4.1. Therapeutic indications

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 (see sections 4.4 and 5.1).

4.2. Posology and method of administration

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 the treatment (see also Package leaflet).

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 is shown in table 1.

Table 1. Recommended dosing schedule

Treatment visit

Treatment interval

Maximum total injection volume

Dose concentrations

Prioritisation of lesions to be injected

Initial

-

Up to 4 mL

106

(1 million)

PFU/mL

• Inject largest lesion(s) first.

• Prioritise injection of remaining lesions based on lesion size until maximum injection volume is reached.

Second

3 weeks after initial treatment

Up to 4 mL

108

(100 million)

PFU/mL

• First inject any new lesions (lesions that may have developed since initial treatment).

• Prioritise injection of remaining lesions based on lesion size until maximum injection volume is reached.

All subsequent treatment visits (including re-initiation)

2 weeks after previous treatment

Up to 4 mL

108

(100 million)

PFU/mL

• First inject any new lesions (lesions that may have developed since previous treatment).

• Prioritise injection of remaining lesions based on lesion size until maximum injection volume is reached.

Determining Imlygic dose volume (per lesion)

The volume to be injected into each lesion is dependent on the size of the lesion and should be determined according to table 2. The total injection volume for each treatment session should be up to a maximum of 4 mL.

Table 2. Selection of Imlygic injection volume based on lesion size

Lesion size (longest dimension)

Imlygic injection volume

> 5 cm

up to 4 mL

> 2.5 cm to 5 cm

up to 2 mL

> 1.5 cm to 2.5 cm

up to 1 mL

> 0.5 cm to 1.5 cm

up to 0.5 mL

≤ 0.5 cm

up to 0.1 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.

Special populations

Elderly population

No adjustment of the dose is required in patients ≥ 65 years old (see section 5.1).

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.

Paediatric population

The safety and efficacy of Imlygic in paediatric patients has not been established. Currently available data for paediatric and young adult patients aged 7 to ≤ 21 years with advanced non-central nervous system tumours amenable to direct injection are described in section 5.1.

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.

Precautions to be taken before manipulating or administering the medicinal product

This medicinal product contains genetically modified organisms. Personal protective equipment should be worn while preparing or administering talimogene laherparepvec (see section 6.6).

Healthcare professionals who are immunocompromised or pregnant should not administer Imlygic and should not come into direct contact with the injection site(s) or body fluids of treated patients (see sections 4.3 and 4.4).

Follow the instructions below to prepare and administer Imlygic to patients:

Pre-injection

• Thaw Imlygic vial(s) at room temperature. Thawed vials may be stored prior to administration (see section 6.3). For handling of thawed vials, see section 6.6.

• Draw the desired amount of Imlygic from the vial into a syringe using aseptic technique. A 22- to 26-gauge needle is recommended.

• The injection site may be treated with a topical anaesthetic agent. Injectable anaesthetic may be injected around the periphery of the lesion but should not be injected directly into the lesion.

• Clean the lesion and surrounding areas with an alcohol swab and let dry.

Injection

• Inject Imlygic intralesionally into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable or detectable by ultrasound guidance.

• Determine injection volume for each lesion using table 2 above.

• Using a single insertion point, inject Imlygic along multiple tracks as far as the radial reach of the needle allows within the lesion to achieve even and complete dispersion. Multiple insertion points may be used if a lesion is larger than the radial reach of the needle.

Cutaneous lesions

Subcutaneous lesions

Nodal lesions

Figure 1.

Injection administration for cutaneous lesions

Figure 2.

Injection administration for subcutaneous lesions

Figure 3.

Injection administration for nodal lesions

• Disperse Imlygic evenly and completely within the lesion by pulling the needle back without exiting the lesion. Redirect the needle as many times as necessary while injecting the remainder of the dose. Continue until the full dose is evenly and completely dispersed.

• When removing the needle, withdraw it from the lesion slowly to avoid leakage or splash back of Imlygic at the insertion point.

• Repeat these steps for other lesions that need to be injected. Use a new needle anytime the needle is completely removed from a lesion and each time a different lesion is injected.

Post-injection

• Apply pressure to the injection site with a sterile gauze for at least 30 seconds.

• Swab the injection site and surrounding area with alcohol, and cover the injected lesion with an absorbent pad and dry occlusive dressing.

4.3. Contraindications

• 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) (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Previously treated patients

Efficacy data for Imlygic in the current second or later line treatment settings are limited.

Disseminated herpetic infection

Disseminated herpetic infection, including serious cases of disseminated herpetic infection, have been reported in patients treated with Imlygic (see section 4.8).

Imlygic has not been studied in immunocompromised patients. Based on epidemiological data, immunocompromised patients (such as those with HIV/AIDS, leukaemia, lymphoma, common variable immunodeficiency, or who require chronic high-dose steroids or other immunosuppressive agents) may be at increased risk of disseminated herpetic infection. Consider the risks and benefits of treatment before administering Imlygic to 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).

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 (see section 6.6). Accidental needle stick and splashback have been reported in healthcare professionals during preparation and administration.

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 (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 section 6.6).

In the event of an accidental exposure to Imlygic, follow instructions in section 6.6. If signs or symptoms of herpetic infection develop, exposed individuals should contact their healthcare professional. 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.

Herpetic infection in Imlygic-treated patients

Herpetic infections (including but not limited to cold sores and herpes keratitis) and serious cases of disseminated herpetic infections have been reported in patients treated with Imlygic (see section 4.8). 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 the treatment if administered systemically or topically directly to the injection site.

Information on herpetic lesions is provided in the Patient Alert Card.

Cellulitis at 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.

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 vascularised 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 (see section 4.8).

Hepatic haemorrhage from transcutaneous intrahepatic route of administration

Imlygic is not indicated for transcutaneous intrahepatic route of administration. In clinical studies, cases of hepatic haemorrhage resulting in hospitalisation and death have been reported in patients receiving transcutaneous intrahepatic Imlygic injections.

All patients

This medicinal product contains 20 mg sorbitol per 1 mL vial. 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 7.7 mg sodium per 1 mL vial, equivalent to 0.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been conducted with Imlygic. Acyclovir and other anti-viral agents may interfere with the effectiveness of the treatment 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception

Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment.

All patients should be advised to use a latex condom during sexual contact to prevent possible transmission of Imlygic (see section 4.4).

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 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 the medicinal product, the patient should be apprised of the potential hazards to the foetus and/or neonate.

Breast-feeding

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.

Fertility

No clinical studies have been performed to evaluate the effects of talimogene laherparepvec on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the 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, 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 (≥ 1/1000 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*, Herpes infections**

Uncommon

Incision site infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common

Tumour pain, Infected neoplasm

Uncommon

Plasmacytoma at injection site*

Blood and lymphatic system disorders

Very common

Oedema peripheral

Common

Anaemia

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

Dyspnoea, Oropharyngeal pain, Upper respiratory tract infection

Uncommon

Obstructive airways disorder

Gastrointestinal disorders

Very common

Vomiting, Diarrhoea, 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 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

**Herpetic infections (including, but not limited to Oral herpes)

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

Ninety percent (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.

Paediatric population

A paediatric phase 1 clinical trial (study 20110261) was conducted in 15 paediatric and young adult patients aged 7 to ≤ 21 years with advanced non-central nervous system tumours amenable to direct injection (see section 5.1). The safety data was consistent with the patients' underlying disease and the known safety profile of talimogene laherparepvec in adults.

Reporting of suspected adverse reactions

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no clinical experience with overdose with Imlygic. Doses up to 4 mL at a concentration of 108 PFU/mL every 2 weeks have been administered in clinical trials with no evidence of dose limiting toxicity. The maximum dose 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 (see section 4.4) and supportive measures instituted as required.