Erbitux 5mg/ml solution for infusion

To change the ATC Code of cetuximab in section 5.1, from L01XC06 to L01FE01.

Our ref: TW3503659

Amendment of "United Kingdom" with "United Kingdom (Northern Ireland).

TW1735675.

Amendment of "United Kingdom" with "United Kingdom (Northern Ireland).

TW1735675.

Section 4.8 Undesirable effects - how to report a side effect - was updated with the addition of Malta. Internal Ref: TW1230178.

Section 4.4 Special warnings and prcautions for use:
Skin Reaction

Main adverse reactions of cetuximab are skin reactions which may become severe, especially incombination with chemotherapy. The risk for secondary infections (mainly bacterial) is increased andcases of staphylococcal scalded skin syndrome, necrotising fasciitis and sepsis, in some cases withfatal outcome, have been reported (see section 4.8).

If a patient experiences an intolerable or a severe skin reaction (≥ grade 3; US National CancerInstitute - Common Terminology Criteria for Adverse Events, CTCAE), cetuximab therapy must beinterrupted. Treatment may only be resumed if the reaction has resolved to grade 2.

Section 4.8 Undesirable effects
Skin Reaction

Skin reactions may develop in more than 80% of patients and mainly present as acne-like rash and/or,less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail disorders (e.g. paronychia).Approximately 15% of the skin reactions are severe, including single cases of skin necrosis. Themajority of skin reactions develop within the first three weeks of therapy. They generally resolve,without sequelae, over time following cessation of treatment if the recommended adjustments in doseregimen are followed (see section 4.4).Skin lesions induced by cetuximab may predispose patients to superinfections (e.g. with S. aureus),which may lead to subsequent complications, e.g. cellulitis, erysipelas, or, potentially with fataloutcome, staphylococcal scalded skin syndrome, necrotising fasciitis or sepsis.

Throughout SPC:

was ml now mL

4.8 Undesirable effects

General disorders and administration site conditions

Very common: Mild or moderate infusion-related reactions*; mucositis, in some cases severe. Mucositis may lead to epistaxis.

Common: Severe infusion-related reactions*, fatigue.

10. DATE OF REVISION OF THE TEXT

01/2013

There are minor editorial changes in sections 2 and 3 of the SPC.

The main change is the update of the 5-year overall survival data in study EMR 62 202-006 in section 5.1. This is shown as follows by the red text:

     

(Changes highlighted in red)
4.1          Therapeutic indications

Erbitux is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer

·                in combination with irinotecan-based chemotherapy,

·                in first-line in combination with FOLFOX,

·                as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.

For details, see section 5.1.

Erbitux is indicated for the treatment of patients with squamous cell cancer of the head and neck

·                in combination with radiation therapy for locally advanced disease,

·                in combination with platinum-based chemotherapy for recurrent and/or metastatic disease.

4.2          Posology and method of administration

Colorectal cancer

In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy or as a single agent (see section 5.1). Wild-type KRAS tumour status must be verified prior to the first cetuximab infusion. It is important that a validated test method is used by an experienced laboratory (see section 4.4 and 5.1).

Paediatric population

The efficacy of cetuximab in paediatric patients below the age of 18 years has not been established. No new safety signals were identified in paediatric patients as reported from a phase‑I study.

There is no relevant use of cetuximab in the paediatric population in the granted indications.

4.3          Contraindications

Erbitux is contraindicated in patients with known severe (grade 3 or 4) hypersensitivity reactions to cetuximab.

The combination of Erbitux with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant KRAS metastatic colorectal cancer (mCRC) or for whom KRAS mCRC status is unknown (see also section 4.4).

Before initiation of combination treatment, contraindications for concomitantly used chemotherapeutic agents or radiation therapy must be considered.

4.4          Special warnings and precautions for use

Skin reactions 

(New paragraph added)
Skin reactions are very common and treatment interruption or discontinuation may be required. According to clinical practice guidelines prophylactic use of oral tetracyclines (6 ‑ 8 weeks) and topical application of 1% hydrocortisone cream with moisturiser should be considered. Medium to high-potency topical corticosteroids or oral tetracyclines have been used for the treatment of skin reactions.

If a patient........

Colorectal cancer patients with KRAS mutated tumours

Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have KRAS mutations or for whom KRAS tumour status is unknown. Results from clinical studies show a negative benefit-risk balance in tumours with KRAS mutations. In particular, in these patients negative effects on progression-free survival (PFS) and overall survival (OS) were seen as add-on to FOLFOX4 (see section 5.1).

Similar findings were also reported when cetuximab was given as add-on to XELOX in combination with bevacizumab (CAIRO2). However, in this study no positive effects on PFS or OS were demonstrated in patients with KRAS wild‑type tumours, either.

5.1          Pharmacodynamic properties

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with cetuximab in all subsets of the paediatric population in the indications adenocarcinoma of the colon and rectum and oropharyngeal, laryngeal or nasal epithelial carcinoma (excluding nasopharyngeal carcinoma or lymphoepithelioma, see section 4.2 for information on paediatric use).

10.          DATE OF REVISION OF THE TEXT

01/2012

In Section 4.4 under the heading of Respiratory disorders the test now reads:
"Cases of interstitial lung disease have been reported, with the majority of patients from the Japanese population. If interstitial lung disease is diagnosed, cetuximab must be discontinued and the patient be treated appropriately".

An additional paragraph is added under Eye disorders:
"Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. 

If a diagnosis of ulcerative keratitis is confirmed, treatment with cetuximab should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered.

Cetuximab should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration".

Under Section 4.8 - Respiratory, thoracic and mediastinal disorders - now reads:

Respiratory, thoracic and mediastinal disorders

Uncommon:              Pulmonary embolism, interstitial lung disease.

Under heading Skin and subcutaneous tissue diosrders - now reads:
Very common:          Skin reactions*
Very rare:                 Stevens-Johnson syndrome/toxic epidermal necrolysis.
Frequency not known: Superinfection of skin lesions*.

Fertility, pregnancy and lactation

4.8       Undesirable effects

The main undesirable effects of cetuximab are skin reactions, which occur in more than 80% of patients, hypomagnesaemia which occurs in more than 10% of patients and infusion-related reactions, which occur with mild to moderate symptoms in more than 10% of patients and with severe symptoms in more than 1% of patients.

The following definitions apply to the frequency terminology used hereafter:

Very common (³ 1/10)

Common (³ 1/100 to < 1/10)

Uncommon (³ 1/1,000 to < 1/100)

Rare (³ 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Frequency not known (cannot be estimated from the available data)

An asterisk (*) indicates that additional information on the respective undesirable effect is provided below the table.

Metabolism and nutrition disorders

Very common:          Hypomagnesaemia (see section 4.4).

Common:                  Dehydration, in particular secondary to diarrhoea or mucositis; hypocalcaemia (see section 4.4); anorexia which may lead to weight decrease.

Nervous system disorders

Common:                  Headache.

Frequency not known: Aseptic meningitis.

Eye disorders

Common:                  Conjunctivitis.

Uncommon:              Blepharitis, keratitis.

Vascular disorders

Uncommon:              Deep vein thrombosis.

Respiratory, thoracic and mediastinal disorders

Uncommon:              Pulmonary embolism.

Gastrointestinal disorders

Common:                  Diarrhoea, nausea, vomiting.

Hepatobiliary disorders

Very common:          Increase in liver enzyme levels (ASAT, ALAT, AP).

Skin and subcutaneous tissue disorders

Very common:          Skin reactions*.

Frequency not known: Superinfection of skin lesions*.

General disorders and administration site conditions

Very common:          Mild or moderate infusion-related reactions*; mild to moderate mucositis which may lead to epistaxis.

Common:                  Severe infusion-related reactions*, fatigue.

Additional information

Overall, no clinically relevant difference between genders was observed.

Infusion-related reactions

Mild or moderate infusion-related reactions are very common comprising symptoms such as fever, chills, dizziness, or dyspnoea that occur in a close temporal relationship mainly to the first cetuximab infusion.

Severe infusion-related reactions may commonly occur, in rare cases with fatal outcome. They usually develop during or within 1 hour of the initial cetuximab infusion, but may occur after several hours or with subsequent infusions. Although the underlying mechanism has not been identified, some of these reactions may be anaphylactoid/anaphylactic in nature and may include symptoms such as bronchospasm, urticaria, increase or decrease in blood pressure, loss of consciousness or shock. In rare cases, angina pectoris, myocardial infarction or cardiac arrest have been observed.

For clinical management of infusion-related reactions, see section 4.4.

Skin reactions

Skin reactions may develop in more than 80% of patients and mainly present as acne-like rash and/or, less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail disorders (e.g. paronychia). Approximately 15% of the skin reactions are severe, including single cases of skin necrosis. The majority of skin reactions develop within the first three weeks of therapy. They generally resolve, without sequelae, over time following cessation of treatment if the recommended adjustments in dose regimen are followed (see section 4.4).

Skin lesions induced by cetuximab may predispose patients to superinfections (e.g. with S. aureus), which may lead to subsequent complications, e.g. cellulitis, erysipelas, or, potentially with fatal outcome, staphylococcal scalded skin syndrome or sepsis.

Combination treatment

When cetuximab is used in combination with chemotherapeutic agents, also refer to their respective product information.

In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severe neutropenia may be increased, and thus may lead to a higher rate of infectious complications such as febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see section 4.4).

In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardial infarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantar erythrodysaesthesia) were increased compared to that with fluoropyrimidines.

In combination with local radiation therapy of the head and neck area, additional undesirable effects were those typical of radiation therapy (such as mucositis, radiation dermatitis, dysphagia or leukopenia, mainly presenting as lymphocytopenia). In a randomised controlled clinical study with 424 patients, reporting rates of severe acute radiation dermatitis and mucositis as well as of late radiation-therapy-related events were slightly higher in patients receiving radiation therapy in combination with cetuximab than in those receiving radiation therapy alone.

4.2 Posology and method of administration

Colorectal cancer

In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy or

as a single agent (see section 5.1). Detection of KRAS mutational status must be performed prior to

the first cetuximab infusion. It is important that a validated test method is used by an experienced

laboratory (see section 4.4 and 5.1).It is recommended that the detection of KRAS mutational status be

performed by an experienced laboratory using a validated test method.

4.4 Special warnings and precautions for use

Cardiovascular disorders

An increased frequency of severe and sometimes fatal cardiovascular events and treatment emergent

deaths has been observed in the treatment of non-small cell lung cancer, squamous cell carcinoma of

the head and neck and colorectal carcinoma. In some studies (non-small cell lung cancer) association

with age ≥ 65 years has been observed. When prescribing cetuximab, the cardiovascular status of the

patients and concomitant administration of cardiotoxic compounds such as fluoropyrimidines should

be taken into account.

Colorectal cancer patients with KRAS mutated tumours

Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have

KRAS mutations or for whom KRAS tumour status is unknown. Results from clinical studies show a

negative benefit-risk balance in tumours with KRAS mutations.

4.5 Interaction with other medicinal products and other forms of interaction

In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severe

neutropenia may be increased, and thus may lead to a higher rate of infectious complications such as

febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see

section 4.4).

In combination with fluoropyrimidinesinfusional 5-fluorouracil, the frequency of cardiac ischaemia

including myocardial infarction and congestive heart failure as well as the frequency of hand-foot

syndrome (palmar-plantar erythrodysaesthesia) were increased compared to that with

fluoropyrimidinesinfusional 5-fluorouracil.

4.8 Undesirable effects

Combination treatment

When cetuximab is used in combination with chemotherapeutic agents, also refer to their respective

product information.

In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severe

neutropenia may be increased, and thus may lead to a higher rate of infectious complications such as

febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see

section 4.4).

In combination with fluoropyrimidinesinfusional 5-fluorouracil, the frequency of cardiac ischaemia

including myocardial infarction and congestive heart failure as well as the frequency of hand-foot

syndrome (palmar-plantar erythrodysaesthesia) were increased compared to that with

fluoropyrimidinesinfusional 5-fluorouracil.

5.1 Pharmacodynamic properties

The KRAS status was recognised as predictive factor for the treatment with cetuximab in 4 of the randomised controlled studies. KRAS mutational status was available for 1261 2072 patients. Only in study EMR 62 202-007, an analysis was not possible.

Table amended in section 5.1 also.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

of 10 ml contains 50 mg cetuximab.

Severe infusion-related reactions may commonly occur, in rare cases with fatal outcome. They usually develop during or within 1 hour of the initial cetuximab infusion, but may occur after several hours or with subsequent infusions. Although the underlying mechanism has not been identified, some of these reactions may be anaphylactoid/anaphylactic in nature and may include symptoms such as bronchospasm, urticaria, hypotension increase or decrease in blood pressure, loss of consciousness or shock. In rare cases, angina pectoris, myocardial infarction or cardiac arrest have been observed.

4.       Clinical particulars

4.1     Therapeutic indications

Erbitux is indicated for the treatment of patients with squamous cell cancer of the head and neck

                in combination with radiation therapy for locally advanced disease

                in combination with platinum-based chemotherapy for recurrent and/or metastatic disease.

Chemical and physical in-use stability of Erbitux 5 mg/ml has been demonstrated for 48 hours at 25°C, if the solution is prepared as described in section 6.6.