Imlygic Drug Information

IMLYGIC is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Limitations of use: IMLYGIC has not been shown to improve overall survival or have an effect on visceral metastases.

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-dose vials of 1 mL each in two different dose strengths: 10 6 (1 million) plaque-forming units (PFU) per mL (light green cap) – for initial dose only 10 8 (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 recommended dosing schedule for Imlygic is shown in Table 1. Table 1.

Recommended Dose and Schedule for Imlygic Dose Volume Determination (per Lesion) Use Table 2 to determine the volume of Imlygic injection for each lesion. Table 2. Determination of Imlygic 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.

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. Avoid accidental exposure to Imlygic and follow below instructions 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.

Clean all surfaces that may have come in contact with Imlygic and treat all Imlygic spills with a virucidal agent such as 1% sodium hypochlorite or 70% isopropyl alcohol 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) as biohazardous waste. 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. 2. Thaw frozen Imlygic vials at room temperature until Imlygic is liquid.

The time to achieve complete vial thaw is expected to be 30 to 70 minutes, depending on the ambient temperature. 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, as follows: Thawed Imlygic is stable when stored at temperatures of 2°C (36°F) up to 25°C (77°F) protected from light in its original vial and carton for the storage times specified in Table 3.

Do not exceed the storage times specified in Table 3. Imlygic must not be refrozen once it is thawed. Discard any thawed Imlygic in the vial stored longer than the specified times in Table 3.

Table 3. Maximum Storage Time for Thawed Imlygic in Vial 5. Prepare sterile syringes and needles.

A detachable 18-26 G needle or nondetachable 22-26 G staked needle (which minimizes hold up volume) may be used for Imlygic withdrawal and a detachable or nondetachable staked needle of 22–26 G 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.

• Administration Follow the steps below to administer Imlygic to patients: Pre-Injection Clean the lesion and surrounding areas with an alcohol swab and let dry. 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. 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.
• Figure 1: Injection administration for cutaneous lesions Figure 2: Injection administration for subcutaneous lesions Figure 3: Injection administration for nodal lesions 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. When removing the needle, withdraw it from the lesion slowly to avoid leakage of Imlygic at the insertion point. Repeat steps 1-2 under pre-injection and steps 1-3 under injection for other lesions to be injected. Use a new needle any time the needle is completely removed from a lesion and each time a different lesion is injected. Swab the injection site(s) and surrounding area with alcohol. Change gloves and cover the injected lesion(s) with an absorbent pad and dry occlusive dressing. Wipe the exterior of occlusive dressing with alcohol.
• 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.

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 evaluated 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. The median duration of exposure to IMLYGIC was 23 weeks (5.3 months).

Twenty-six patients were exposed to IMLYGIC for at least 1 year. Most adverse reactions reported were mild or moderate in severity and generally resolved within 72 hours. The most common grade 3 or higher adverse reaction was cellulitis.

Pyrexia, chills, and influenza-like illness can occur any time during IMLYGIC treatment but were more frequent during the first 3 months of treatment. Table 4 below lists adverse reactions with a 5% or greater incidence in the IMLYGIC arm compared to the GM-CSF arm in the clinical study. Table 4.

Adverse Reactions Reported with At Least a 5% Greater Incidence in Patients Treated with IMLYGIC Compared to GM-CSF Other adverse reactions associated with IMLYGIC in the open-label, randomized study include rash, dermatitis, glomerulonephritis, vitiligo, worsening psoriasis, cellulitis, pneumonitis, vasculitis, herpetic keratitis, obstructive airway disorder, plasmacytoma at the injection site, deep vein thrombosis, and oral herpes.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of IMLYGIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Herpetic infections including disseminated herpetic infections.

Serious including fatal disseminated herpetic infections in immunocompromised patient population.

IMLYGIC is sensitive to acyclovir. Acyclovir or other antiherpetic viral agents may interfere with the effectiveness of IMLYGIC. No drug interaction studies have been conducted with IMLYGIC.

Pregnancy Risk Summary Adequate and well-controlled studies with IMLYGIC have not been conducted in pregnant women. No effects on embryo-fetal development have been observed in a study conducted in pregnant mice. The design of the study limits application of the animal data to humans.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations If the patient becomes pregnant while taking IMLYGIC, the patient should be apprised of the potential hazards to the fetus and neonate. Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with IMLYGIC.

If a pregnant woman has an infection with wild-type Herpes Simplex Virus Type 1 (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 IMLYGIC infections in pregnant women, there could be a risk to the fetus or neonate if IMLYGIC were to act in the same manner.

Data Animal Data No effects on embryo-fetal development were observed when IMLYGIC was intravenously administered during organogenesis to immunocompetent pregnant mice at doses up to million PFU per kg (60-fold higher, on a PFU per kg basis, compared to the maximum clinical dose). Levels of IMLYGIC DNA in pooled fetal blood were at or below the assay detection level. Study design limitations included: 1 administration of IMLYGIC expressing human granulocyte-macrophage colony-stimulating factor (huGM-CSF), which is not biologically active in mice; 2 unknown transplacental kinetics of IMLYGIC following intravenous administration in pregnant mice; and 3 unknown significance of IMLYGIC dose extrapolation from animal to human based on body weight.

Pediatric Use Safety and effectiveness of IMLYGIC have not been established in pediatric patients.

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.

Pregnant Patients

Do not administer IMLYGIC to pregnant patients.

There is no clinical experience with an overdose with IMLYGIC. The maximum dose of IMLYGIC that can be safely administered has not been determined. In the event of a suspected overdose, the patient should be treated symptomatically and supportive measures instituted as required.