Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of safety profile
The safety of Imlygic was evaluated in the pivotal study where 292 patients received at least 1 dose of Imlygic (see section 5.1). The median duration of exposure to Imlygic was 23 weeks (5.3 months).
Twenty six (26) patients were exposed to Imlygic for at least one year.

The most commonly reported adverse reactions (≥ 25%) in Imlygic-treated patients were fatigue (50.3%), chills (48.6%), pyrexia (42.8%), nausea (35.6%), influenza-like illness (30.5%), and injection site pain (27.7%). Overall, ninety eight per cent (98%) of these adverse reactions reported were mild or moderate in severity. The most common grade 3 or higher adverse reaction was cellulitis (2.1%) (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions were determined based on clinical trials in patients with melanoma treated with Imlygic compared to GM-CSF and post-marketing experience. Incidence of adverse reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Adverse reactions from clinical trials in patients with melanoma and post-marketing experience

Infections and infestations
Common              Cellulitis*, Oral herpes
Uncommon            Incision site infection
Neoplasms benign, malignant and unspecified (including cysts and polyps) Common              Tumor pain, Infected neoplasm
Uncommon            Plasmacytoma at injection site*
Blood and lymphatic system disorders
Very common         edema peripheral
Common              Anemia
Immune system disorders
Common              Immune-mediated events†*
Uncommon            Hypersensitivity
Metabolism and nutrition disorders
Common              Dehydration
Nervous system disorders
Very common         Headache
Common              Confusional state, Anxiety, Depression, Dizziness, Insomnia Eye disorders
Uncommon            Keratitis herpetic
Ear and labyrinth disorders
Common              Ear pain
Cardiac disorders
Common              Tachycardia
Vascular disorders
Common              Deep vein thrombosis, Hypertension, Flushing
Respiratory, thoracic and mediastinal disorders
Very common         Cough
Common              Dyspnea, Oropharyngeal pain, Upper respiratory tract infection Uncommon            Obstructive airways disorder
Gastrointestinal disorders
Very common         Vomiting, Diarrhea, Constipation, Nausea
Common              Abdominal pain, Abdominal discomfort
Skin and subcutaneous tissue disorders
Common              Vitiligo, Rash, Dermatitis
Uncommon            Granulomatous dermatitis
Musculoskeletal and connective tissue disorders
Very common         Myalgia, Arthralgia, Pain in extremity
Common              Back pain, Groin pain
General disorders and administration site conditions
Very common         Influenza-like illness*, Pyrexia, Chills, Fatigue, Pain, Injection site reactions§ Common              Malaise, Axillary pain
Investigations
Common              Weight decreased
Injury, poisoning and procedural complications
Common              Wound complication, Wound secretion, Contusion, Procedural pain §
Injection site reactions include: very common term of injection site pain, common terms of injection site erythema, injection site hemorrhage, injection site swelling, injection site reaction, injection site inflammation, secretion discharge, injection site discharge, uncommon term of injection site warmth.
†
Immune-mediated events include: uncommon terms of vasculitis, pneumonitis, worsening psoriasis and glomerulonephritis.
* See Description of selected adverse reactions.

Description of selected adverse reactions

Immune-mediated events
Immune-mediated events reported in the pivotal clinical study included a case of worsening psoriasis in a patient with a prior history of psoriasis, one case of pneumonitis in a patient with a prior history of autoimmune disease, one case of vasculitis, and two cases of glomerulonephritis of which one presented with acute renal failure.

Plasmacytoma

In clinical trials, one case of plasmacytoma at injection site was observed in a patient who was found to have multiple myeloma.

Cellulitis

In the pivotal clinical trial (study 005/05), events of cellulitis were recorded, some of them being considered as serious adverse events. However, none lead to permanent discontinuation of Imlygic 
treatment. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds.

Influenza-like symptoms

90% of patients treated with Imlygic experienced influenza-like symptoms. Pyrexia, chills, and influenza-like illness, which can occur any time during treatment, generally resolved within 72 hours.
These events were reported more frequently within the period of the first 6 treatments, particularly in patients who were HSV-1 negative at baseline.

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/