2.1       Dose

Administer IMLYGIC by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.

IMLYGIC is provided in single-use vials of 1 mL each in two different dose strengths:

• 106 (1 million) plaque-forming units (PFU) per mL (light green cap) – for initial dose only
• 108 (100 million) PFU per mL (royal blue cap) – for all subsequent doses

Recommended Dose and Schedule

The total injection volume for each treatment visit should not exceed 4 mL for all injected lesions combined. It may not be possible to inject all lesions at each treatment visit or over the full course of treatment. Previously injected and/or uninjected lesion(s) may be injected at subsequent treatment visits. The initial recommended dose is up to 4 mL of IMLYGIC at a concentration of 106 (1 million) PFU per mL. The recommended dose for subsequent administrations is up to 4 mL of IMLYGIC at a concentration of 108 (100 million) PFU per mL. The recommended dosing schedule for IMLYGIC is shown in Table 1.

Dose Volume Determination (per Lesion)

Use Table 2 to determine the volume of IMLYGIC injection for each lesion.

When lesions are clustered together, inject them as a single lesion according to Table 2.

Continue IMLYGIC treatment for at least 6 months unless other treatment is required or until there are no injectable lesions to treat.

Reinitiate IMLYGIC treatment if new unresectable cutaneous, subcutaneous, or nodal lesions appear after a complete response.

2.2       Preparation and Handling

Healthcare providers who are immunocompromised or pregnant should not prepare or administer IMLYGIC and should not come into direct contact with the IMLYGIC injection sites, dressings, or body fluids of treated patients [see Warnings and Precautions (5.1)].

Avoid accidental exposure to IMLYGIC and follow universal biohazard precautions for preparation, administration, and handling of IMLYGIC:

• Wear personal protective equipment (protective gown or laboratory coat, safety glasses or face shield, and gloves) while preparing or administering IMLYGIC.
• Avoid accidental exposure to IMLYGIC, especially contact with skin, eyes, and mucous membranes.
  ○ Cover any exposed wounds before handling.
  ○ In the event of an accidental occupational exposure (e.g., through a splash to the eyes or mucous membranes), flush with clean water for at least 15 minutes.
  ○ In the event of exposure to broken skin or needle stick, clean the affected area thoroughly with soap and water and/or a disinfectant.
• Treat all IMLYGIC spills with a virucidal agent such as 1% sodium hypochlorite and blot using absorbent materials.
• Dispose of all materials that may have come in contact with IMLYGIC (e.g., vial, syringe, needle, cotton gauze, gloves, masks, or dressings) in accordance with universal biohazard precautions.
• Advise patients to place used dressings and cleaning materials into a sealed plastic bag and dispose in household waste.

Thawing IMLYGIC Vials

1. Determine the total volume required for injection, up to 4 ml [see Dosage and Administration (2.1)].

2. Thaw frozen IMLYGIC vials at room temperature [20º to 25ºC (68º to 77ºF)] until IMLYGIC is liquid (approximately 30 minutes). Do not expose the vial to higher temperatures. Keep the vial in original carton during thawing.

3. Swirl gently. Do NOT shake.

4. After thawing, administer IMLYGIC immediately or store in its original vial and carton, protected from light in a refrigerator [2° to 8°C (36° to 46°F)] for no longer than the specified duration in Table 3. Do not refreeze IMLYGIC after thawing. Discard any IMLYGIC vial left in the refrigerator longer than the specified times in Table 3.

5. Prepare sterile syringes and needles. A detachable needle of 18–26G may be used for IMLYGIC withdrawal and a detachable needle of 22–26G may be used for injection. Small unit syringes (e.g., 0.5 mL insulin syringes) are recommended for better injection control.

6. Using aseptic technique, remove the vial cap and withdraw the product from the vial into the syringe(s), noting the total volume. Avoid generating aerosols when loading syringes with product, and use a biologic safety cabinet if available.

2.3       Administration

Follow the steps below to administer IMLYGIC to patients:

Pre-Injection

1. Clean the lesion and surrounding areas with an alcohol swab and let dry.
2. Treat the injection site with a topical or local anesthetic agent, if necessary. Do not inject anesthetic agent directly into the lesion. Inject anesthetic agent around the periphery of the lesion.

Injection

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

2. Inject 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 of IMLYGIC. Continue until the full dose is evenly and completely dispersed.

3. When removing the needle, withdraw it from the lesion slowly to avoid leakage of IMLYGIC at the insertion point.

4. Repeat steps 1-2 under pre-injection and steps 1-3 under injection for other lesions to be injected.

5. Use a new needle any time the needle is completely removed from a lesion and each time a different lesion is injected.

Post-Injection

1. Apply pressure to the injection site(s) with sterile gauze for at least 30 seconds.
2. Swab the injection site(s) and surrounding area with alcohol.
3. Change gloves and cover the injected lesion(s) with an absorbent pad and dry occlusive dressing. 
4. Wipe the exterior of occlusive dressing with alcohol.
5. Advise patients to:
          •     Keep the injection site(s) covered for at least the first week after each treatment visit or longer if the injection site is weeping or oozing.
          •     Replace the dressing if it falls off.

4.1       Immunocompromised Patients

IMLYGIC is a live, attenuated herpes simplex virus and may cause life-threatening disseminated herpetic infection in patients who are immunocompromised. Do not administer IMLYGIC to immunocompromised patients, including those with a history of primary or acquired immunodeficient states, leukemia, lymphoma, AIDS or other clinical manifestations of infection with human immunodeficiency viruses, and those on immunosuppressive therapy [see Nonclinical Toxicology (13.2)].

4.2       Pregnant Patients

Do not administer IMLYGIC to pregnant patients.

5.1       Accidental Exposure to IMLYGIC

Accidental exposure may lead to transmission of IMLYGIC and herpetic infection. Accidental needle stick and splashback to the eyes have been reported in healthcare providers during preparation and administration of IMLYGIC.  

Healthcare providers, close contacts (household members, caregivers, sex partners, or persons sharing the same bed), pregnant women, and newborns should avoid direct contact with injected lesions, dressings, or body fluids of treated patients [see Dosage and Administration (2.2)]. Healthcare providers who are immunocompromised or pregnant should not prepare or administer IMLYGIC.

Caregivers should wear protective gloves when assisting patients in applying or changing occlusive dressings and observe safety precautions for disposal of used dressings, gloves, and cleaning materials [see Dosage and Administration (2.2)].

In the event of an accidental exposure to IMLYGIC, exposed individuals should clean the affected area thoroughly with soap and water and/or a disinfectant. If signs or symptoms of herpetic infection develop, the exposed individuals should contact their healthcare provider for appropriate treatment [see Warnings and Precautions (5.2)].

Patients should avoid touching or scratching injection sites or their occlusive dressings, as doing so could lead to inadvertent transfer of IMLYGIC to other areas of the body.

5.2        Herpetic Infection

In clinical studies, herpetic infections (including cold sores and herpetic keratitis) have been reported in patients treated with IMLYGIC. Disseminated herpetic infection may also occur in immunocompromised patients [see Contraindications (4.1)].

Patients who develop suspicious herpes-like lesions should follow standard hygienic practices to prevent viral transmission. Patients or close contacts with suspected herpetic infections should also contact their healthcare provider to eva luate the lesions. Suspected herpetic lesions should be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442); patients or close contacts have the option of follow-up testing for further characterization of the infection.

IMLYGIC is sensitive to acyclovir. Acyclovir or other antiviral agents may interfere with the effectiveness of IMLYGIC. Therefore, consider the risks and benefits of IMLYGIC treatment before administering antiviral agents to manage herpetic infection.

5.3       Injection Site Complications

Necrosis or ulceration of tumor tissue may occur during IMLYGIC treatment. Cellulitis and systemic bacterial infection have been reported in clinical studies. 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 vascularized areas). One patient had an amputation of a lower extremity 6 months after IMLYGIC injection due to an infected non-healing wound. This wound area had been treated with surgery and radiation prior to IMLYGIC treatment and had previous wound complications.

If there is persistent infection or delayed healing of the injection site(s), consider the risks and benefits of IMLYGIC before continuing treatment with IMLYGIC.

5.4       Immune-Mediated Events

IMLYGIC may result in immune-mediated events. In clinical studies, immune-mediated events, including glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been reported in patients treated with IMLYGIC.

Consider the risks and benefits of IMLYGIC before initiating treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events.

5.5       Plasmacytoma at Injection Site

In a clinical study, a plasmacytoma has been reported in proximity to the injection site after administration of IMLYGIC in a patient with smoldering multiple myeloma.

Consider the risks and benefits of IMLYGIC in patients with multiple myeloma or in whom plasmacytoma develops during treatment.

6.1       Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of IMLYGIC was eva luated in 419 patients who received at least 1 dose of either IMLYGIC (n = 292) or subcutaneously administered granulocyte-macrophage colony-stimulating factor (GM-CSF) (n = 127) in an open-label, randomized clinical study of patients with stage IIIB, IIIC, and IV melanoma that was not considered to be surgically resectable [see Clinical Studies