VECTIBIX 20 MGML

Israel - English - Ministry of Health

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Active ingredient:
PANITUMUMAB
Available from:
AMGEN EUROPE B.V.
ATC code:
L01XC08
Pharmaceutical form:
CONCENTRATE FOR SOLUTION FOR INFUSION
Composition:
PANITUMUMAB 20 MG / 1 ML
Administration route:
I.V. INFUSION
Prescription type:
Required
Manufactured by:
AMGEN EUROPE B.V., NETHERLANDS
Therapeutic area:
PANITUMUMAB
Therapeutic indications:
In combination with chemotherapy for the treatment of unresectable, advanced or recurrent colorectal cancer (mCRC) with wild-type RAS.Monotherapy for the treatment of patients with metastatic colorectal carcinoma with wild-type RAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
Authorization number:
142 92 32951 00
Authorization date:
2015-02-28

לירפא

8

201

ml

mg/

20

)

anitumumab

P

(

VECTIBIX

Concentrate for solution for infusion

,ה/דבכנ ת/חקור ,ה/דבכנ ה/אפור

לע ךעידוהל תשקבמ ,םושירה תלעב ,יו יב הפוריא ן'גמא ולעב םינוכדע אפורל ן

רישכתל סקיביטקו

דבלב הרמחה םיווהמה םייונישה םיניוצמ וז העדוהב

:תורשואמה תויוותהה

In combination with chemotherapy for the treatment of unresectable, advanced or

recurrent

colorectal cancer (mCRC) with wild-type RAS.

Monotherapy for the treatment of patients with metastatic colorectal carcinoma with

wild-type

RAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing

chemotherapy

regimens.

:אפורל ןולעב תורמחה

4.8

Undesirable effects

….

Tabulated summary of adverse reactions

The data in the table below describe adverse reactions reported from clinical studies in

patients with mCRC who received panitumumab as a single agent or in combination with

chemotherapy (n = 2,224) and spontaneous reporting. Within each frequency grouping,

undesirable effects are presented in order of decreasing seriousness.

Adverse reactions

MedDRA system

organ class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to< 1/100)

Infections and

infestations

Conjunctivitis

Paronychia

Rash pustular

Cellulitis

Urinary tract infection

Folliculitis

Localized infection

Eye infection

Eyelid infection

Blood and

lymphatic system

disorders

Anemia

Leukopenia

Immune system

disorders

Hypersensitivity

Anaphylactic reaction

Metabolism and

nutrition

disorders

Hypokalemia

Hypomagnesemia

Decreased appetite

Hypocalcemia

Dehydration

Hyperglycemia

Hypophosphatemia

Psychiatric

disorders

Insomnia

Anxiety

Adverse reactions

MedDRA system

organ class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to< 1/100)

Nervous system

disorders

Headache

Dizziness

Eye disorders

Blepharitis

Growth of eyelashes

Lacrimation increased

Ocular hyperemia

Dry eye

Eye pruritus

Eye irritation

Ulcerative keratitis

Keratitis

Eyelid irritation

Cardiac disorders

Tachycardia

Cyanosis

Vascular

disorders

Deep vein thrombosis

Hypotension

Hypertension

Flushing

Respiratory,

thoracic and

mediastinal

disorders

Dyspnea

Cough

Pulmonary embolism

Epistaxis

Interstitial lung disease

Bronchospasm

Nasal dryness

Gastrointestinal

disorders

Diarrhea

Nausea

Vomiting

Abdominal pain

Stomatitis

Constipation

Rectal hemorrhage

Dry mouth

Dyspepsia

Aphthous ulcer

Cheilitis

Gastroesophageal reflux

disease

Chapped lips

Dry lips

Skin and

subcutaneous

tissue disorders

Dermatitis acneiform

Rash

Erythema

Pruritus

Dry skin

Skin fissures

Acne

Alopecia

Skin ulcer

Skin exfoliation

Exfoliative rash

Dermatitis

Rash papular

Rash pruritic

Rash erythematous

Rash generalized

Rash macular

Rash maculo-papular

Skin lesion

Skin toxicity

Scab

Hypertrichosis

Onychoclasis

Nail disorder

Hyperhidrosis

Palmar-plantar

erythrodysesthesia

syndrome

Toxic epidermal necrolysis

Stevens-Johnson syndrome

Skin necrosis

Angioedema

Hirsutism

Ingrowing nail

Onycholysis

Adverse reactions

MedDRA system

organ class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to< 1/100)

Musculoskeletal

and connective

tissue disorders

Back pain

Pain in extremity

General disorders

administration

site conditions

Fatigue

Pyrexia

Asthenia

Mucosal

inflammation

Edema peripheral

Chest pain

Pain

Chills

Injury, poisoning

and procedural

complications

Infusion-related reaction

Investigations

Weight decreased

Blood magnesium

decreased

See section “Description of selected adverse reactions” below

See section 4.4 Infusion-related reactions

See section 4.4 Pulmonary complications

Ulcerative keratitis, skin necrosis, Stevens-Johnson syndrome and toxic epidermal necrolysis are

panitumumab ADRs that were reported in the post-marketing setting. For these ADRs the maximum

frequency category was estimated from the upper limit of 95% confidence interval for the point

estimate based on regulatory guidelines for estimation of the frequency of adverse reactions from

spontaneous reporting. The maximum frequency estimated from the upper limit of 95% confidence

interval for the point estimate, i.e., 3/2244 (or 0.13%).

פורל ןולעה ולבקל ןתינו ,תואירבה דרשמ רתאש תופורתה רגאמב םוסרפל חלשנ ןכדועמה א םג

לע

ץיפמל הינפ ידי

תרבח ,הפורתה לש ימוקמ ןוסידמ

.המראפ

:תוחוקל תורש

CS@medison.co.il

Medison

ןופלט

*5634

רבב הכ

רוד ןב לגיס

הנוממ תחקור

The content of this leaflet was approved by the Ministry of Health in July 2015, and updated

according to the guidelines of the Ministry of Health in November 2019.

1.

NAME OF THE MEDICINAL PRODUCT

Vectibix 20 mg/mL concentrate for solution for infusion.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of concentrate contains 20 mg panitumumab.

Each vial contains either 100 mg of panitumumab in 5 mL, or 400 mg of panitumumab in 20 mL.

When prepared according to the instructions given in section 6.6, the final panitumumab concentration

should not exceed 10 mg/mL.

Panitumumab is a fully human monoclonal IgG2 antibody produced in a mammalian cell line (CHO)

by recombinant DNA technology.

Excipient with known effect

Each mL of concentrate contains 0.150 mmol sodium, which is 3.45 mg sodium.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Colorless, pH 5.6 to 6.0 solution that may contain translucent-to-white, visible amorphous,

proteinaceous panitumumab particles.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

In combination with chemotherapy for the treatment of unresectable, advanced or recurrent colorectal

cancer (mCRC) with wild-type

RAS.

Monotherapy for the treatment of patients with metastatic colorectal carcinoma with wild-type

RAS

after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

4.2

Posology and method of administration

Vectibix treatment should be supervised by a physician experienced in the use of anti-cancer therapy.

Evidence of wild-type

RAS

KRAS

NRAS

) status is required before initiating treatment with

Vectibix. 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.

Posology

The recommended dose of Vectibix is 6 mg/kg of body weight given once every two weeks. Prior to

infusion, Vectibix should be diluted in sodium chloride 9 mg/mL (0.9%) solution for injection to a

final concentration not to exceed 10 mg/mL (for preparation instructions see section 6.6).

Modification of the dose of Vectibix may be necessary in cases of severe (≥ grade 3) dermatological

reactions (see section 4.4).

Special populations

The safety and efficacy of Vectibix have not been studied in patients with renal or hepatic impairment.

There is no clinical data to support dose adjustments in the elderly.

Pediatric population

There is no relevant use of Vectibix in the pediatric population in the indication treatment of colorectal

cancer.

Method of administration

Vectibix must be administered as an intravenous infusion via an infusion pump, using a low protein

binding 0.2 or 0.22 micrometer in-line filter, through a peripheral line or indwelling catheter. The

recommended infusion time is approximately 60 minutes. If the first infusion is tolerated, then

subsequent infusions may be administered over 30 to 60 minutes. Doses higher than 1,000 mg should

be infused over approximately 90 minutes (for handling instructions, see section 6.6).

The infusion line should be flushed with sodium chloride solution before and after Vectibix

administration to avoid mixing with other medicinal products or intravenous solutions.

A reduction in the rate of infusion of Vectibix may be necessary in cases of infusion-related reactions

(see section 4.4).

Vectibix must not be administered as an intravenous push or bolus.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3

Contraindications

Patients with a history of severe or life-threatening hypersensitivity to the active substance or to any of

the excipients listed in section 6.1 (see section 4.4).

Patients with interstitial pneumonitis or pulmonary fibrosis (see section 4.4).

The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patients

with mutant

RAS

mCRC or for whom

RAS

mCRC status is unknown (see section 4.4).

4.4

Special warnings and precautions for use

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 and soft tissue toxicity

Dermatologic related reactions, a pharmacologic effect observed with epidermal growth factor

receptor (EGFR) inhibitors, are experienced with nearly all patients (approximately 94%) treated with

Vectibix. Severe (NCI-CTC grade 3) skin reactions were reported in 23% and life-threatening

(NCI-CTC grade 4) skin reactions in < 1% of patients who received Vectibix monotherapy and in

combination with chemotherapy (n = 2,224) (see section 4.8). If a patient develops dermatologic

reactions that are grade 3 (CTCAE v 4.0) or higher, or that are considered intolerable, the following

dose modification is recommended:

Occurrence of

skin symptom(s):

≥ grade 3

1

Administration

of Vectibix

Outcome

Dose regulation

Initial occurrence

Withhold 1 or 2

doses

Improved (< grade 3)

Continuing infusion at

100% of original dose

Not recovered

Discontinue

At the second

occurrence

Withhold 1 or 2

doses

Improved (< grade 3)

Continuing infusion at 80%

of original dose

Not recovered

Discontinue

At the third

occurrence

Withhold 1 or 2

doses

Improved (< grade 3)

Continuing infusion at 60%

of original dose

Not recovered

Discontinue

At the fourth

occurrence

Discontinue

Greater than or equal to grade 3 is defined as severe or life-threatening

In clinical studies, subsequent to the development of severe dermatologic reactions (including

stomatitis), infectious complications including sepsis and necrotizing fasciitis, in rare cases leading to

death, and local abscesses requiring incisions and drainage were reported. Patients who have severe

dermatologic reactions or soft tissue toxicity or who develop worsening reactions whilst receiving

Vectibix should be monitored for the development of inflammatory or infectious sequelae (including

cellulitis and necrotizing fasciitis), and appropriate treatment promptly initiated. Life-threatening and

fatal infectious complications including necrotizing fasciitis and sepsis have been observed in patients

treated with Vectibix. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have

been reported in patients treated with Vectibix in the post-marketing setting

Withhold or discontinue

Vectibix in the event of dermatologic or soft tissue toxicity associated with severe or life-threatening

inflammatory or infectious complications.

Treatment and management of dermatologic reactions should be based on severity and may include a

moisturizer, sunscreen (SPF > 15 UVA and UVB), 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 moisturizer 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.

Pulmonary complications

Patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded

from clinical studies. Cases of Interstitial Lung Disease (ILD), both fatal and non-fatal, have been

reported, mainly from the Japanese population. In the event of acute onset or worsening pulmonary

symptoms, Vectibix treatment should be interrupted and a prompt investigation of these symptoms

should occur. If ILD is diagnosed, Vectibix should be permanently discontinued and the patient should

be treated appropriately. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, the

benefits of therapy with panitumumab versus the risk of pulmonary complications must be carefully

considered.

Electrolyte disturbances

Progressively decreasing serum magnesium levels leading to severe (grade 4) hypomagnesemia have

been observed in some patients. Patients should be periodically monitored for hypomagnesemia and

accompanying hypocalcemia prior to initiating Vectibix treatment, and periodically thereafter for up to

8 weeks after the completion of treatment (see section 4.8). Magnesium repletion is recommended, as

appropriate.

Other electrolyte disturbances, including hypokalemia, have also been observed. Monitoring as above

and repletion as appropriate of these electrolytes is also recommended.

Infusion-related reactions

Across monotherapy and combination mCRC clinical studies (n = 2,224), infusion-related reactions

(occurring within 24 hours of an infusion) were reported in Vectibix-treated patients, including severe

infusion-related reactions (NCI-CTC grade 3 and grade 4).

In the post-marketing setting, serious infusion-related reactions have been reported, including rare

post-marketing reports with a fatal outcome. If a severe or life-threatening reaction occurs during an

infusion or at any time post-infusion [e.g. presence of bronchospasm, angioedema, hypotension, need

for parenteral treatment, or anaphylaxis], Vectibix should be permanently discontinued (see sections

4.3 and 4.8).

In patients experiencing a mild or moderate (CTCAE v 4.0 grades 1 and 2) 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.

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 physician if

symptoms of a hypersensitivity reaction occur.

Acute renal failure

Acute renal failure has been observed in patients who develop severe diarrhea and dehydration.

Patients who experience severe diarrhea should be instructed to consult a healthcare professional

urgently.

Vectibix in combination with irinotecan, bolus 5-fluorouracil, and leucovorin (IFL) chemotherapy

Patients receiving Vectibix in combination with the IFL regimen [bolus 5-fluorouracil (500 mg/m

leucovorin (20 mg/m

) and irinotecan (125 mg/m

)] experienced a high incidence of severe diarrhea

(see section 4.8). Therefore administration of Vectibix in combination with IFL should be avoided (see

section 4.5).

Vectibix in combination with bevacizumab and chemotherapy regimens

Shortened progression-free survival time and increased deaths were observed in the patients receiving

Vectibix in combination with bevacizumab and chemotherapy. A greater frequency of pulmonary

embolism, infections (predominantly of dermatologic origin), diarrhea, electrolyte imbalances, nausea,

vomiting and dehydration was also observed in the treatment arms using Vectibix in combination with

bevacizumab and chemotherapy. Vectibix should not be administered in combination with

bevacizumab-containing chemotherapy (see sections 4.5 and 5.1).

Vectibix in combination with oxaliplatin-based chemotherapy in patients with mutant

RAS

mCRC or

for whom

RAS

tumor status is unknown

The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patients

with mutant

RAS

mCRC or for whom

RAS

mCRC status is unknown (see sections 4.3 and 5.1).

A shortened progression-free survival (PFS) and overall survival (OS) time were observed in patients

with mutant

KRAS

(exon 2) tumors and additional

RAS

mutations (

KRAS

[exons 3 and 4] or

NRAS

[exons 2, 3, 4]) who received panitumumab in combination with infusional 5-fluorouracil, leucovorin,

and oxaliplatin (FOLFOX) versus FOLFOX alone ( see section 5.1).

RAS

mutational

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

laboratory (see section 4.2). If Vectibix is to be used in combination with FOLFOX then it is

recommended that mutational status be determined by a laboratory that participates in a

RAS

External

Quality Assurance program or wild-type status be confirmed in a duplicate test.

Ocular toxicities

Serious cases of keratitis and ulcerative keratitis have been rarely reported in the post-marketing

setting. 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 Vectibix should be interrupted or

discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be

carefully considered.

Vectibix 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.

Patients with ECOG 2 performance status treated with Vectibix in combination with chemotherapy

For patients with ECOG 2 performance status, assessment of benefit-risk is recommended prior to

initiation of Vectibix in combination with chemotherapy for treatment of mCRC. A positive

benefit-risk balance has not been documented in patients with ECOG 2 performance status.

Elderly patients

No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age)

treated with Vectibix monotherapy. However, an increased number of serious adverse reactions were

reported in elderly patients treated with Vectibix in combination with FOLFIRI or FOLFOX

chemotherapy compared to chemotherapy alone (see section 4.8).

Warnings for excipients

This medicinal product contains 3.45 mg sodium per mL, equivalent to 0.017% of the WHO

recommended maximum daily intake of 2 g sodium for an adult.

4.5

Interaction with other medicinal products and other forms of interaction

Data from an interaction study involving Vectibix and irinotecan in patients with mCRC indicated that

the pharmacokinetics of irinotecan and its active metabolite, SN-38, are not altered when the

medicinal products are co-administered. Results from a cross-study comparison indicated that

irinotecan-containing regimens (IFL or FOLFIRI) have no effect on the pharmacokinetics of

panitumumab.

Vectibix should not be administered in combination with IFL chemotherapy or with

bevacizumab-containing chemotherapy. A high incidence of severe diarrhea was observed when

panitumumab was administered in combination with IFL (see section 4.4), and increased toxicity and

deaths were seen when panitumumab was combined with bevacizumab and chemotherapy (see

sections 4.4 and 5.1).

The combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patients

with mutant

RAS

mCRC or for whom

RAS

mCRC status is unknown. A shortened progression-free

survival and overall survival time were observed in a clinical study in patients with mutant

RAS

tumors who received panitumumab and FOLFOX (see sections 4.4 and 5.1).

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Vectibix in pregnant women. Studies in animals have

shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. EGFR has

been implicated in the control of pre-natal development and may be essential for normal

organogenesis, proliferation, and differentiation in the developing embryo. Therefore, Vectibix has the

potential to cause fetal 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 fetus. In women of childbearing potential, appropriate contraceptive

measures must be used during treatment with Vectibix, and for 2 months following the last dose. If

Vectibix is 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

fetus.

Breast-feeding

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 breast-feed during treatment

with Vectibix 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 (see section 5.3). Panitumumab may impact the ability of a woman to become pregnant.

4.7

Effects on ability to drive and use machines

Vectibix may have a minor influence on the ability to drive and use machines. If patients experience

treatment-related symptoms affecting their vision and/or ability to concentrate and react, it is

recommended that they do not drive or use machines until the effect subsides.

4.8

Undesirable effects

Summary of safety profile

Based on an analysis of all mCRC clinical trial patients receiving Vectibix monotherapy and in

combination with chemotherapy (n = 2,224), the most commonly reported adverse reactions are skin

reactions occurring in approximately 94% of patients. These reactions are related to the pharmacologic

effects of Vectibix, and the majority are mild to moderate in nature with 23% severe (grade 3

NCI-CTC) and < 1% life-threatening (grade 4 NCI-CTC). For clinical management of skin reactions,

including dose modification recommendations, see section 4.4.

Very commonly reported adverse reactions occurring in ≥ 20% of patients were gastrointestinal

disorders [diarrhea (46%), nausea (39%), vomiting (26%), constipation (23%) and abdominal pain

(23%)]; general disorders [fatigue (35%), pyrexia (21%)]; metabolism and nutrition disorders

[decreased appetite (30%)]; infections and infestations [paronychia (20%)]; and skin and subcutaneous

disorders [rash (47%), dermatitis acneiform (39%), pruritus (36%), erythema (33%) and dry skin

(21%)].

Tabulated list of adverse reactions

The data in the table below describe adverse reactions reported from clinical studies in patients with

mCRC who received panitumumab as a single agent or in combination with chemotherapy (n = 2,224)

and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order

of decreasing seriousness.

Adverse reactions

MedDRA system organ

class

Very common

(≥ 1/10)

Common

(≥ 1/100 to <

1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Infections and

infestations

Conjunctivitis

Paronychia

Rash pustular

Cellulitis

Urinary tract infection

Folliculitis

Localized infection

Eye infection

Eyelid infection

Blood and lymphatic

system disorders

Anemia

Leukopenia

Immune system

disorders

Hypersensitivity

Anaphylactic reaction

Metabolism and

nutrition disorders

Hypokalemia

Hypomagnesemia

Decreased appetite

Hypocalcemia

Dehydration

Hyperglycemia

Hypophosphatemia

Psychiatric disorders

Insomnia

Anxiety

Nervous system

disorders

Headache

Dizziness

Eye disorders

Blepharitis

Growth of eyelashes

Lacrimation increased

Ocular hyperemia

Dry eye

Eye pruritus

Eye irritation

Ulcerative keratitis

Keratitis

Eyelid irritation

Cardiac disorders

Tachycardia

Cyanosis

Vascular disorders

Deep vein thrombosis

Hypotension

Hypertension

Flushing

Respiratory, thoracic and

mediastinal disorders

Dyspnea

Cough

Pulmonary embolism

Epistaxis

Interstitial lung disease

Bronchospasm

Nasal dryness

Gastrointestinal

disorders

Diarrhea

Nausea

Vomiting

Abdominal pain

Stomatitis

Constipation

Rectal hemorrhage

Dry mouth

Dyspepsia

Aphthous ulcer

Cheilitis

Gastroesophageal reflux

disease

Chapped lips

Dry lips

Adverse reactions

MedDRA system organ

class

Very common

(≥ 1/10)

Common

(≥ 1/100 to <

1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Skin and subcutaneous

tissue disorders

Dermatitis acneiform

Rash

Erythema

Pruritus

Dry skin

Skin fissures

Acne

Alopecia

Skin ulcer

Skin exfoliation

Exfoliative rash

Dermatitis

Rash papular

Rash pruritic

Rash erythematous

Rash generalized

Rash macular

Rash maculo-papular

Skin lesion

Skin toxicity

Scab

Hypertrichosis

Onychoclasis

Nail disorder

Hyperhidrosis

Palmar-plantar

erythrodysesthesia syndrome

Toxic epidermal necrolysis

Stevens-Johnson syndrome

Skin necrosis

Angioedema

Hirsutism

Ingrowing nail

Onycholysis

Musculoskeletal and

connective tissue

disorders

Back pain

Pain in extremity

General disorders and

administration site

conditions

Fatigue

Pyrexia

Asthenia

Mucosal inflammation

Edema peripheral

Chest pain

Pain

Chills

Injury, poisoning and

procedural

complications

Infusion-related reaction

Investigations

Weight decreased

Blood magnesium decreased

See section “Description of selected adverse reactions” below

See section 4.4 Infusion-related reactions

See section 4.4 Pulmonary complications

Ulcerative keratitis, skin necrosis, Stevens-Johnson syndrome and toxic epidermal necrolysis are panitumumab

ADRs that were reported in the post-marketing setting. For these ADRs the maximum frequency category was

estimated from the upper limit of 95% confidence interval for the point estimate based on regulatory guidelines

for estimation of the frequency of adverse reactions from spontaneous reporting. The maximum frequency

estimated from the upper limit of 95% confidence interval for the point estimate, i.e., 3/2,224 (or 0.13%).

The safety profile of Vectibix in combination with chemotherapy consisted of the reported adverse

reactions of Vectibix (as a monotherapy) and the toxicities of the background chemotherapy regimen.

No new toxicities or worsening of previously recognized toxicities beyond the expected additive

effects were observed. Skin reactions were the most frequently occurring adverse reactions in patients

receiving panitumumab in combination with chemotherapy. Other toxicities that were observed with a

greater frequency relative to monotherapy included hypomagnesemia, diarrhea, and stomatitis. These

toxicities infrequently led to discontinuation of Vectibix or of chemotherapy.

Description of selected adverse reactions

Gastrointestinal disorders

Diarrhea when reported was mainly mild or moderate in severity. Severe diarrhea (NCI-CTC grade 3

and 4) was reported in 2% of patients treated with Vectibix as a monotherapy and in 16% of patients

treated with Vectibix in combination with chemotherapy.

There have been reports of acute renal failure in patients who develop diarrhea and dehydration (see

section 4.4).

Infusion-related reactions

Across monotherapy and combination mCRC clinical studies (n = 2,224), infusion-related reactions

(occurring within 24 hours of any infusion), which may include symptoms/signs such as chills, fever

or dyspnea, were reported in approximately 5% of Vectibix-treated patients, of which 1% were severe

(NCI-CTC grade 3 and grade 4).

A case of fatal angioedema occurred in a patient with recurrent and metastatic squamous cell

carcinoma of the head and neck treated with Vectibix in a clinical trial. The fatal event occurred after

re-exposure following a prior episode of angioedema; both episodes occurred greater than 24 hours

after administration (see sections 4.3 and 4.4). Hypersensitivity reactions occurring more than

24 hours after infusion have also been reported in the post-marketing setting.

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

Skin and subcutaneous tissue disorders

Skin rash most commonly occurred on the face, upper chest, and back, but could extend to the

extremities. Subsequent to the development of severe skin and subcutaneous reactions, infectious

complications including sepsis, in rare cases leading to death, cellulitis and local abscesses requiring

incisions and drainage were reported. The median time to first symptom of dermatologic reaction was

10 days, and the median time to resolution after the last dose of Vectibix was 31 days.

Paronychial inflammation was associated with swelling of the lateral nail folds of the toes and fingers.

Dermatological reactions (including nail effects), observed in patients treated with Vectibix or other

EGFR inhibitors, are known to be associated with the pharmacologic effects of therapy.

Across all clinical trials, skin reactions occurred in approximately 94% of patients receiving Vectibix

as monotherapy or in combination with chemotherapy (n = 2,224). These events consisted

predominantly of rash and dermatitis acneiform and were mostly mild to moderate in severity. Severe

(NCI-CTC grade 3) skin reactions were reported in 23% and life-threatening (NCI-CTC grade 4) skin

reactions in < 1% of patients. Life-threatening and fatal infectious complications including necrotizing

fasciitis and sepsis have been observed in patients treated with Vectibix (see section 4.4).

For clinical management of dermatological reactions, including dose modification recommendations,

see section 4.4.

In the post-marketing setting, rare cases of skin necrosis, Stevens-Johnson syndrome and toxic

epidermal necrolysis (see section 4.4) have been reported.

Ocular toxicities

Non-serious cases of keratitis have been observed in 0.3% of clinical trial patients. In the

post-marketing setting, serious cases of keratitis and ulcerative keratitis have been rarely reported (see

section 4.4).

Other special populations

No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age)

treated with Vectibix monotherapy. However, an increased number of serious adverse events were

reported in elderly patients treated with Vectibix in combination with FOLFIRI (45% versus 32%) or

FOLFOX (52% versus 37%) chemotherapy compared to chemotherapy alone (see section 4.4). The

most increased serious adverse events included diarrhea in patients treated with Vectibix in

combination with either FOLFOX or FOLFIRI, and dehydration and pulmonary embolism when

patients were treated with Vectibix in combination with FOLFIRI.

The safety of Vectibix has not been studied in patients with renal or hepatic impairment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected

adverse events should be reported to the Ministry of Health according to the National Regulation by

using an online form

https://sideeffects.health.gov.il./

4.9

Overdose

Doses up to 9 mg/kg have been tested in clinical trials. There have been reports of overdose at doses

up to approximately twice the recommended therapeutic dose (12 mg/kg). Adverse events observed

included skin toxicity, diarrhea, dehydration and fatigue and were consistent with the safety profile at

the recommended dose.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC08

Mechanism of action

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high-affinity

and specificity to the human 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 tumor 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 internalization 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

NRAS

genes encode small, GTP-binding proteins involved in signal transduction. A variety of stimuli,

including that from the EGFR activate

KRAS

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 tumors and have been

implicated in both oncogenesis and tumor progression.

Pharmacodynamic effects

In vitro

assays and

in vivo

animal studies have shown that panitumumab inhibits the growth and

survival of tumor cells expressing EGFR. No anti-tumor effects of panitumumab were observed in

human tumor xenografts lacking EGFR expression. The addition of panitumumab to radiation,

chemotherapy or other targeted therapeutic agents, in animal studies resulted in an increase in

anti-tumor effects compared to radiation, chemotherapy or targeted therapeutic agents alone.

Dermatological reactions (including nail effects), observed in patients treated with Vectibix or other

EGFR inhibitors, are known to be associated with the pharmacologic effects of therapy (with

cross-reference to sections 4.2 and 4.8).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Data on the development of

anti-panitumumab antibodies has been evaluated using two different screening immunoassays for the

detection of binding anti-panitumumab antibodies (an ELISA which detects high-affinity antibodies,

and a Biosensor Immunoassay which detects both high and low-affinity antibodies). For patients

whose sera tested positive in either screening immunoassay, an

in vitro

biological assay was

performed to detect neutralizing antibodies.

As monotherapy:

The incidence of binding antibodies (excluding predose and transient positive patients) was

< 1% as detected by the acid-dissociation ELISA and 3.8% as detected by the Biacore assay;

The incidence of neutralizing antibodies (excluding predose and transient positive patients) was

< 1%;

Compared with patients who did not develop antibodies, no relationship between the presence

of anti-panitumumab antibodies and pharmacokinetics, efficacy and safety has been observed.

In combination with irinotecan- or oxaliplatin-based chemotherapy:

The incidence of binding antibodies (excluding predose positive patients) was 1% as detected

by the acid-dissociation ELISA and < 1% as detected by the Biacore assay;

The incidence of neutralizing antibodies (excluding predose positive patients) was < 1%;

No evidence of an altered safety profile was found in patients who tested positive for antibodies

to Vectibix.

The detection of antibody formation is dependent on the sensitivity and specificity of the assay. The

observed incidence of antibody positivity in an assay may be influenced by several factors including

assay methodology, sample handling, timing of sample collection, concomitant medicinal products

and underlying disease, therefore, comparison of the incidence of antibodies to other products may be

misleading.

Clinical efficacy as monotherapy

The efficacy of Vectibix as monotherapy in patients with metastatic colorectal cancer (mCRC) who

had disease progression during or after prior chemotherapy was studied in open-label, single-arm trials

(585 patients) and in two randomized controlled trials versus best supportive care (463 patients) and

versus cetuximab (1,010 patients).

A multinational, randomized, controlled trial was conducted in 463 patients with EGFR-expressing

metastatic carcinoma of the colon or rectum after confirmed failure of oxaliplatin and

irinotecan-containing regimens. Patients were randomized 1:1 to receive Vectibix at a dose of 6 mg/kg

given once every two weeks plus best supportive care (not including chemotherapy) (BSC) or BSC

alone. Patients were treated until disease progression or unacceptable toxicity occurred. Upon disease

progression BSC alone patients were eligible to crossover to a companion study and receive Vectibix

at a dose of 6 mg/kg given once every two weeks.

The primary endpoint was PFS. The study was retrospectively analyzed by wild-type

KRAS

(exon 2)

status versus mutant

KRAS

(exon 2) status. Tumor samples obtained from the primary resection of

colorectal cancer were analyzed for the presence of the seven most common activating mutations in

the codon 12 and 13 of the

KRAS

gene. 427 (92%) patients were evaluable for

KRAS

status of which

184 had mutations. The efficacy results from an analysis adjusting for potential bias from unscheduled

assessments are shown in the table below. There was no difference in overall survival (OS) seen in

either group.

Wild-type KRAS (exon 2)

population

Mutant KRAS (exon 2)

population

Vectibix plus

BSC

(n = 124)

BSC

(n = 119)

Vectibix plus

BSC

(n = 84)

BSC

(n = 100)

ORR n (%)

Response rate (investigator

assessed)

(95% CI)

(14, 32)

(0, 4)

Stable disease

PFS

Hazard ratio (95% CI)

0.49 (0.37, 0.65), p < 0.0001

1.07 (0.77, 1.48), p = 0.6880

Median (weeks)

16.0

CI = confidence interval

In patients that crossed over to panitumumab after progression on BSC alone (95% CI)

In an exploratory analysis of banked tumor specimens from this study, 11 of 72 patients (15%) with

wild-type

RAS

tumors receiving panitumumab had an objective response compared to only 1 of

95 patients (1%) with mutant

RAS

tumor status. Moreover, panitumumab treatment was associated

with improved PFS compared to BSC in patients with wild-type

RAS

tumors (HR = 0.38 [95% CI:

0.27, 0.56]), but not in patients with tumors harboring a

RAS

mutation (HR = 0.98 [95% CI: 0.73,

1.31]).

The efficacy of Vectibix was also evaluated in an open-label trial in patients with wild-type

KRAS

(exon 2) mCRC. A total of 1,010 patients refractory to chemotherapy were randomized 1:1 to receive

Vectibix or cetuximab to test whether Vectibix is non-inferior to cetuximab. The primary endpoint

was OS. Secondary endpoints included PFS and objective response rate (ORR).

The efficacy results for the study are presented in the table below.

Wild-type KRAS (exon 2)

population

Vectibix

(n = 499)

Cetuximab

(n = 500)

OS

Median (months) (95% CI)

10.4 (9.4, 11.6)

10.0 (9.3, 11.0)

Hazard ratio (95% CI)

0.97 (0.84, 1.11)

PFS

Median (months) (95% CI)

4.1 (3.2, 4.8)

4.4 (3.2, 4.8)

Hazard ratio (95% CI)

1.00 (0.88, 1.14)

ORR

n (%) (95% CI)

22% (18%, 26%)

20% (16%, 24%)

Odds ratio (95% CI)

1.15 (0.83, 1.58)

Overall, the safety profile of panitumumab was similar to that of cetuximab, in particular regarding

skin toxicity. However, infusion reactions were more frequent with cetuximab (13% versus 3%) but

electrolyte disturbances were more frequent with panitumumab, especially hypomagnesemia (29%

versus 19%).

Clinical efficacy in combination with chemotherapy

Among patients with wild-type

RAS

mCRC, PFS, OS, and ORR were improved for subjects receiving

panitumumab plus chemotherapy (FOLFOX or FOLFIRI) compared with those receiving

chemotherapy alone. Patients with additional

RAS

mutations beyond

KRAS

exon 2 were unlikely to

benefit from the addition of panitumumab to FOLFIRI and a detrimental effect was seen with the

addition of panitumumab to FOLFOX in these patients.

BRAF

mutations in exon 15 were found to be

prognostic of worse outcome.

BRAF

mutations were not predictive of the outcome for panitumumab

treatment in combination with FOLFOX or FOLFIRI.

First-line combination with FOLFOX

The efficacy of Vectibix in combination with oxaliplatin, 5-fluorouracil (5-FU), and leucovorin

(FOLFOX) was evaluated in a randomized, controlled trial of 1,183 patients with mCRC with the

primary endpoint of PFS. Other key endpoints included the OS, ORR, time to response, time to

progression (TTP), and duration of response. The study was prospectively analyzed by tumor

KRAS

(exon 2)

status which was evaluable in 93% of the patients.

A predefined retrospective subset analysis of 641 patients of the 656 patients with wild-type

KRAS

(exon 2) mCRC was performed. Patient tumor samples with wild-type

KRAS

exon 2 (codons 12/13)

status were tested for additional

RAS

mutations in

KRAS

exon 3 (codons 61) and exon 4

(codons 117/146) and

NRAS

exon 2 (codons 12/13), exon 3 (codon 61), and exon 4 (codons 117/146)

BRAF

exon 15 (codon 600). The incidence of these additional

RAS

mutations in the wild-type

KRAS

exon 2 population was approximately 16%.

Results in patients with wild-type

RAS

mCRC and mutant

RAS

mCRC are presented in the table

below.

Vectibix plus

FOLFOX

(months)

Median (95% CI)

FOLFOX

(months)

Median (95% CI)

Difference

(months)

Hazard ratio

(95% CI)

Wild-type RAS population

10.1

(9.3, 12.0)

(7.2, 9.3)

0.72

(0.58, 0.90)

26.0

(21.7, 30.4)

20.2

(17.7, 23.1)

0.78

(0.62, 0.99)

Mutant RAS population

(6.3, 7.9)

(7.6, 9.4)

-1.4

1.31

(1.07, 1.60)

15.6

(13.4, 17.9)

19.2

(16.7, 21.8)

-3.6

1.25

(1.02, 1.55)

Additional mutations in

KRAS

NRAS

at exon 3 (codon 59) were subsequently identified (n = 7).

An exploratory analysis showed similar results to those in the previous table.

Combination with FOLFIRI

The efficacy of Vectibix in second-line in

combination with irinotecan, 5-fluorouracil (5-FU) and

leucovorin (FOLFIRI) was evaluated in a randomized, controlled trial of 1,186 patients with mCRC

with the primary endpoints of OS and PFS. Other key endpoints included the ORR, time to response,

TTP, and duration of response. The study was prospectively analyzed by tumor

KRAS

(exon 2) status

which was evaluable in 91% of the patients.

A predefined retrospective subset analysis of 586 patients of the 597 patients with wild-type

KRAS

(exon 2) mCRC was performed, where tumor samples from these patients were tested for additional

RAS

BRAF

mutations as previously described. The

RAS/BRAF

ascertainment was 85% (1,014 of

1,186 randomized patients). The incidence of these additional

RAS

mutations (

KRAS

exons 3, 4 and

NRAS

exons 2, 3, 4) in the wild-type

KRAS

(exon 2) population was approximately 19%. The

incidence of

BRAF

exon 15 mutation in the wild-type

KRAS

(exon 2) population was approximately

8%. Efficacy results in patients with wild-type

RAS

mCRC and mutant

RAS

mCRC are shown in the

below table.

Vectibix plus

FOLFIRI

(months)

Median (95% CI)

FOLFIRI

(months)

Median (95% CI)

Hazard ratio

(95% CI)

Wild-type RAS population

(5.5, 7.4)

(3.7, 5.6)

0.70

(0.54, 0.91)

16.2

(14.5, 19.7)

13.9

(11.9, 16.0)

0.81

(0.63, 1.02)

Mutant RAS population

(3.7, 5.5)

(3.6, 5.5)

0.86

(0.70, 1.05)

11.8

(10.4, 13.1)

11.1

(10.2, 12.4)

0.91

(0.76, 1.10)

The efficacy of Vectibix in first-line in combination with FOLFIRI was evaluated in a single-arm

study of 154 patients with the primary endpoint of objective response rate (ORR). Other key endpoints

included the PFS, time to response, TTP, and duration of response.

A predefined retrospective subset analysis of 143 patients of the 154 patients with wild-type

KRAS

(exon 2) mCRC was performed, where tumor samples from these patients were tested for additional

RAS

mutations. The incidence of these additional

RAS

mutations (

KRAS

exons 3, 4 and

NRAS

exons 2,

3, 4) in the wild-type

KRAS

(exon 2) population was approximately 10%.

Results in patients with wild-type

RAS

mCRC and mutant

RAS

mCRC from the primary analysis are

presented in the table below.

Panitumumab + FOLFIRI

Wild-type RAS (n = 69)

Mutant RAS (n = 74)

ORR (%)

(95% CI)

(46, 71)

(30, 53)

Median PFS (months)

(95% CI)

11.2

(7.6, 14.8)

(5.8, 7.5)

Median duration of response (months)

(95% CI)

13.0

(9.3, 15.7)

(3.9, 7.8)

Median TTP (months)

(95% CI)

13.2

(7.8, 17.0)

(6.1, 7.6)

First-line combination with bevacizumab and oxaliplatin or irinotecan-based chemotherapy

In a randomized, open-label, controlled clinical trial, chemotherapy (oxaliplatin or irinotecan) and

bevacizumab were given with and without panitumumab in the first-line treatment of patients with

metastatic colorectal cancer (n = 1,053 [n = 823 oxaliplatin cohort, n = 230 irinotecan cohort]).

Panitumumab treatment was discontinued due to a statistically significant reduction in PFS in patients

receiving panitumumab observed in an interim analysis.

The major study objective was comparison of PFS in the oxaliplatin cohort. In the final analysis, the

hazard ratio for PFS was 1.27 (95% CI: 1.06, 1.52). Median PFS was 10.0 (95% CI: 8.9, 11.0) and

11.4 (95% CI: 10.5, 11.9) months in the panitumumab and the non-panitumumab arm, respectively.

There was an increase in mortality in the panitumumab arm. The hazard ratio for overall survival was

1.43 (95% CI: 1.11, 1.83). Median overall survival was 19.4 (95% CI: 18.4, 20.8) and 24.5 (95% CI:

20.4, 24.5) in the panitumumab arm and the non-panitumumab arm.

An additional analysis of efficacy data by

KRAS

(exon 2) status did not identify a subset of patients

who benefited from panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapy

and bevacizumab. For the wild-type

KRAS

subset of the oxaliplatin cohort, the hazard ratio for PFS

was 1.36 with 95% CI: 1.04-1.77. For the mutant

KRAS

subset, the hazard ratio for PFS was 1.25 with

95% CI: 0.91-1.71. A trend for OS favouring the control arm was observed in the wild-type

KRAS

subset of the oxaliplatin cohort (hazard ratio = 1.89; 95% CI: 1.30, 2.75). A trend towards worse

survival was also observed with panitumumab in the irinotecan cohort regardless of

KRAS

mutational

status. Overall, panitumumab treatment combined with chemotherapy and bevacizumab is associated

with an unfavourable benefit-to-risk profile irrespective of tumor

KRAS

mutational status.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with

Vectibix in all subsets of the pediatric population in colorectal cancer (see section 4.2 for information

on pediatric use).

5.2

Pharmacokinetic properties

Vectibix administered as a single agent or in combination with chemotherapy exhibits nonlinear

pharmacokinetics.

Following a single-dose administration of panitumumab as a 1-hour infusion, the area under the

concentration-time curve (AUC) increased in a greater than dose-proportional manner and clearance

(CL) of panitumumab decreased from 30.6 to 4.6 mL/day/kg as the dose increased from 0.75 to

9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increases in an approximately

dose-proportional manner.

Following the recommended dose regimen (6 mg/kg given once every 2 weeks as a 1-hour infusion),

panitumumab concentrations reached steady-state levels by the third infusion with mean (± Standard

Deviation [SD]) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively. The

mean (± SD) AUC0-tau and CL were 1,306 ± 374 mcgday/mL and 4.9 ± 1.4 mL/kg/day, respectively.

The elimination half-life was approximately 7.5 days (range: 3.6 to 10.9 days).

A population pharmacokinetic analysis was performed to explore the potential effects of selected

covariates on panitumumab pharmacokinetics. Results suggest that age (21-88), gender, race, hepatic

function, renal function, chemotherapeutic agents, and EGFR membrane staining intensity (1+, 2+,

3+) in tumor cells had no apparent impact on the pharmacokinetics of panitumumab.

No clinical studies have been conducted to examine the pharmacokinetics of panitumumab in patients

with renal or hepatic impairment.

5.3

Preclinical safety data

Adverse reactions seen in animals at exposure levels similar to clinical exposure levels and with

possible relevance to clinical use were as follows:

Skin rash and diarrhea were the major findings observed in repeat-dose toxicity studies of up to

26 weeks duration in cynomolgus monkeys. These findings were observed at doses approximately

equivalent to the recommended human dose and were reversible upon termination of administration of

panitumumab. The skin rash and diarrhea observed in monkeys are considered related to the

pharmacological action of panitumumab and are consistent with the toxicities observed with other

anti-EGFR inhibitors.

Studies to evaluate the mutagenic and carcinogenic potential of panitumumab have not been

performed.

Animal studies are insufficient with respect to embryo-fetal development since fetal panitumumab

exposure levels were not examined. Panitumumab has been shown to cause fetal abortions and/or fetal

deaths in cynomolgus monkeys when administered during the period of organogenesis at doses

approximately equivalent to the recommended human dose.

Formal male fertility studies have not been conducted; however, microscopic evaluation of male

reproductive organs from repeat-dose toxicity studies in cynomolgus monkeys at doses up to

approximately 5-fold the human dose on a mg/kg basis, revealed no differences compared to control

male monkeys. Fertility studies conducted in female cynomolgus monkeys showed that panitumumab

may produce prolonged menstrual cycle and/or amenorrhea and reduced pregnancy rate which

occurred at all doses evaluated.

No pre- and post-natal development animal studies have been conducted with panitumumab. All

patients should be advised regarding the potential risk of panitumumab on pre- and post-natal

development prior to initiation of Vectibix therapy.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium chloride

Sodium acetate trihydrate

Acetic acid, glacial (for pH-adjustment)

Water for injections.

6.2

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

6.3

Shelf life

Vial

The expiry date of the product is indicated on the packaging materials.

Diluted solution

Vectibix does not contain any antimicrobial preservative or bacteriostatic agent. The product should be

used immediately after dilution. If not used immediately, in-use storage times and conditions prior to

use are the responsibility of the user and should be no longer than 24 hours at 2°C – 8°C. The diluted

solution must not be frozen.

6.4

Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

Type I glass vial with an elastomeric stopper, aluminum seal and flip-off plastic cap.

One vial contains either 100 mg of panitumumab in 5 mL, or 400 mg panitumumab in 20 mL of

concentrate for solution for infusion.

Pack of 1 vial.

6.6

Special precautions for disposal and other handling

Vectibix is intended for single-use only. Vectibix should be diluted in sodium chloride 9 mg/mL

(0.9%) solution for injection by healthcare professional using aseptic technique. Do not shake or

vigorously agitate the vial. Vectibix should be inspected visually prior to administration. The solution

should be colorless and may contain visible translucent-to-white, amorphous, proteinaceous

particulates (which will be removed by in-line filtration). Do not administer Vectibix if its appearance

is not as described above. Using only a 21-gauge or smaller diameter hypodermic needle, withdraw

the necessary amount of Vectibix for a dose of 6 mg/kg. Do not use needle-free devices (e.g. vial

adapters) to withdraw vial contents. Dilute in a total volume of 100 mL. The final concentration

should not exceed 10 mg/mL. Doses higher than 1,000 mg should be diluted in 150 mL sodium

chloride 9 mg/mL (0.9%) solution for injection (see section 4.2). The diluted solution should be mixed

by gentle inversion, do not shake.

No incompatibilities have been observed between Vectibix and sodium chloride 9 mg/mL (0.9%)

solution for injection in polyvinyl chloride bags or polyolefin bags.

Discard the vial and any liquid remaining in the vial after the single-use.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MARKETING AUTHORIZATION HOLDER

Amgen Europe B.V.

Minervum 7061

NL-4817 ZK Breda

The Netherlands

8.

LICENSE HOLDER

Amgen Europe B.V.

P.O. BOX 53313

Tel - Aviv

Israel

Announcement regarding harshment (safety information) in the

Announcement regarding harshment (safety information) in the

Physician Leaflet

Physician Leaflet

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

:ךיראת

06/02/2012

Name of the product:

םש

רישכת

:תילגנאב

Vectibix 20mg/ml

Registration No's:

רפסמ

:םושיר

142923295100

Name of the registration owner:

Amgen Europe

B.V.

םש

לעב

םושירה

Details regarding the requested changes

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לע

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םי/שקובמה

Chapter in leaflet

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ןולעב

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4.4

Special

warnings and

precautions for

use

In clinical studies, subsequent to the development of severe dermatological

reactions (including stomatitis), infectious complications including sepsis, in

rare cases leading to death, and local abscesses requiring incisions and

drainage were reported. Patients who have severe dermatologic reactions or

who develop worsening reactions whilst receiving Vectibix should be

monitored for the development of inflammatory or infectious sequelae

(including cellulitis), and appropriate treatment promptly initiated

Treatment of dermatologic reactions should be based on severity and may

include a moisturiser, sun screen (SPF > 15 UVA and UVB), and topical

steroid cream (not stronger than 1% hydrocortisone) applied to affected

areas, and/or oral antibiotics. 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

In clinical studies, subsequent to the development of severe dermatological

reactions (including stomatitis), infectious complications including sepsis, in

rare cases leading to death, and local abscesses requiring incisions and

drainage were reported. Patients who have severe dermatologic reactions

or who develop worsening reactions whilst receiving Vectibix should be

monitored for the development of inflammatory or infectious sequelae

(including cellulitis), and appropriate treatment promptly initiated. Life

threatening and fatal infectious complications including events of

necrotizing fasciitis and/or sepsis have been observed in patients

treated with Vectibix. Withhold or discontinue Vectibix for

dermatologic toxicity with severe or life threatening inflammatory or

infectious complications

Treatment of dermatologic reactions should be based on severity and may

include a moisturiser, sun screen (SPF > 15 UVA and UVB), and topical

steroid cream (not stronger than 1% hydrocortisone) applied to affected

areas, and/or oral antibiotics. 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

Details regarding the requested changes

םיטרפ

לע

םי/יונישה

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4.8

Undesirable

effects

Commonly reported adverse reactions occurring in ≥ 20% of patients

were gastrointestinal disorders [diarrhoea (50%), nausea (41%),

vomiting (27%), constipation (23%) and abdominal pain (23%)]; general

disorders [fatigue (37%), pyrexia (20%)]; metabolism and nutrition

disorders [anorexia (27%)]; infections and infestations [paronychia

(20%)]; and skin and subcutaneous disorders [rash (45%), dermatitis

acneiform (39%), pruritus (35%), erythema (30%) and dry skin (22%)]

Very commonly reported adverse reactions occurring in ≥ 20% of

patients were gastrointestinal disorders [diarrhoea (50%), nausea

(41%), vomiting (27%), constipation (23%) and abdominal pain (23%)];

general disorders [fatigue (37%), pyrexia (20%)]; metabolism and

nutrition disorders [anorexia (27%)]; infections and infestations

[paronychia (20%)]; and skin and subcutaneous disorders [rash (45%),

dermatitis acneiform (39%), pruritus (35%), erythema (30%) and dry

skin (22%)]

Fertility,

pregnancy

and lactation

Breast-feeding

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 breast feed during treatment with Vectibix and for 3 months after

the last dose

Breast-feeding

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 breast feed during treatment with Vectibix and for 2 months after

the last dose

The leaflet, in which the changes requested are yellow highlighted, was sent by e-mail on

…………………

ובש ,ןולעה

םינמוסמ

םייונישה

םישקובמה

לע

עקר

בוהצ

םודאו

רבעוה

ראודב

ינורטקלא

...................ךיראתב

A patient leaflet exists and it's adequately updated

. ןכרצל ןולע םייק אל

Reference for the request

:השקבל אתכמסא הפוריאב ורשואש תוחיטב ינוכדע

Safety updates EU v38 & v37

The above change was approved by the health authorities in

:ב תואירבה תויושר ידי לע רשוא ל"נה יונישה

European Union

I, the appointed pharmacist of the company ……., hereby declare that there are no additional changes in the leaflet

תרבח לש הנוממה חקורה ,ינא

Amgen

Europe B.V

.ןולעב םיפסונ םייוניש ןיא יכ הזב ריהצמ

______

Sigal Bendor

_______

תמיתח

חקורה

הנוממה

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