertuzumab is administered intravenously by infusion. It should not be administered as an intravenous push or bolus. For the initial dose, the recommended infusion period is 60 minutes. If the first infusion is well tolerated, subsequent infusions may be administered over a period of 30 minutes to 60 minutes

Infusion reactions

• The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. The infusion may be resumed when symptoms abate. Treatment including oxygen, beta agonists, antihistamines, rapid i.v. fluids and antipyretics may also help alleviate symptoms

Hypersensitivity reactions/anaphylaxis

• The infusion should be discontinued immediately and permanently if the patient experiences a NCI-CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome

Instructions for dilution

• Pertuzumab does not contain any antimicrobial preservative. Therefore, care must be taken to ensure the sterility of the prepared solution for infusion and should be prepared by a healthcare professional
• Pertuzumab is for single use only
• The vial must not be shaken
• 14ml of pertuzumab concentrate should be withdrawn from the vial using a sterile needle and syringe and diluted into a 250ml PVC or non-PVC polyolefin infusion bag of sodium chloride 9mg/ml (0.9%) solution for infusion. After dilution, one ml of solution should contain approximately 3.02mg of pertuzumab (840mg/278ml) for the initial dose where two vials are required and approximately 1.59mg of pertuzumab (420mg/264ml) for the maintenance dose where one vial is required
• The bag should be gently inverted to mix the solution in order to avoid foaming 
• Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration. If particulates or discoloration are observed, the solution should not be used. Once the infusion is prepared it should be administered immediately

Pertuzumab is a recombinant humanised monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2), and thereby, blocks ligand-dependent heterodimerisation of HER2 with other HER family members, including EGFR, HER3 and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signalling through two major signal pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these signalling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC).

Injection 420mg/14ml (or 30mg/ ml)

• Perjeta (Roche) originator