Panitumumab

Registered South African indications:

• Wild-type KRAS metastatic colorectal cancer (mCRC)

Contraindications 

South African manufacturer recommendations

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

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients 
• Interstitial pneumonitis
• Pulmonary fibrosis
• Coadministration with oxaliplatin-containing chemotherapy in patients with mutant RAS mCRC or for whom RAS status unknown

Cautions

South African manufacturer recommendations

• Renal impairment
• Hepatic impairment
• Women of childbearing potential and for 6 months following the last dose
• Japanese descent
• Hypomagnesaemia
• Hypocalcaemia
• Interstitial pneumonitis
• Pulmonary fibrosis
• Pre-existing pulmonary symptoms
• Severe diarrhoea and dehydration
• Risk factors for ocular toxicities 
  - History of keratitis 
  - Ulcerative keratitis 
  - Severe dry eye  
  - Contact lenses  
• Controlled sodium content
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly 
• Women of childbearing potential and for 2 months following the last dose
• Pre-existing pulmonary symptoms
• Severe diarrhoea and dehydration
• Hypomagnesaemia
• Hypocalcaemia
• Risk factors for ocular toxicities
  - History of keratitis
  - Ulcerative keratitis
  - Severe dry eye 
  - Contact lenses 
• Eastern Cooperative Oncology Group (ECOG) 2 performance status treated with panitumumab in combination with chemotherapy
• Coadministration with irinotecan, bolus 5-fluorouracil, and leucovorin (IFL) chemotherapy
• Combination with bevacizumab-containing chemotherapy regimens
• Controlled sodium content
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Treatment should be supervised by a medical practitioner experienced in the use of anti-cancer therapy

Used in the treatment of 

Wild-type KRAS metastatic colorectal cancer (mCRC) 
- As monotherapy in those who have failed treatment with oxaliplatin, fluoropyrimidine, and irinotecan-containing chemotherapy regimens 

•  IV: 6mg/kg, once every two weeks  

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KRAS mutational status should be determined by an experienced laboratory using a validated test method

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Dose modification may be necessary in cases of severe (≥grade 3) dermatological reactions (See additional prescribing points) 

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Administered as intravenous infusion via an infusion pump. DO NOT administer as IV push or bolus

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Consult specialist for dosages and regimens

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International manufacturer recommendations

Treatment should be supervised by a physician experienced in the use of anti-cancer therapy

Used for the treatment of

Wild-type RAS metastatic colorectal cancer (mCRC)
- First-line in combination with FOLFOX or FOLFIRI
- Second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excl. irinotecan)
- As monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens

•  IV: 6mg/kg, once every two weeks  

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Evidence of wild- type RAS (KRAS and NRAS) status is required before initiating treatment. Mutational status should be determined by an experienced laboratory using validated test methods for detection of KRAS (exons 2,3 and 4) and NRAS (exons 2,3 and 4 mutations)

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Dose modification may be necessary in cases of severe (≥grade 3) dermatological reactions (See additional prescribing points) 

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Administered as intravenous infusion via an infusion pump. DO NOT administer as IV push or bolus

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Consult specialist for dosages and regimens

Not indicated for use in children

Pregnancy

South African manufacturer recommendations

• Contraindicated 
• There are no adequate data from use in pregnant women
• Studies in animals have shown reproductive toxicity 
• In women of childbearing potential, appropriate contraceptive measures must be used during treatment, and for 6 months following the last dose. If used during pregnancy or if the patient becomes pregnant while receiving this medicinal product, she should be advised of the potential risk for loss of the pregnancy or potential hazard to the foetus

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• There are no adequate data from the use in pregnant women
• Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown
• EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Therefore, panitumumab has the potential to cause foetal harm when administered to pregnant women
• Human IgG is known to cross the placental barrier, and panitumumab may therefore be transmitted from the mother to the developing foetus
• In women of childbearing potential, appropriate contraceptive measures must be used during treatment, and for 2 months following the last dose. If used during pregnancy or if the patient becomes pregnant while receiving this medicinal product, she should be advised of the potential risk for loss of the pregnancy or potential hazard to the foetus

Breastfeeding

South African manufacturer recommendations

• Contraindicated  
• Women should not breastfeed during treatment and for 3 months after the last dose

International manufacturer recommendations

• Caution; not recommended 
• It is unknown whether panitumumab is excreted in human breast milk
• Because human IgG is secreted into human milk, panitumumab might also be secreted. The potential for absorption and harm to the infant after ingestion is unknown
• It is recommended that women do not breastfeed during treatment and for 2 months after the last dose

Fertility

• Animal studies have shown reversible effects on the menstrual cycle and reduced female fertility in monkeys.  Panitumumab may impact the ability of a woman to become pregnant

Renal Impairment

• Caution; no information available 

Hepatic Impairment

• Caution; no information available 

Elderly

South African manufacturer recommendations

• No dose adjustment recommended 

International manufacturer recommendations

• Caution; no dose adjustment recommended 
  Increased number of serious adverse reactions were reported in elderly patients treated with panitumumab in combination with FOLFIRI or FOLFOX chemotherapy compared to chemotherapy alone

Porphyria Information

• Not porphyrinogenic

Drug in Sport 

• Permitted - No warnings 

Central Nervous System Disorders

• Fatigue
• Insomnia
• Anxiety 
• Headache
• Dizziness 

Cardiovascular Disorders

• Tachycardia
• Deep vein thrombosis
• Hypotension
• Hypertension
• Flushing
• Cyanosis 
• Chest pain 

Respiratory Disorders

• Dyspnoea
• Cough
• Pulmonary embolism
• Epistaxis
• Interstitial lung disease
• Bronchospasm
• Nasal dryness

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Constipation
• Abdominal pain
• Stomatitis
• Rectal haemorrhage
• Dry mouth
• Dyspepsia
• Aphthous ulcer
• Cheilitis
• Gastro-oesophageal reflux disease
• Chapped lips
• Dry lips

Genitourinary Disorders

• Urinary tract infection 

Endocrine and Metabolic Disorders

• Decreased appetite
• Hypokalaemia
• Hypomagnesaemia
• Hypocalcaemia
• Dehydration
• Hyperglycaemia
• Hypophosphataemia
• Decreased weight 

Musculoskeletal Disorders

• Back pain

Skin and Subcutaneous Tissue Disorders

• Paronychia
• Rash
  - Pustular rash 
  - Papular rash 
  - Pruritic rash 
  - Erythematous rash 
  - Generalised rash 
  - Macular rash 
  - Maculo-papular rash 
  - Exfoliative rash 
• Dermatitis acneiform
• Pruritus
• Erythema
• Dry skin
• Cellulitis 
• Folliculitis 
• Skin fissures
• Acne
• Alopecia
• Skin ulcer
• Skin exfoliation
• Dermatitis
• Skin lesion
• Skin toxicity
• Scab
• Hypertrichosis
• Onychoclasis
• Nail disorder
• Hyperhidrosis
• Palmar-plantar erythrodysaesthesia syndrome
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Skin necrosis
• Hirsutism
• Ingrowing nail
• Onycholysis
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Pyrexia
• Localised infection 
• Anaemia
• Leucopenia 
• Hypersensitivity
• Anaphylactic reaction 
• Peripheral oedema 
• Chills 
• Infusion-related reaction (See additional prescribing points) 
  - Bronchospasm
  - Angioedema
  - Hypotension
  - Anaphylaxis
  - Chills
  - Fever
  - Dyspnoea 

Sensory Disorders

• Conjunctivitis 
• Eye infection
• Eyelid infection 
• Blepharitis
• Growth of eyelashes
• Increased lacrimation
• Ocular hyperaemia
• Dry eye
• Eye pruritus
• Eye irritation
• Keratitis
  - Ulcerative keratitis
• Eyelid irritation

Others

• Mucosal inflammation
• Pain
  - Pain in extremity 

• Oxaliplatin-containing chemotherapy in patients with mutant RAS mCRC or for whom RAS status unknown
• Irinotecan, bolus 5-fluorouracil, and leucovorin (IFL) chemotherapy
• Bevacizumab-containing chemotherapy

• RAS genotyping of tumour tissue to establish RAS mutation status and confirm RAS wild-type (prior to treatment initiation)
• Electrolytes
  - Magnesium
  - Calcium
  - Potassium
• Temperature (before, during, and after infusion)
• Vital signs (before, during, and after infusion)
• Hepatitis B virus screening 
  - Hepatitis B surface antigen 
  - Hepatitis B core antibody 
  - Total Ig or IgG 
  - Antibody to hepatitis B surface antigen

Additional monitoring 

• Signs and symptoms of ocular toxicity and keratitis
  - Eye inflammation
  - Lacrimation
  - Light sensitivity
  - Blurred vision
  - Eye pain
  - Red eye
• Signs and symptoms of 
  - Skin toxicity  
  - Acute or worsening pulmonary symptoms

Traceability

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

Dermatologic reactions

• Patients who have severe dermatologic reactions or who develop worsening reactions should be monitored for the development of inflammatory or infectious sequelae (including cellulitis and necrotising fasciitis), and appropriate treatment promptly initiated
• Withhold or discontinue in the event of dermatologic toxicity associated with severe or life-threatening inflammatory or infectious complications
• Treatment and management should be based on severity and may include a moisturiser, sunscreen, and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics (e.g. doxycycline). It is also recommended that patients experiencing rash/dermatological toxicities wear sunscreen and hats and limit sun exposure as sunlight can exacerbate any skin reactions that may occur
• Patients may be advised to apply moisturiser and sunscreen to face, hands, feet, neck, back and chest every morning during treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every night during treatment
• Median time to first symptom of dermatologic reaction was 10 days, and the median time to resolution after the last dose was 31 days
• If a patient develops dermatologic reactions that are grade 3 or higher, or that are considered intolerable, see the recommendation for dose modification (See table)

Occurrence of skin symptom(s) ≥grade 3	Administration	Outcome and dose regulation
Initial occurrence	Withhold 1 or 2 doses	Improved (<grade 3): Continuing infusion at 100% of original dose Not recovered: Discontinue
Second occurrence	Withhold 1 or 2 doses	Improved (<grade 3): Continuing infusion at 80% of original dose Not recovered: Discontinue
Third occurrence	Withhold 1 or 2 doses	Improved (<grade 3): Continuing infusion at 60% of original dose Not recovered: Discontinue
Fourth occurrence	Discontinue	N/A

Infusion-related reactions

• A reduction in the rate of infusion of panitumumab may be necessary in cases of infusion-related reactions
  - If a mild or moderate infusion-related reaction, the infusion rate should be reduced for the duration of that infusion. It is recommended to maintain this lower infusion rate in all subsequent infusions
  - If a severe or life-threatening reaction occurs (e.g. presence of bronchospasm, angioedema, need for parenteral treatment, hypotension or anaphylaxis), stop infusion and consider permanent discontinuation
• Infusion-related reactions occuring within 24 hours of infusion, adverse events included abdominal pain, anaphylactic reactions, angioedema, back pain, bronchospasm, cardiorespiratory arrrest, chest pain, chills, cyanosis, dyspnoea, flushing, hypertension, hypotension, pyrexia, tachycardia and vomiting
• Hypersensitivity reactions occurring more than 24 hours after infusion have been reported including a fatal case of angioedema that occurred more than 24 hours after the infusion. Patients should be informed of the possibility of a late onset reaction and instructed to contact their medical practitioner if symptoms of a hypersensitivity reaction occur

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinity and specificity to the human epidermal growth factor receptor (EGFR). EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR (HER1/c-ErbB-1), HER2, HER3, and HER4. EGFR promotes cell growth in normal epithelial tissues, including the skin and hair follicle, and is expressed on a variety of tumour cells. Panitumumab binds to the ligand binding domain of EGFR and inhibits receptor autophosphorylation induced by all known EGFR ligands. Binding of panitumumab to EGFR results in internalisation of the receptor, inhibition of cell growth, induction of apoptosis, and decreased interleukin 8 and vascular endothelial growth factor production.

KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) and NRAS (Neuroblastoma RAS viral oncogene homologue) are highly related members of the RAS oncogene family. KRAS and NRAS genes encode small, GTP-binding proteins involved in signal transduction. A variety of stimuli, including that from the EGFR activate KRAS and NRAS which in turn stimulate other intracellular proteins to promote cell proliferation, cell survival and angiogenesis. Activating mutations in the RAS genes occur frequently in a variety of human tumours and have been implicated in both oncogenesis and tumour progression.

Injection (per 5ml) 100mg

• Vectibix 5ml (Amgen) originator