Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands
Efficacy data for Imlygic in the current second or later line treatment settings are limited.
Imlygic has not been studied in immunocompromised patients. Based on animal data, patients who are severely immunocompromised may be at an increased risk of disseminated herpetic infection and should not be treated with Imlygic (see sections 4.3 and 5.3). Disseminated herpetic infection may also occur in immunocompromised patients (such as those with HIV/AIDS, leukaemia, lymphoma, common variable immunodeficiency, or who require chronic high-dose steroids or other immunosuppressive agents). The risks and benefits of treatment should be considered before administering Imlygic to these patients.
Accidental exposure may lead to transmission of Imlygic and herpetic infection. Healthcare professionals and close contacts (e.g. household members, caregivers, sex partners or persons sharing the same bed) should avoid direct contact with injected lesions or body fluids of treated patients during the entirety of the treatment period and up to 30 days after the last treatment administration (see section 6.6). Accidental needle stick and splash-back have been reported in healthcare professionals during preparation and administration of Imlygic.
Close contacts who are pregnant or immunocompromised should not change the patient’s dressing or clean their injection site. Pregnant women, neonates, and immunocompromised individuals should not be exposed to potentially contaminated materials.
Healthcare professionals should ensure that patients are able to comply with the requirement to cover injection sites with occlusive dressings (see section 6.6). Patients should also be advised to avoid touching or scratching injection sites as this could lead to inadvertent transfer of Imlygic to other areas of their body or to their close contacts.
Although it is not known if Imlygic could be transmitted through sexual contact, it is known that wild-type HSV-1 can be transmitted through sexual contact. Patients should be advised to use a latex condom during sexual contact to prevent possible transmission of Imlygic. Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with Imlygic (see section 4.6).
Caregivers should be advised to wear protective gloves when assisting patients in applying or changing occlusive dressings and to observe safety precautions for disposal of used dressings and cleaning materials (see sections 4.2 and 6.6).
In the event of an accidental exposure to Imlygic, exposed individuals should be advised to clean the affected area thoroughly with soap and water and/or a disinfectant. If signs or symptoms of herpetic infection develop, they should contact their healthcare professional. Talimogene laherparepvec is sensitive to acyclovir. In case suspected herpetic lesions occur, patients, close contacts or healthcare providers have the option of follow-up testing by the Marketing Authorisation Holder for further characterisation of the infection.
In clinical studies, herpetic infections (including cold sores and herpes keratitis) have been reported in patients treated with Imlygic. Symptoms of a local or systemic infection possibly related to Imlygic are anticipated to be similar to symptoms caused by wild-type HSV-1 infections.
Individuals with wild-type HSV-1 infection are known to be at a lifelong risk for symptomatic herpetic infection due to reactivation of latent wild-type HSV-1. Symptomatic herpetic infection due to possible reactivation of Imlygic should be considered.
Patients who develop herpetic infections should be advised to follow standard hygienic practices to prevent viral transmission.
Talimogene laherparepvec is sensitive to acyclovir. The risks and benefits of Imlygic treatment should be considered before administering acyclovir or other anti-viral agents indicated for management of herpetic infection. These agents may interfere with the effectiveness of Imlygic if administered systemically or topically directly to the injection site.
Necrosis or ulceration of tumour tissue may occur following Imlygic treatment. Cellulitis and systemic bacterial infection have been reported. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds.
In clinical studies, impaired healing at the injection site has been reported. Imlygic may increase the risk of impaired healing in patients with underlying risk factors (e.g. previous radiation at the injection site, or lesions in poorly vascularised areas).
The risks and benefits of Imlygic should be considered before continuing treatment if persistent infection or delayed healing develops.
In clinical studies, immune-mediated events including as glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been reported in patients treated with Imlygic.
The risks and benefits of Imlygic should be considered before initiating treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events.
Plasmacytoma has been reported in proximity to the injection site after administration of Imlygic. The risks and benefits of Imlygic should be considered in patients with multiple myeloma or in whom plasmacytoma develops during treatment.
Obstructive airway disorder has been reported following Imlygic treatment. Caution should be used when injecting lesions close to major airways.
Patients who were HSV-1 seronegative at baseline were reported to have a greater incidence of pyrexia, chills, and influenza-like illness compared with those who were HSV-1 seropositive at baseline, especially within the period of the first 6 treatments (see section 4.8).
This medicinal product contains 80 mg sorbitol (E420) per 4 mL dose. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
This medicinal product contains approximately 30 mg sodium per 4 mL dose, equivalent to 1.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
No interaction studies have been conducted with Imlygic. Acyclovir and other anti-viral agents may interfere with the effectiveness of Imlygic if administered systemically or topically directly to the injection site. Consider the risks and benefits of Imlygic treatment before administering acyclovir or other anti-viral agents indicated for management of herpetic infection.
Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with Imlygic.
All patients should be advised to use a latex condom during sexual contact to prevent possible transmission of Imlygic (see section 4.4).
Adequate and well controlled studies with talimogene laherparepvec have not been conducted in pregnant women.
If a pregnant woman has an infection with wild type HSV-1 (primary or reactivation), there is potential for the virus to cross the placental barrier, and also a risk of transmission during birth due to viral shedding. Infections with wild-type HSV-1 have been associated with serious adverse effects, including multi-organ failure and death, if a foetus or neonate contracts the wild type herpes infection.
While there are no clinical data to date on talimogene laherparepvec infections in pregnant women, there could be a risk to the foetus or neonate if talimogene laherparepvec were to act in the same manner. No effects on embryo-foetal development have been observed in animal studies (see section 5.3). As a precautionary measure, it is preferable to avoid the use of talimogene laherparepvec during pregnancy.
Transplacental metastases of malignant melanoma can occur. Because talimogene laherparepvec is designed to enter and replicate in the tumour tissue, there could be a risk of foetal exposure to talimogene laherparepvec from tumour tissue that has crossed the placenta.
If Imlygic is used during pregnancy, or if the patient becomes pregnant while taking Imlygic, the patient should be apprised of the potential hazards to the foetus and/or neonate.
It is unknown whether talimogene laherparepvec is transferred into human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Imlygic therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
No clinical studies have been performed to evaluate the effects of talimogene laherparepvec on fertility (see section 5.3).
Talimogene laherparepvec may have a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as dizziness and confusional state (see section 4.8), patients should be advised to use caution when driving or operating machinery until they are certain that talimogene laherparepvec does not adversely affect them.
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).
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:
Common: Cellulitis*, Oral herpes
Uncommon: Incision site infection
Common: Tumour pain, Infected neoplasm
Uncommon: Plasmacytoma at injection site*
Very common: Oedema peripheral
Common: Anaemia
Common: Immune-mediated events†*
Uncommon: Hypersensitivity
Common: Dehydration
Very common: Headache
Common: Confusional state, Anxiety, Depression, Dizziness, Insomnia
Uncommon: Keratitis herpetic
Common: Ear pain
Common: Tachycardia
Common: Deep vein thrombosis, Hypertension, Flushing
Very common: Cough
Common: Dyspnoea, Oropharyngeal pain, Upper respiratory tract infection
Uncommon: Obstructive airways disorder
Very common: Vomiting, Diarrhoea, Constipation, Nausea
Common: Abdominal pain, Abdominal discomfort
Common: Vitiligo, Rash, Dermatitis
Uncommon: Granulomatous dermatitis
Very common: Myalgia, Arthralgia, Pain in extremity
Common: Back pain, Groin pain
Very common: Influenza like illness*, Pyrexia, Chills, Fatigue, Pain, Injection site reactions§
Common: Malaise, Axillary pain
Common: Weight decreased
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 haemorrhage, 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
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.
In clinical trials, one case of plasmacytoma at injection site was observed in a patient who was found to have multiple myeloma.
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.
90% of patients treated with Imlygic experienced influenza-like symptoms. Pyrexia, chills, and influenza like illness, which can occur any time during Imlygic 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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