Vectibix 20 mg/ml 5 ml

Pharmacotherapeutic group

Antitumor agent, monoclonal antibody.

The ATX code: L01XC0

Pharmacological properties

Pharmacodynamics

Mechanism of action

Panitumumab is a recombinant human monoclonal antibody (IgG2) with high affinity and specificity for human epithelial growth factor receptor (EGFR). The EGF receptor is a transmembrane glycoprotein in the tyrosine kinase receptor type I family, which also includes EGFR (HER1/c-ErbB-1), HER2, HER3 and HER4. The EGF receptor stimulates the growth of normal epithelial cells, including skin and hair follicle cells, and is expressed on various tumor cell types.

Panitumumumab binds to the ligand-binding domain of the EGF receptor and inhibits autophosphorylation, which is induced by all known EGF receptor ligands. Binding of panitumumumab to the EGF receptor leads to internalization of the receptor, inhibition of cell growth processes, induction of apoptosis and reduction of interleukin-8 and vascular endothelial growth factor production.

The genes KRAS (homologue of the Kirsten rat sarcoma viral oncogene 2) and NRAS (homologue of the neuroblastoma viral oncogene RAS) belong to the RAS family of oncogenes. The KRAS and NRAS genes encode a small guanosine triphosphate-binding protein that is involved in signal transduction. KRAS and NRAS are activated by various signals, including those from the EGF receptor, and in turn stimulate the synthesis of other intracellular proteins involved in cell proliferation, survival and angiogenesis.

The activating mutations of the RAS genes frequently occur in various human tumor cells and play a role in both oncogenesis and tumor progression.

Pharmacodynamic effects

The studies in vitro and in vivo on animals showed that panitumumab inhibited the growth and survival of EGFR-expressing tumor cells. No antitumor activity of panitumumumab was observed in experiments with human tumor xenografts that did not express EGFR. Adding panitumumab to radiation, chemo- or other targeted therapy in animal studies resulted in an increased antitumor effect compared to radiation, chemo- or targeted therapy alone.

Skin reactions (including nail manifestations) have been noted in patients treated with Vectibix or other EGFR inhibitors and are known to be associated with pharmacological effects of therapy (see Administration and Dose and Side Effects).

Immunogenicity

Like all therapeutic proteins, panitumumumab has potential immunogenicity. Antipanitumumumab antibody production was evaluated using two different screening immunoassay systems to determine anti-panitumumumab binding antibodies (ELISA, an enzyme immunoassay that detects high-affinity antibodies, and biosensor immunoassay, which detects high- and low-affinity antibodies). Patients whose serum was positive in either of the two screening immunoassays also had a in vitro biological test to detect neutralizing antibodies.

As a monotherapy:

• The detectability of binding antibodies (except when antibodies were detected before drug administration and temporarily positive) was < 1%, as determined by acid dissociation ELISA assay, and 3.8%, as determined by Biacore immunoassay;
• The detectability of neutralizing antibodies (except when antibodies were detected before drug administration and temporarily positive) was <1%;
• When compared with patients in whom no antibodies were produced, no relationship was noted between the presence of anti-panitumumab antibodies and changes in pharmacokinetic parameters, efficacy, and safety of the drug.

In combination with irinotecan or oxaliplatin-based chemotherapy regimens:

• The detectability of binding antibodies (except when antibodies were detected before drug administration) was 1%, as determined by acid dissociation ELISA assay, and < 1%, as determined by Biacore immunoassay;
• The detectability of neutralizing antibodies (except when antibodies were detected prior to drug administration) was < 1%;
• No evidence was found to alter the safety profile in patients who tested positive for Vectibix antibodies.

The determination of antibody formation depends on the sensitivity and specificity of the method used. Various factors may affect a positive antibody result, including the method of testing, method of sampling and sample preparation, timing of sample collection, use of concomitant medications, and the nature of the underlying disease; therefore, comparing the incidence of antibodies to other drugs may lead to unreliable results.

Pharmacokinetics

When Vectibix is used as monotherapy or in combination with chemotherapy, the pharmacokinetics of the drug are non-linear.

After a single administration of panitumumumab as a 1-hour infusion, the area under the concentration-time curve (AUC) increased more than is typical in a dose-proportional relationship, and the clearance (CL) of panitumumumab decreased from 30.6 to 4.6 ml/day/kg with increasing doses from 0.75 to 9 mg/kg. However, when panitumumumab was administered at doses above 2 mg/kg, the pattern of AUC increase was close to a dose-proportional relationship.

When the recommended dosing regimen (6 mg/kg once every 2 weeks as a 1-hour ‑infusion) was followed‑, the equilibrium concentration of panitumumumab was reached by the third infusion with mean maximum (± standard deviation [SD]) and minimum concentrations of 213 ± 59 and 39 ± 14 µg/mL, respectively. The mean (± SD) AUC₀-t and clearance were 1306 ± 374 μg/day/ml and 4.9 ± 1.4 mL/kg/day, respectively. The half-life of the drug was approximately 7.5 days (range: 3.6 to 10.9 days).

A population-based pharmacokinetic analysis was performed to assess the potential effect of individual covariates on panitumumumab pharmacokinetic parameters. Its results showed that age (range 21-88 years), sex, race, liver and kidney function, use of concomitant chemotherapy drugs, and intensity of EGFR membrane staining (1+, 2+, 3+) in tumor cells had no apparent effect on panitumumumab pharmacokinetics.

There have been no studies of the pharmacokinetics of panitumumumab in patients with impaired renal or hepatic function.

Indications

Treatment of metastatic colorectal cancer (mCRC) in adult patients with wild-type RAS genes in the tumor:

– As first-line therapy in combination with regimens containing fluorouracil, calcium folinate and oxaliplatin (FOLFOX) or fluorouracil, calcium folinate and irinotecan (FOLFIRI);

– As second-line therapy in combination with a regimen containing fluorouracil, calcium folinate and irinotecan (FOLFIRI) in patients who have previously received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan);

– As monotherapy when fluoropyrimidine, oxaliplatin and irinotecan-based regimens are not effective.

Active ingredient

Composition

1 ml of the concentrate contains:

active ingredient: panitumumumab – 20 mg;

excipients: sodium acetate trihydrate – 6.8 mg, sodium chloride – 5.8 mg, glacial acetic acid – to pH 5.8, water for injection – sufficient amount.

How to take, the dosage

Vectibix therapy must be supervised by a physician experienced in antitumor treatment. The wild-type RAS gene (KRAS and NRAS) must be confirmed before starting Vectibix therapy. The mutational status of the gene must be determined by a laboratory experienced in relevant studies using validated techniques to detect KRAS mutations (in exons 2, 3 and 4) and NRAS mutations (in exons 2, 3 and 4).

Dosing regimen

The recommended dose of Vectibix is 6 mg/kg body weight and is administered once every 2 weeks.

If severe (≥3 degree) dermatological reactions develop, the following dosage modification regimen of Vectibix may be required:

Event of skin symptoms:
≥ grade 31

Injection of Vectibix

Result

Dose adjustment

First occurrence

Cancellation of 1 or 2 doses

Decreased response intensity (< 3rd degree)

Resumption of infusion at a dose that is 100% of the original dose

No improvement

Discontinuation

Second occurrence

Cancellation of 1 or 2 doses

Decrease in response intensity (< 3rd degree)

Resumption of infusion at a dose that is 80% of the original dose

No improvement

Discontinued

Third occurrence

Cancellation of 1 or 2 doses

Reducing response intensity (< 3rd degree)

Resuming the infusion at a dose that is 60% of the original dose

No improvement

Termination

Fourth occurrence

Termination

–

–

1 .Grade 3 or higher reactions are considered severe or life-threatening

Application in selected patient populations

The safety and effectiveness of Vectibix has not been evaluated in patients with renal or hepatic impairment.

There is no clinical evidence to justify the need to adjust the dose of the drug in the elderly.

Children

There is no experience with Vectibix in children.

Method of administration

Vectibix should be administered as an intravenous infusion using an infusion pump.

Vectibix must be diluted by a healthcare professional in 9 mg/mL (0.9%) sodium chloride solution for injection under aseptic conditions to obtain a final concentration of no more than 10 mg/mL before infusion. Do not shake or shake vial vigorously. The vial of Vectibix should be visually assessed before use. The solution should be colorless and may contain translucent or white amorphous protein particles (which are removed by the filter of the infusion system). Vectibix, which is not described above, should not be administered. Using a hypodermic needle of size 21G or less, the necessary amount of Vectibix to obtain a dose of 6 mg/kg is withdrawn from the vial and dissolved in a total volume of 100 ml. Do not use needleless devices (e.g., vial adapters) to remove the drug from the vial. The final concentration should not exceed 10 mg/ml. Doses above 1000 mg should be dissolved in 150 ml of 9 mg/ml (0.9%) sodium chloride solution for injection. The resulting diluted solution should be stirred by gentle inversion, do not shake.

No incompatibility has been observed between Vectibix and 9 mg/ml (0.9%) sodium chloride solution for injection in polyvinyl chloride or polyolefin infusion bags.

Vectibix should be administered in a peripheral probe or permanent catheter through an integrated 0.2 or 0.22 µm pore size filter with low protein binding capacity. The recommended duration of infusion is approximately 60 minutes. If the first infusion is well tolerated, subsequent infusions may be given within 30-60 minutes. Doses greater than 1000 mg should be administered for approximately 90 minutes (see Special Precautions for Administration and Disposal for handling instructions).

Before and after administration of Vectibix, the infusion system should be flushed with sodium chloride solution to avoid mixing Vectibix with other medications or IV solutions.

In case of infusion reactions it may be necessary to decrease the infusion rate of Vectibix (see section “Special Precautions”).

Vectibix should not be administered as a jet or bolus.

Interaction

The data from a study on the interaction of Vectibix and irinotecan in patients with mCRC showed that the pharmacokinetic properties of irinotecan and its active metabolite, SN-38, are not altered by concomitant drug administration. The results of a cross-comparison study showed that regimens including irinotecan (IFL or FOLFIRI) did not affect the pharmacokinetic properties of panitumumumab.

Vectibix should not be administered in combination with IFL chemotherapy regimens or chemotherapy regimens including bevacizumab. When panitumumumab was prescribed in combination with IFL, there was a high incidence of severe diarrhea (see section “Special Precautions”) and an increased incidence of toxicity and death when panitumumumumab was prescribed in combination with a chemotherapy regimen that included bevacizumab (see section “Special Precautions”).

The combination of Vectibix with oxaliplatin-based chemotherapy is contraindicated in patients with mCRP and RAS mutations and in patients with mCRP with unknown RAS status. In a clinical trial, patients with RAS mutations in the tumor who received panitumumumab and FOLFOX chemotherapy had a shorter progression-free survival and overall survival (see “Special Instructions”).

Pharmaceutical Incompatibilities

This medication should not be used with any other medications except those listed under “Special Precautions for Use and Disposal”.

Special Instructions

Trackability

In order to improve traceability of biological medications, the name and batch number of the injected drug should be accurately recorded.

Adverse soft tissue and skin reactions

Dermatological reactions, a pharmacological effect characteristic of EGFR inhibitors, are reported in virtually all patients (approximately 94%) receiving Vectibix. Severe skin reactions (grade 3 according to the NCICTC classification) were observed in 23% of patients, life-threatening skin reactions (grade 4 NCI-CTC) – in 1% of patients who received Vectibix as monotherapy and in combination with chemotherapy (n = 2224) (see section “Adverse effects”). If a patient develops a grade 3 (Common Criteria for the Assessment of Adverse Events CTCAE version 4.0) or greater skin reactions or is considered intolerable, see the Dose Modification Guidelines in the Administration and Doses section.

In clinical trials, after the development of severe skin reactions (including stomatitis), infectious complications occurred, including sepsis and necrotizing fasciitis, which in rare cases resulted in death, as well as the formation of abscesses that required autopsy and drainage. Patients who have noted severe skin reactions or manifestations of soft tissue toxicity, or who demonstrated worsening of these reactions during therapy with Vectibix should be monitored for inflammatory or infectious effects (including subcutaneous tissue inflammation and necrotizing fasciitis), and if clinically indicated, appropriate therapy should be initiated. Life-threatening and fatal infectious complications were necrotizing fasciitis and sepsis, which were reported in patients treated with Vectibix. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving Vectibix during the post-registration period. Temporary withdrawal or discontinuation of Vectibix is necessary if skin or soft tissue toxicity develops and is associated with the development of severe or life-threatening inflammatory or infectious complications.

The treatment and management of dermatologic reactions should be based on the severity of manifestations and may include moisturizers, sunscreens (sunscreen > 15 UVA and UVB), and creams with glucocorticosteroids (no higher than 1% hydrocortisone) for use on affected areas and/or oral antibiotics (such as doxycycline). Also, patients with signs of rash/dermatologic toxicity are advised to use sunscreen and headgear and limit sun exposure, as sunlight can exacerbate any possible skin reactions.

Patients may be advised to apply moisturizing, sunscreen to the face, arms, legs, neck, back, and chest each morning, and to apply glucocorticosteroid-containing cream to the face, arms, legs, neck, back, and chest at night during treatment.

Pulmonary complications

Patients with a history or evidence of interstitial pneumonitis or pulmonary fibrosis were excluded from clinical trials. Cases of interstitial lung disease, with or without death, occurred predominantly in the Japanese population. Therefore, in case of acute onset or worsening of pulmonary symptoms, treatment with Vectibix should be suspended and an immediate investigation of the symptoms should be initiated. If interstitial lung disease is detected, Vectibix should be temporarily withdrawn and appropriate treatment prescribed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, the ratio of the likely benefit of the drug to the risk of lung complications should be evaluated.

Water-electrolyte balance disorders

In some patients there has been a progressive decrease in serum magnesium concentrations leading to severe (grade 4) hypomagnesemia. Patients should be monitored periodically for hypomagnesemia and concomitant hypocalcemia before initiation of Vectibix treatment, and after treatment up to 8 weeks after completion (see side effects section). Magnesium preparations are recommended if necessary.

Disorders of other electrolytes, including hypokalemia, have also been noted. Monitoring and appropriate adequate administration of these electrolytes is recommended.

Infusion reactions

. In clinical trials of monotherapy and combination therapy for mCRP (n = 2224), infusion reactions, including severe infusion reactions (occurring within 24 hours of infusion), were noted in patients receiving Vectibix (NCI-CTC grades 3 and 4).

Serious infusion reactions have been reported in post-registration studies, including rare post-registration reports of death. If a severe or life-threatening reaction occurs during the infusion or at any time after completion [e.g., if bronchospasm, angioedema, hypotension, need for parenteral therapy, or anaphylaxis], Vectibix should be discontinued completely (see Contraindications and Adverse Effects).

In patients with mild to moderate (CTCAE version 4.0 grades 1 and 2) infusion reactions, the infusion rate should be reduced throughout the infusion. It is recommended that the reduced infusion rate be maintained for all subsequent infusions.

Hypersensitivity reactions occurring more than 24 hours after infusion have been reported, including fatal angioedema developing more than 24 hours after infusion. Patients should be warned 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 noted in patients with severe diarrhea and dehydration. Patients should be instructed to seek immediate medical attention if severe diarrhea develops.

Vectibix in combination with irinotecan, fluorouracil bolus and calcium folinate chemotherapy (IFL regimen)

. In patients who received Vectibix in combination with the IFL regimen [fluorouracil bolus (500 mg/m2), calcium folinate (20 mg/m2), and irinotecan (125 mg/m2)] had a high incidence of severe diarrhea (see Section “Side effects”). Therefore, the use of Vectibix in combination with the IFL regimen should be avoided (see section “Interaction with other drugs”).

Vectibix in combination with bevacizumab and chemotherapy regimens

. Patients who received Vectibix in combination with bevacizumab and chemotherapy had shorter progression-free survival and increased mortality. In addition, Vectibix in combination with bevacizumab and chemotherapy showed an increased incidence of pulmonary embolism, infections (mostly skin), diarrhea, electrolyte disturbances, nausea, vomiting, and dehydration. Vectibix should not be used in combination with chemotherapy including bevacizumab (see section “Interaction with other medicinal products”).

Vectibix in combination with oxaliplatin-based chemotherapy in patients with mCRP and RAS mutations and unspecified RAS status

Vectibix in combination with chemotherapy including bevacizumab. The combination of Vectibix with oxaliplatin-based chemotherapy is contraindicated in patients with mCRP and RAS mutations and in patients with mCRP with unspecified RAS gene mutation status (see Contraindications).

There was a reduction in progression-free survival (PFS) and overall survival (OS) in patients with KRAS mutations (in exon 2) in the tumor and additional RAS mutations (KRAS [in exons 3 and 4] or NRAS [in exons 2, 3, 4]) who received panitumumumab in combination with an infusion regimen containing fluorouracil, calcium folinate and oxaliplatin (FOLFOX) compared with patients who received FOLFOX alone.

The evaluation of mutational status RAS must be determined using a validated method in a laboratory experienced in such studies (see section “Dosage and administration”). If Vectibix is to be used in combination with the FOLFOX regimen, determination of mutational status by a laboratory participating in an external quality assurance program for RAS status, or wild-type must be confirmed with results of a two-fold assay, is recommended.

Ophthalmic toxicity

Serious cases of keratitis and ulcerative keratitis have been reported, which can lead to corneal perforation. Patients with signs and symptoms suggestive of keratitis, including acute or worsening: inflammatory changes in the eye, lacrimation, photophobia, decreased visual clarity, pain in the eye and/or redness of the eye, should be referred to an ophthalmologist immediately.

If the diagnosis of ulcerative keratitis is confirmed, therapy with Vectibix should be temporarily or completely discontinued. If a diagnosis of keratitis is made, the benefits and risks of continued therapy should be carefully balanced.

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 a general status score 2 on the ECOG scale who received Vectibix in combination with chemotherapy

. For patients with mCRI who have an ECOG score of 2, a benefit-risk assessment is recommended before starting Vectibix in combination with chemotherapy. No positive benefit-risk ratios have been found in patients with ECOG 2 status.

Elderly Patients

There were no differences in safety or efficacy of Vectibix in monotherapy in elderly patients (≥65 years). However, there was an increase in serious adverse reactions in elderly patients who received Vectibix in combination with FOLFIRI or FOLFOX chemotherapy compared to chemotherapy regimens alone (see section “Adverse effects”).

Warning about excipients

This drug contains 3.45 mg of sodium in 1 mL, which is 0.17% of the WHO recommended maximum daily sodium intake for an adult of 2 g.

Special Precautions for Use and Disposal

Vectibix should be administered in a peripheral probe or permanent catheter through an integrated 0.2 or 0.22 μm pore size filter with low protein binding capacity.

Diluted solution

Vectibix contains no antimicrobial preservatives or bacteriostatic agents. The product must be used immediately after dilution. If the product is not used immediately after dilution, the user is responsible for the time and conditions of storage until the next administration (no more than 24 hours at 2 °C 8 °C). Do not freeze the diluted solution.

Vectibix is for single use only.

The bottle and any remaining drug solution in it must be disposed of after a single use.

All unused residual medication and consumables must be disposed of in accordance with proper procedures.

Effects on the ability to operate vehicles, machinery

Vectibix may affect the ability to drive vehicles and operate machinery. In case of development of adverse reactions on the visual organs and/or reduced ability to concentrate and reaction time, patients are advised to refrain from driving vehicles or operating complex equipment until the specified adverse reactions of the drug are resolved.

Synopsis

Contraindications

Side effects

Review of drug safety profile

An analysis of data from all patients with mCRC who participated in clinical trials and received Vectibix monotherapy and in combination with chemotherapy (n = 2224) showed that the most common adverse reactions were skin reactions, occurring in approximately 94% of cases. These reactions were due to the pharmacological properties of Vectibix and were usually mild to moderate in severity; only 23% of dermatological reactions were severe (NCI-CTC severity 3) and < 1% were life-threatening (NCI-CTC severity 4). Medical management of skin reactions, including recommendations for dosage adjustment, are listed in the Special Indications section.

The most common adverse reactions that occurred in ≥20% of patients were gastrointestinal disorders [diarrhea (46%), nausea (39%), vomiting (26%), constipation (23%), and abdominal pain (23%)]; general reactions [increased fatigue (35%), pyrexia (21%) metabolic and nutritional disorders [decreased appetite (30%)]; infections and invasions [paronychia (20%)]; and skin and subcutaneous tissue pathology [rash (47%), acneiform dermatitis (39%), itching (36%), erythema (33%) and dry skin (21%)].

Table list of adverse reactions

Adverse reactions observed in patients with mCRP who received panitumumumab as monotherapy or in combination with chemotherapy in clinical trials (n = 2224), as well as in spontaneous reports, are listed below. Unwanted effects are presented in descending order of severity.

Unwanted reactions

inflammation of subcutaneous tissue1,

urinary tract infection,

folliculitis,

localized infection

Infection of the eye,

p> eyelid infection

Disorders of the blood and lymphatic system

/p>

Anemia

Leukopenia

Immune system disorders

Hypersensitivity1

Anaphylactic reaction2

Metabolic and nutritional disorders

Hypokalemia,

hypomagnesemia,

decreased appetite

Hypocalcemia,

dehydration,

hyperglycemia,

hypophosphatemia

/p>

Mental disorders

Insomnia

Anxiety

Nervous system disorders

Headache,

dizziness

/td>

Visual disturbances

/p>

Blepharitis,

eyelash growth,

/p>

increased lacrimation,

hyperemia of the eye,

dry eyes,

p> itchy eyes,

eye irritation

Ulcerative keratitis1.4,

keratitis1,

eyelid irritation

Cardiac disorders

Tachycardia

Cyanosis

vascular disorders

/p>

Deep vein thrombosis,

hypertension,

hypertension,

/p>

hypertension

Respiratory, thoracic, and mediastinal disorders

dyspnea,

p> cough

Pulmonary artery thromboembolism,

Nasal bleeding

Interstitial lung disease3,

bronchospasm,

dry nasal mucosa

Digestive system disorders

Diarrhea1,

nausea,

vomiting,

abdominal pain,

stomatitis,

/p>

constipation

Rectal bleeding,

dry mouth,

/p>

dyspepsia,

aphthous ulcers,

heilitis,

gastroesophageal reflux disease

painful lips,

dry lips

Skin and subcutaneous tissue disorders1

Acneiform dermatitis,

dermal rash,

erythema,

itchy skin,

dry skin,

cracked skin,

acne,

/p>

alopecia

Skin ulcers,

skin exfoliations,

exfoliative skin rashes,

dermatitis,

papular skin rashes,

/p>

itchy skin rashes,

erythematous skin rashes,

generalized skin rashes,

maculopapular skin rashes,

maculopapular skin rashes,

dermal lesions,

cutaneous toxicity,

crusts,

p> hypertrichosis,

onychoclasia,

nail disorders,

Hyperhidrosis,

palmar and plantar erythrodysesthesia syndrome

Toxic epidermal necrolysis1,4,

Stevens-Johnson syndrome1,4,

dermal necrosis1.4,

angioedema1,

hirsutism,

ingrown toenail,

onycholysis

Musculoskeletal and connective tissue disorders

Back pain

Limb pain

/td>

Systemic disorders and complications at the injection site

Fatigue,

pyrexia,

Asthenia,

Mucosal inflammation,

/p>

peripheral edema

Chest pain,

p> pain,

chills

Injuries, poisonings, and complications of procedures

Infusion reaction1

Changes in laboratory and instrumental results

Decreased body weight

Decreased blood magnesium concentration

/p>

1 See.

1 See subsection “Description of individual adverse reactions.

2 See “Special Indications” (infusion reactions).

3 See Special Precautions (pulmonary complications).

4 Skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and ulcerative keratitis are adverse reactions of panitumumumab that have been noted during its post-registration use. The maximum frequency of these adverse reactions was estimated based on the upper limit of the 95% confidence interval for the point estimate, taking into account regulatory guidelines for estimating the frequency of adverse reactions in spontaneous reports. The maximum frequency based on the upper limit of the 95% confidence interval for the point estimate was 3/2224 (or 0.13%).

The safety profile of Vectibix in combination with chemotherapy is consistent with reported adverse reactions of Vectibix (used in monotherapy) and manifestations of background chemotherapy toxicity. No new manifestations of toxicity or aggravation of previously known manifestations of toxicity beyond the expected additive effects were observed. Skin reactions were consistent with the most commonly reported adverse reactions in patients receiving panitumumumab in combination with chemotherapy. Hypomagnesemia, diarrhea, and stomatitis were other toxicities observed with higher frequency compared to monotherapy use. These toxicities did not often lead to early termination of Vectibix or chemotherapy.

Description of individual adverse reactions

.Digestive system disorders

In most cases, diarrhea was mild to moderate in severity. Severe cases of diarrhea (NCI-CTC grades 3 and 4) have been reported in 2% of patients who received Vectibix as monotherapy and in 16% of patients who received Vectibix in combination with chemotherapy.

The development of acute renal failure with severe diarrhea and dehydration has been reported (see section “Special Precautions”).

Infusion reactions

. In all clinical trials of mono- and combination therapy for mCRR (n = 2224), infusion reactions (developing within 24 hours of the first drug administration), of which chills, elevated body temperature, or dyspnea may have been a symptom/sign, were reported in approximately 5% of patients receiving Vectibix, of which 1% were severe (grade 3 and 4 NCI-CTC).

A case of fatal angioedema has been reported in a patient with recurrent metastatic squamous cell head and neck cancer treated with Vectibix. A fatal complication developed when therapy was resumed after a previous episode of angioedema. Both reactions were recorded more than 24 hours after drug administration (see Sections “Contraindications” and “Special Precautions”). Hypersensitivity reactions developed more than 24 hours after infusion have also been reported in the post-registration period.

The clinical management of reactions to the infusion is described in the “Special Indications” section.

Skin and subcutaneous fatty tissue disorders

The skin rash most commonly localized to the face, upper chest, and back, but in some cases extended to the extremities. As a consequence of severe dermatological reactions, the development of infectious complications, such as sepsis, rarely fatal, subcutaneous inflammation and local abscesses requiring surgical intervention and drainage, was also noted. The median time to development of the first dermatological reactions was 10 days, and the median time to their resolution since the last administration of Vectibix was 31 days.

Paronychial inflammation was accompanied by swelling of the lateral nail rollers of the fingers and toes.

The dermatologic reactions (including nail exposure) seen in patients treated with Vectibix or other EGFR inhibitors are known pharmacologic effects of these drugs.

In all clinical trials, skin reactions were observed in approximately 94% of patients who received Vectibix as monotherapy or in combination with chemotherapy (n = 2224). These were mostly rashes and acne-like dermatitis of almost always mild to moderate nature. Severe skin reactions (NCICTC grade 3) were reported in 23% of patients, and life-threatening skin reactions (NCI-CTC grade 4) in < 1% of patients. Life-threatening and fatal infectious complications including necrotizing fasciitis and sepsis have been reported in patients treated with Vectibix (see “Special Indications”).

The clinical management of dermatologic reactions, including recommendations for dosage modification, are listed in the Special Indications section.

In the post-registration period of use, rare cases of skin necrosis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported (see section “Special Indications”).

Ophthalmic toxicity

Serious cases of keratitis and ulcerative keratitis have been reported, which may lead to corneal perforation (see section “Special Precautions”).

Other Special Populations

There were no differences in safety or efficacy in elderly patients (≥65 years) treated with Vectibix monotherapy. However, an increase in serious adverse reactions was registered in elderly patients who received Vectibix therapy in combination with FOLFIRI (45% compared to 32%) or FOLFOX (52% compared to 37%) chemotherapy regimens compared to those who received chemotherapy alone (see section “Special Indications”). The most common serious adverse events were diarrhea in patients who received Vectibix in combination with FOLFOX or FOLFIRI, dehydration, and pulmonary embolism in patients who received Vectibix in combination with FOLFIRI.

There are no data concerning the safety of Vectibix in patients with renal and hepatic impairment.

Overdose

Pregnancy use