Imlygic

/ Amgen

Treatment with talimogene laherparepvec should be initiated and supervised by a qualified physician experienced in the treatment of cancer.
Patients treated with Imlygic must be given the patient alert card and be informed about the risks of Imlygic.
Posology: Imlygic is provided in single-use vials of 1 mL each in two different concentrations:
– 10⁶ (1 million) PFU/mL – For initial dose only.
– 10⁸ (100 million) PFU/mL – For all subsequent doses.
The total injection volume for each treatment visit should be up to a maximum of 4 mL. The initial recommended dose is up to a maximum of 4 mL of Imlygic at a concentration of 10⁶ (1 million) PFU/mL. Subsequent doses should be administered up to 4 mL of Imlygic at a concentration of 10⁸ (100 million) PFU/mL.
The recommended dosing schedule for Imlygic is shown in table 1 at the attached doctor’s leaflet.
Determining Imlygic dose volume (per lesion): The volume of Imlygic to be injected into each lesion is dependent on the size of the lesion and should be determined according to table 2 at the attached doctor’s leaflet. The total injection volume for each treatment session should be up to a maximum of 4 mL.
Patients may experience increase in size of existing lesion(s) or the appearance of a new lesion prior to achieving a response. As long as there are injectable lesion(s) remaining, Imlygic should be continued for at least 6 months unless the physician considers that the patient is not benefitting from Imlygic treatment or that other treatment is required.
Imlygic treatment may be reinitiated if new lesions appear following a complete response and the physician considers that the patient will benefit from treatment.
Pediatric population: The safety and efficacy of Imlygic in pediatric patients has not been established. No data are available.
Elderly population: No adjustment of the dose is required in patients ≥ 65 years old.
Hepatic and renal impairment: No clinical studies have been conducted to evaluate the effect of hepatic or renal impairment on the pharmacokinetics of talimogene laherparepvec. However, no adjustment in dosage is necessary for patients with hepatic or renal impairment.
Method of administration: Imlygic is to be administered by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable or detectable by ultrasound guidance.
If healthcare professionals are accidentally exposed to Imlygic, see Special Precautions.
Healthcare professionals who are immunocompromised or pregnant should not administer Imlygic and should not come into direct contact with the Imlygic injection site(s) or body fluids of treated patients.
See prescribing information for full details.

Imlygic is indicated for the treatment of adults with unresectable melanoma that is regionally or
distantly metastatic (Stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral disease

Patients with a history of hypersensitivity to talimogene laherparepvec or any of its excipients.
Patients who are severely immunocompromised (e.g. patients with severe congenital or acquired cellular and/or humoral immune deficiency).

Previously treated patients: Efficacy data for Imlygic in the current second or later line treatment settings are limited.
Immunocompromised patients: 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. Disseminated herpetic infection may also occur in immunocompromised patients (such as those with HIV/AIDS, leukemia, 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 to Imlygic: 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. 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. 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.
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.
In the event of an accidental exposure to Imlygic, exposed ,in case suspected herpetic lesions occur, patients, close contacts or healthcare providers have the option of follow-up testing by the Marketing Authorization Holder for further characterization of the infection.
Herpetic infection in Imlygic-treated patients: 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.
Cellulitis at the injection site: Necrosis or ulceration of tumor 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.
Impaired healing at the injection site: 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 vascularized areas).
The risks and benefits of Imlygic should be considered before continuing treatment if persistent infection or delayed healing develops.
Immune-mediated events: 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 at injection site: 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: Obstructive airway disorder has been reported following Imlygic treatment. Caution should be used when injecting lesions close to major airways.
HSV-1 seronegative patients: 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.
All patients: 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.
Traceability of Imlygic: 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.

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 prescribing information for full details.

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.

Pregnancy: 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 fetus 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 fetus or neonate if talimogene laherparepvec were to act in the same manner. No effects on embryo-fetal development have been observed in animal studies.
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 tumor tissue, there could be a risk of fetal exposure to talimogene laherparepvec from tumor 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 fetus and/or neonate.
Lactation: 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.

There is no clinical experience with overdose with Imlygic. Doses up to 4 mL at a concentration of 10^8 PFU/mL every 2 weeks have been administered in clinical trials with no evidence of dose limiting toxicity. The maximum dose of Imlygic that can be safely administered has not been determined. In the event of a suspected overdose or inadvertent intravenous administration, the patient should be treated symptomatically, e.g. with acyclovir or other anti-viral agents  and supportive measures instituted as required.

Storage: Store and transport frozen (-90°C to -70°C). Store in the original carton in order to protect from light.