Adverse reactions : תופעות לוואי

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               Very common                   Common                    Uncommon organ class                    (≥ 1/10)             (≥ 1/100 to < 1/10)       (≥ 1/1,000 to < 1/100) Infections and          Conjunctivitis        Rash pustular                 Eye infection infestations            Paronychia1           Cellulitis1                   Eyelid infection Urinary tract infection
Folliculitis
Localized infection
Blood and lymphatic     Anemia                Leukopenia system disorders
Immune system                                 Hypersensitivity1             Anaphylactic reaction2 disorders
Metabolism and          Hypokalemia           Hypocalcemia nutrition disorders     Hypomagnesemia        Dehydration
Decreased appetite    Hyperglycemia
Hypophosphatemia
Psychiatric disorders   Insomnia              Anxiety
Nervous system                                Headache disorders                                     Dizziness
Eye disorders                                 Blepharitis                   Ulcerative keratitis1,4 Growth of eyelashes           Keratitis1
Lacrimation increased         Eyelid irritation
Ocular hyperemia
Dry eye
Eye pruritus
Eye irritation
Cardiac disorders                             Tachycardia                   Cyanosis Vascular disorders                            Deep vein thrombosis
Hypotension
Hypertension
Flushing
Respiratory, thoracic   Dyspnea               Pulmonary embolism            Interstitial lung disease3 and mediastinal         Cough                 Epistaxis                     Bronchospasm disorders                                                                   Nasal dryness Gastrointestinal        Diarrhea1             Rectal hemorrhage             Chapped lips disorders               Nausea                Dry mouth                     Dry lips Vomiting              Dyspepsia
Abdominal pain        Aphthous ulcer
Stomatitis            Cheilitis
Constipation          Gastroesophageal reflux disease



Adverse reactions

MedDRA system                 Very common                       Common                         Uncommon organ class                       (≥ 1/10)                 (≥ 1/100 to < 1/10)            (≥ 1/1,000 to < 1/100) Skin and subcutaneous    Dermatitis acneiform        Skin ulcer                        Toxic epidermal tissue disorders1        Rash                        Skin exfoliation                  necrolysis1,4 Erythema                    Exfoliative rash                  Stevens-Johnson Pruritus                    Dermatitis                        syndrome1,4 Dry skin                    Rash papular                      Skin necrosis1,4 Skin fissures               Rash pruritic                     Angioedema1 Acne                        Rash erythematous                 Hirsutism Alopecia                    Rash generalized                  Ingrowing nail Rash macular                      Onycholysis
Rash maculo-papular
Skin lesion
Skin toxicity
Scab
Hypertrichosis
Onychoclasis
Nail disorder
Hyperhidrosis
Palmar-plantar erythrodysesthesia syndrome
Musculoskeletal and      Back pain                   Pain in extremity connective tissue disorders
General disorders and    Fatigue                     Chest pain administration site      Pyrexia                     Pain conditions               Asthenia                    Chills
Mucosal inflammation
Edema peripheral
Injury, poisoning and                                                                    Infusion-related reaction1 procedural complications
Investigations              Weight decreased           Blood magnesium decreased 1
See section “Description of selected adverse reactions” below
2
See section 4.4 Infusion-related reactions
3
See section 4.4 Pulmonary complications
4
Skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis and ulcerative keratitis 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

Serious cases of keratitis and ulcerative keratitis, which may lead to corneal perforation, have been 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./