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Cemiplimab-rwlc Injection

TABLE OF CONTENTS

1. DESCRIPTION 6. ADVERSE REACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACOKINETICS
5. WARNINGS AND PRECAUTIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Cemiplimab-rwlc is a human programmed death receptor-1 (PD-1) blocking antibody. Cemiplimab-rwlc is a recombinant human IgG4 monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2. Cemiplimab-rwlc is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture. Cemiplimab-rwlc has an approximate molecular weight of 146 kDa.

Cemiplimab-rwlc injection for intravenous use is a sterile, clear to slightly opalescent, colorless to pale yellow solution with a pH of 6. The solution may contain trace amounts of translucent to white particles.

Each vial contains 350 mg of cemiplimab-rwlc. Each mL contains cemiplimab-rwlc 50 mg, L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.1 mg), sucrose (50 mg), Lproline (15 mg), Polysorbate 80 (2 mg), and Water for Injection, USP.

2. INDICATIONS AND USAGE

Cemiplimab-rwlc is indicated for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage

The recommended dosage of cemiplimab-rwlc is 350 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

3.2 Dosage Modifications for Adverse Reactions

Withhold or discontinue cemiplimab-rwlc to manage adverse reactions as described in Table 1. No dose reduction of cemiplimab-rwlc is recommended.

Table 1: Recommended Dosage Modifications for Adverse Reactions

* Toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0

† Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper.

3.3 Preparation and Administration

 Visually inspect for particulate matter and discoloration prior to administration. Cemiplimab-rwlc is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. Discard the vial if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of translucent to white particles.

Preparation

 Do not shake.

 Withdraw 7 mL from a vial and dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration between 1 mg/mL to 20 mg/mL.

 Mix diluted solution by gentle inversion. Do not shake.

 Discard any unused medicinal product or waste material.

Storage of Infusion Solution

 Store at room temperature up to 25°C (77°F) for no more than 8 hours from the time of preparation to the end of the infusion or at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of preparation to the end of infusion.

 Allow the diluted solution to come to room temperature prior to administration.

 Do not freeze.

Administration

 Administer by intravenous infusion over 30 minutes through an intravenous line containing a sterile, in-line or add-on 0.2-micron to 5-micron filter.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Cemiplimab-rwlc is a monoclonal antibody that belongs to a class of drugs that binds to the programmed death receptor-1 (PD-1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response with the potential for breaking of peripheral tolerance and induction of immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not be inclusive of all possible immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor for symptoms and signs of immune-mediated adverse reactions. Evaluate clinical chemistries, including liver tests and thyroid function tests, at baseline and periodically during treatment. Institute medical management promptly to include specialty consultation as appropriate.

In general, withhold cemiplimab-rwlc for Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions. Permanently discontinue cemiplimab-rwlc for Grade 4 and certain Grade 3 immune-mediated adverse reactions [see Dosage and Administration (3.2)]. For Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions, administer corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or other appropriate therapy until improvement to Grade 1 or less followed by a corticosteroid taper over one month [see Dosage and Administration (3.2)]. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroids. Institute hormone replacement therapy for endocrinopathies as warranted.

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis occurred in 2.4% of 534 patients receiving cemiplimab-rwlc, including Grade 5 (0.2%), Grade 3 (0.7%) and Grade 2 (1.3%) [see Adverse Reactions (6.1)]. Pneumonitis led to permanent discontinuation of cemiplimab-rwlc in 1.3% of patients. Systemic corticosteroids were required in all patients with pneumonitis, including 85% who received prednisone ≥ 40 mg per day or equivalent. Pneumonitis resolved in 62% of patients.

Immune-Mediated Colitis

Immune-mediated colitis occurred in 0.9% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.4%) and Grade 2 (0.6%) [see Adverse Reactions (6.1)]. Colitis led to permanent discontinuation of cemiplimab-rwlc in 0.2% of patients. Systemic corticosteroids were required in all patients with colitis, including 60% who received prednisone ≥ 40 mg per day or equivalent. Colitis resolved in 80% of patients.

Immune-Mediated Hepatitis

Immune-mediated hepatitis occurred in 2.1% of 534 patients receiving cemiplimab-rwlc, including Grade 5 (0.2%), Grade 4 (0.2%), and Grade 3 (1.7%) [see Adverse Reactions (6.1)]. Hepatitis led to permanent discontinuation of cemiplimab-rwlc in 0.9% of patients. Systemic corticosteroids were required in all patients with hepatitis, including 91% who received prednisone ≥ 40 mg per day or equivalent. Hepatitis resolved in 64% of patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

Adrenal insufficiency occurred in 0.4% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.2%), and Grade 2 (0.2%) [see Adverse Reactions (6.1)].

Hypophysitis

Hypophysitis, which can result in hypopituitarism, occurred in 0.2% of 534 patients receiving cemiplimab-rwlc, which consisted of one patient with Grade 3 hypophysitis.

Hypothyroidism

Hypothyroidism occurred in 6% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.2%) and Grade 2 (5.6%). No patients discontinued hormone replacement therapy.

Hyperthyroidism

Hyperthyroidism occurred in 1.5% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.2%) and Grade 2 (0.4%). Hyperthyroidism resolved in 38% of patients.

Type 1 Diabetes Mellitus

Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, occurred in 0.7% of 534 patients, including Grade 4 (0.4%) and Grade 3 (0.4%). Type 1 diabetes mellitus led to permanent discontinuation of cemiplimab-rwlc in 0.2% of patients.

Immune-Mediated Nephritis with Renal Dysfunction

Immune-mediated nephritis occurred in 0.6% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.4%) and Grade 2 (0.2%) [see Adverse Reactions (6.1)]. Nephritis led to permanent discontinuation of cemiplimab-rwlc in 0.2% of patients. Systemic corticosteroids were required in all patients with nephritis, including 67% who received prednisone ≥ 40 mg per day or equivalent. Nephritis resolved in all patients.

Immune-Mediated Dermatologic Adverse Reactions

Immune-mediated dermatologic reactions, including erythema multiforme and pemphigoid, occurred in 1.7% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (1.1%) and Grade 2 (0.6%) [see Adverse Reactions (6.1)]. In addition, SJS and TEN have been observed with

Cemiplimab-rwlc and with other products in this class. Systemic corticosteroids were required in all patients with dermatologic reactions, including 89% who received prednisone ≥ 40 mg per day or equivalent. Dermatologic reactions resolved in 33% of patients. Approximately 22% of patients had recurrence of dermatologic reactions after re-initiation of cemiplimab-rwlc.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% in 534 patients who received cemiplimab-rwlc [see Adverse Reactions (6.1)] or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Neurological: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome / myasthenia gravis, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy.

Cardiovascular: Myocarditis, pericarditis, vasculitides.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and Connective Tissue: Myositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.

Hematological and Immunological: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

5.2 Infusion-Related Reactions

Severe infusion-related reactions (Grade 3) occurred in 0.2% of patients receiving cemiplimab-rwlc [see Adverse Reactions (6.1)]. Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue cemiplimab-rwlc based on severity of reaction [see Dosage and Administration (3.2)].

5.3 Embryo-Fetal Toxicity

Based on its mechanism of action, cemiplimab-rwlc can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with cemiplimab-rwlc and for at least 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6. ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling.

 Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]

 Infusion-Related Reactions [see Warnings and Precautions (5.2)]

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 data described in WARNINGS AND PRECAUTIONS reflect exposure to cemiplimab-rwlc in 534 patients in two open-label, single-arm, multicohort studies (Study 1423 and Study 1540), including 98 patients with metastatic (nodal or distant) CSCC, 65 patients with locally advanced CSCC, and 371 patients with other advanced solid tumors. Cemiplimab-rwlc as a single agent or in combination with chemotherapy or radiation was administered intravenously at doses of 1 mg/kg every 2 weeks (n=27), 3 mg/kg every 2 weeks (n=446), 3 mg/kg every 3 weeks (n=12), 10 mg/kg every 2 weeks (n=6), 200 mg every 2 weeks (n=20) or 350 mg every 3 weeks (n=23). Among the 534 patients, 38% were exposed for ≥ 6 months and 16% were exposed for ≥ 12 months.

The data described below reflect exposure to cemiplimab-rwlc in 163 patients with advanced CSCC (metastatic or locally advanced disease) in Study 1423 and Study 1540 [see Clinical Studies]. Patients received cemiplimab-rwlc 1 mg/kg every 2 weeks (n=1), 3 mg/kg every 2 weeks (n=139) or 350 mg every 3 weeks (n=23) as an intravenous infusion until disease progression, unacceptable toxicity, or completion of planned treatment. The median duration of exposure was 20 weeks (3 days to 1.4 years).

The safety population characteristics were: median age of 71 years (38 to 96 years), 85% male, 96% white, and ECOG performance score (PS) of 0 (44%) or 1 (56%).

The most common adverse reactions reported in at least 20% of patients were fatigue, rash and diarrhea. The most common Grade 3-4 adverse reactions (≥ 2%) were cellulitis, sepsis, hypertension, pneumonia, musculoskeletal pain, skin infection, urinary tract infection and fatigue. Cemiplimab-rwlc was permanently discontinued due to adverse reactions in 5% of patients; adverse reactions resulting in permanent discontinuation were pneumonitis, autoimmune myocarditis, hepatitis, aseptic meningitis, complex regional pain syndrome, cough, and muscular weakness. Serious adverse reactions occurred in 28% of patients. Serious adverse reactions that occurred in at least 2% of patients were cellulitis, sepsis, pneumonia, pneumonitis and urinary tract infection.

Table 2 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 3 summarizes Grade 3 and 4 laboratory abnormalities worsening from baseline in ≥ 1% of patients receiving cemiplimab-rwlc.

Table 2: Adverse Reactions in ≥ 10% of Patients with Advanced CSCC Receiving Cemiplimab-rwlc in Study 1423 and Study 1540

* Rash is a composite term that includes rash maculopapular, rash, dermatitis, rash generalized, dermatitis bullous, drug eruption, erythema, rash erythematous, rash macular, rash pruritic, and skin reaction.

† Pruritus is a composite term that includes pruritus and pruritus allergic.

‡ Diarrhea is a composite term that includes diarrhea and colitis.

§ Fatigue is a composite term that includes fatigue and asthenia.

# Musculoskeletal pain is a composite term that includes: musculoskeletal pain, back pain, myalgia, neck pain, pain in extremity.

Table 3: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥ 1% of Patients with Advanced CSCC Receiving Cemiplimab-rwlc in Study 1423 and Study 1540

† Percentages are based on the number of patients with at least 1 post-baseline value available for that parameter.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cemiplimab-rwlc in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Anti-drug antibodies (ADA) were tested in 398 of 534 patients who received cemiplimab-rwlc and the incidence of cemiplimab-rwlc treatment-emergent ADAs was 1.3% using an electrochemiluminescent (ECL) bridging immunoassay; 0.3% were persistent ADA responses. In the patients who developed anti-cemiplimab-rwlc antibodies, there was no evidence of an altered pharmacokinetic profile of cemiplimab-rwlc.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, cemiplimab-rwlc can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. There are no available data on the use of cemiplimab-rwlc in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death (see Data). Human IgG4 immunoglobulins (IgG4) are known to cross the placenta; therefore, cemiplimab-rwlc has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Animal reproduction studies have not been conducted with cemiplimab-rwlc to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering cemiplimab-rwlc during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to cemiplimab-rwlc may increase the risk of developing immune-mediated disorders or altering the normal immune response.

8.2 Lactation

Risk Summary

There is no information regarding the presence of cemiplimab-rwlc in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for at least 4 months after the last dose of cemiplimab-rwlc.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating cemiplimab-rwlc [see Use in Specific Populations (8.1)].

Contraception

Cemiplimab-rwlc can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with cemiplimab-rwlc and for at least 4 months after the last dose.

8.4 Pediatric Use

The safety and effectiveness of cemiplimab-rwlc have not been established in pediatric patients.

8.5 Geriatric Use

Of the 163 patients with metastatic and locally advanced CSCC who received cemiplimab-rwlc in clinical studies, 72% were 65 years or older and 37% were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

10. MECHANISM OF ACTION

Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.

Cemiplimab-rwlc is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

12. PHARMACOKINETICS

Cemiplimab-rwlc pharmacokinetic (PK) data were collected in 505 patients with various solid tumors, including 135 patients with CSCC. The PK of cemiplimab-rwlc was linear and dose proportional in the dose range of 1 mg/kg to 10 mg/kg administered intravenously every two weeks and 350 mg intravenously administered every three weeks.

After a dose of 350 mg cemiplimab-rwlc administered intravenously every 3 weeks, median steady-state concentrations (CV%) of cemiplimab-rwlc ranged between a maximum concentration (Cmax,ss) of 166 mcg/mL (28%) and a minimum concentration (Cmin,ss) of 59 mcg/mL (48%). Steady-state exposure is achieved after approximately 4 months of treatment.

Distribution

The volume of distribution of cemiplimab-rwlc at steady state is 5.3 L (25%).

Elimination

Cemiplimab-rwlc clearance (CV%) after the first dose is 0.32 L/day (39%) and decreases over time by 34%, resulting in a steady-state clearance (CLss) (CV%) of 0.21 L/day (39%). The elimination half-life (CV%) at steady state is 19 days (30%).

Specific Populations

The following factors have no clinically important effect on the exposure of cemiplimab-rwlc: age (27 to 96 years), sex, body weight (31 to 156 kg), race (White, Black, Asian and other), cancer type, albumin level (22 to 48 g/L), renal function (creatinine clearance determined by Cockcroft-Gault 25 to 420 mL/min) and hepatic function (total bilirubin 0.35 to 45 μmol/L). Cemiplimab-rwlc has not been studied in patients with moderate or severe hepatic impairment.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

LIBTAYO (cemiplimab-rwlc) injection is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. It is supplied in a carton containing 1 single-dose vial of:

 250 mg/5 mL (50 mg/mL) (NDC 61755-007-01)

 350 mg/7 mL (50 mg/mL) (NDC 61755-008-01)

Storage and Handling:

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Protect from light. Do not freeze or shake.

Rx only

Rev 09/18