Talimogene Laherparepvec

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intralesional [preservative free]:

Imlygic: 10⁶ (1 million) PFU/mL (1 mL); 10⁸ (100 million) PFU/mL (1 mL) [contains bovine serum]

Pharmacology

Mechanism of Action

Talimogene laherparepvec is a genetically modified attenuated herpes simplex virus 1 (HSV) oncolytic virus which selectively replicates in and lyses tumor cells (Andtbacka 2015). Talimogene laherparepvec is modified through deletion of two nonessential viral genes. Deletion of the herpes virus neurovirulence factor gene ICP34.5 diminishes viral pathogenicity and increases tumor-selective replication; deletion of the ICP47 gene reduces virally mediated suppression of antigen presentation and increases the expression of the HSV US11 gene (Andtbacka 2015). Virally derived GM-CSF recruits and activates antigen-presenting cells, leading to an antitumor immune response.

Pharmacokinetics/Pharmacodynamics

Time to Peak

Peak levels of talimogene laherparepvec were detected in the urine on the day of treatment

Use: Labeled Indications

Melanoma, unresectable: Treatment (local) of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery

Limitations of use: Has not been shown to improve overall survival or have an effect on visceral metastases.

Contraindications

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; pregnancy

Dosage and Administration

Dosing: Adult

Note: Administer by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound. 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 treated at subsequent visits.

Melanoma, unresectable: Intralesional: Maximum volume (per treatment visit, for all injected lesions combined): 4 mL. Continue treatment for at least 6 months unless other therapy is necessary or until there are no injectable lesions to treat. Reinitiate treatment if new unresectable lesions appear after a previous complete response.

Use the following to determine the volume of talimogene laherparepvec to be injected (lesion size is based on longest dimension; when lesions are clustered together, inject them as a single lesion):

• If the lesion size is >5 cm, inject up to 4 mL
• If the lesion size is >2.5 cm to 5 cm, inject up to 2 mL
• If the lesion size is >1.5 cm to 2.5 cm, inject up to 1 mL
• If the lesion size is >0.5 cm to 1.5 cm, inject up to 0.5 mL
• If the lesion size is ≤0.5 cm, inject up to 0.1 mL

Initial treatment visit: Inject up to 4 mL at a concentration of 10⁶ (1 million) PFU/mL. Inject largest lesion(s) first; inject remaining lesion(s) based on lesion size until maximum injection volume is reached or all lesions have been treated.

Second treatment visit (3 weeks after initial treatment): Inject up to 4 mL at a concentration of 10⁸ (100 million) PFU/mL. Inject any new lesion(s) that have developed since initial treatment first; inject remaining lesion(s) based on lesion size until maximum injection volume is reached or all lesions have been treated.

All subsequent treatment visits, including reinitiation (2 weeks after previous treatment): Inject up to 4 mL at a concentration of 10⁸ (100 million) PFU/mL. Inject any new lesion(s) that have developed since previous treatment first; inject remaining lesion(s) based on lesion size until maximum injection volume is reached or all lesions have been treated.

Dosing: Geriatric

Refer to adult dosing.

Reconstitution

Health care providers who are immunocompromised or pregnant should not prepare or administer talimogene laherparepvec and should not handle injection sites, dressings, or body fluids of treated patients. Personal protective equipment (eg, gown or laboratory coat, safety glasses or face shield, gloves) should be worn during preparation or administration. Cover any exposed wounds prior to handling talimogene laherparepvec. If accidental exposure occurs through an eye splash or a splash to mucous membranes, flush the area with clean water for at least 15 minutes. If exposure to broken skin or a needle stick occurs, clean the affected area thoroughly with soap and water and/or a disinfectant. Clean all surfaces that may have come in contact with talimogene laherparepvec and treat spills with virucidal agents such as sodium hypochlorite 1% or 70% isopropyl alcohol and blot using absorbent materials. Dispose of all materials that may have come into contact with talimogene laherparepvec as biohazardous waste.

Thaw vials at room temperature until talimogene laherparepvec is liquid (~30 minutes); do not thaw at higher temperatures. Keep vial in the original carton during thawing. Swirly gently; do not shake. Do not refreeze after thawing. Withdraw the vial contents (using a detachable needle of 18 to 26 gauge or nondetachable needle of 22 to 26 gauge) into the syringe (note the total volume). Avoid generating aerosols; use a biologic safety cabinet if available.

Administration

Intralesional injection: Administer by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound. Clean the lesion and surrounding areas with alcohol and allow to dry. If necessary, treat the injection site with a topical or local anesthetic agent (but do not inject the anesthetic directly into the lesion [inject around periphery of lesion]). Using a single insertion point, inject talimogene laherparepvec (using a detachable or nondetachable 22- to 26-gauge needle) along multiple tracks as far as the needle allows within the lesion to achieve dispersion; multiple lesion points may be used if a lesion is larger than the radial reach of the needle. Small unit syringes (eg, 0.5 mL insulin syringes) are recommended for better injection control.

Inject talimogene laherparepvec evenly and completely within the lesion by pulling the needle back without removing it from the lesion. Redirect the needle as necessary while injecting the remainder of the dose; continue until the full dose is evenly and completely dispersed. Remove the needle from the lesion slowly to avoid leakage. Repeat steps for other lesions to be treated. Use a new needle if the needle is completely removed from a lesion and each time a different lesion is injected. Apply pressure with sterile gauze for at least 30 seconds after the injection is completed; swab the injection site(s) and surrounding areas with alcohol. Change gloves, then cover lesion(s) with an absorbent pad and dry occlusive dressing, and wipe the exterior of the dressing with alcohol. The injection site should be covered for at least the first week after each treatment or longer if the injection site is weeping or oozing (replace dressing if it falls off).

Immunocompromised or pregnant health care providers should not prepare or administer talimogene laherparepvec and should not have direct contact with injection sites, dressings, or body fluids of treated patients. Avoid accidental exposure; follow biohazard precautions (personal protective equipment) for administration. Patients should place used dressings and cleaning materials in a sealed plastic bag and dispose of with household waste.

Storage

Store intact vials at -90°C to -70°C (-130°F to -94°F); protect from light. Store vials in the carton until use. Thaw vials immediately prior to administration. If not used immediately, may store (in the original vial and carton) the 10⁶ [1 million] PFU per mL strength refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature (≤25°C [≤77°F]) for up to 12 hours or the 10⁸ [100 million] PFU per mL strength refrigerated at 2°C to 8°C (36°F to 46°F) for up to 7 days or at room temperature (≤25°C [≤77°F]) for up to 24 hours. Do not refreeze vials after thawing; discard any vial left in the refrigerator if longer than the specified times. After thawed, do not shake.

Drug Interactions

Antiherpetic Antivirals: May diminish the therapeutic effect of Talimogene Laherparepvec. Monitor therapy

Adverse Reactions

Most reactions resolved within 72 hours.

>10%:

Central nervous system: Fatigue (50%), chills (49%), headache (19%)

Gastrointestinal: Nausea (36%), vomiting (21%), diarrhea (19%), constipation (12%)

Local: Pain at injection site (28%)

Neuromuscular & skeletal: Myalgia (18%), arthralgia (17%), limb pain (16%)

Respiratory: Flu-like symptoms (31%)

Miscellaneous: Fever (43%)

1% to 10%:

Central nervous system: Dizziness (10%)

Endocrine & metabolic: Weight loss (6%)

Gastrointestinal: Abdominal pain (9%)

Respiratory: Oropharyngeal pain (6%)

Frequency not defined:

Cardiovascular: Deep vein thrombosis, vasculitis

Dermatologic: Cellulitis, dermatitis, exacerbation of psoriasis, skin rash, vitiligo

Gastrointestinal: Oral herpes

Infection: Bacterial infection (systemic), herpes virus infection

Ophthalmic: Herpes simplex keratitis

Renal: Glomerulonephritis

Respiratory: Acute asthma, pneumonitis

Warnings/Precautions

Concerns related to adverse effects:

• Immune-mediated events: Immune-mediated events (eg, glomerulonephritis, pneumonitis, vasculitis, vitiligo, and worsening psoriasis) have been reported in clinical studies. Consider risk/benefit ratio of initiating treatment in patients with underlying autoimmune disease or prior to continuing talimogene laherparepvec treatment in patients who develop immune-mediated events.
• Infection: Herpetic infections (eg, cold sores and herpetic keratitis) have been reported; disseminated herpetic infection may occur in immunocompromised patients. If herpes-like lesions develop, follow standard practice to prevent viral transmission; contact a health care provider for evaluation. Suspected herpetic lesions should be reported to Amgen at 1-855-465-9442.
• Injection-site complications: Injection-site complications, such as necrosis, tumor tissue ulceration, and impaired healing, may occur during treatment with talimogene laherparepvec. Cellulitis and systemic bacterial infection have been observed. Monitor wounds carefully; infection precautions are recommended, particularly if tissue necrosis results in open wounds. Patients with underlying risk factors for impaired wound healing (eg, previous radiation at the injection site or lesions in poorly vascularized areas) may be at risk for complications. One patient had a lower extremity amputation 6 months after talimogene laherparepvec administration due to an infected non-healing wound. Monitor closely. Consider risk/benefit of continued treatment in patients with persistent infection or impaired wound healing at injection site(s).
• Pulmonary toxicity: Obstructive airway disorder has been observed following talimogene laherparepvec therapy; use caution when injecting lesions close to major airways.

Disease-related concerns:

• Multiple myeloma: In one clinical study, a patient with smoldering multiple myeloma developed a plasmacytoma near the talimogene laherparepvec injection site. Consider the risks/benefits of talimogene laherparepvec therapy in patients with multiple myeloma or in those who develop plasmacytoma during treatment.

Concurrent drug therapy issues:

• Acyclovir: Talimogene laherparepvec is sensitive to acyclovir. Acyclovir (or other antiviral medications) may interfere with the efficacy of talimogene laherparepvec; consider the risks and benefits of treatment prior to administering antiviral agents.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Dose strength: Talimogene laherparepvec is available in two different dose strengths: 10⁶ (1 million) plaque-forming units (PFU) per mL (initial dose only), and 10⁸ (100 million) PFU per mL (all subsequent doses). Verify appropriate dose and vial prior to preparation and administration.

Special handling:

• Handling considerations: Health care providers who are immunocompromised or pregnant should not prepare or administer talimogene laherparepvec. Accidental talimogene laherparepvec exposure may lead to herpetic infection. Health care providers, close contacts (eg, 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 patients treated with talimogene laherparepvec. Protective gloves should be worn when assisting patients with dressing changes; safely dispose of used dressings, gloves, and cleaning materials. Needle stick and/or splashback to the eyes have been reported during talimogene laherparepvec preparation and administration. If accidently exposed to talimogene laherparepvec, clean the affected area thoroughly with soap and water and/or a disinfectant. Contact a health care provider if signs/symptoms of herpetic infection develop. Counsel patients to avoid touching or scratching injection site(s) or the dressings (may lead to inadvertent transfer of drug to other parts of the body).

Monitoring Parameters

Monitor for signs/symptoms of herpetic infections (eg, cold sores and herpetic keratitis), injection-site complications, obstructive airway disease, and immune-mediated events

Pregnancy

Pregnancy Considerations

Use is contraindicated in pregnant women.

Talimogene laherparepvec is a live, attenuated, genetically modified herpes simplex virus type 1 (HSV-1). HSV-1 is known to cross the placenta, can be transmitted during birth, and produce infections in the fetus or neonate. It is not known if this can occur following exposure to talimogene laherparepvec. Pregnant women should not prepare or administer this medication. Pregnant women who are in close contact of patients treated with talimogene laherparepvec should not change dressings or clean injection sites, and should avoid direct contact with the injection site, dressings, or body fluids of patients. Women of reproductive potential should use effective contraception during therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience loss of strength and energy, chills, flu-like symptoms, headache, dizziness, nausea, vomiting, diarrhea, constipation, abdominal pain, painful extremities, weight loss, muscle pain, joint pain, sore throat, or injection site pain. Have patient report immediately to prescriber signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), shortness of breath, chest pain, white patches on skin, injection site irritation or bump, injection site skin discoloration, or signs of a herpes infection (arm or leg weakness; blurred vision, eye pain or discharge; confusion; fatigue; sensitivity to light; or pain, burning, or tingling in a blister around the mouth or genitals, on the fingers, or in the ears) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.