BRIEF SUMMARY-

REZAFUNGIN-(Mar 2023)

Indication-   treat Metastatic  or recurrent locally  advanced Market Cell Carcinoma            

Dosage- Injection: 500 mg/20 mL (25 mg/mL) solution in a single-dose vial.                The recommended dosage of ZYNYZ is 500 mg as an intravenous infusion over 30 minutes every 4 weeks. 

ADR-  most common (= 10%) adverse reactions are fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea

CI- None.

WARNINGS -                                                                                                         Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including:  immune-mediated pneumonitis, immune-mediated colitis,immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction

Pat Infom                                                                                                                  Immune-Mediated Adverse Reactions Advise patients that ZYNYZ can cause immune-mediated adverse reactions including the following.

Pneumonitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pneumonitis, including new or worsening symptoms of cough, chest pain, or shortness of breath. 

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 12

Name-        REZZAYO

Acive  Ingredient -  Rezafungin

 Pharmacological clssificiation-        To  treat Metastatic  or recurrent locally                                                                                advanced Market Cell Carcinoma                                                                                                                                                                       

 Date of Approval-         3/22/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                              ZYNYZ safely and effectively.                                                                                          See full prescribing information for ZYNYZ. ZYNYZ™ (retifanlimab-dlwr) injection, for intravenous use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

ZYNYZ is a programmed death receptor-1 (PD-1)–blocking antibody indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma.

 This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

ADVERSE REACTIONS-

The most common (= 10%) adverse reactions are fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea.

 CONTRAINDICATIONS-

 None.

WARNINGS AND PRECAUTIONS-

 • Immune-Mediated Adverse Reactions

 o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis,immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, and immune-mediated dermatologic adverse reactions, and solid organ transplant rejection

 o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.

o Withhold or permanently discontinue ZYNYZ and administer corticosteroids based on the severity of reaction.

 • Infusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue ZYNYZ based on severity of reaction.

 • Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1–blocking antibody.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception.

 DOSAGE AND ADMINISTRATION

The recommended dosage of ZYNYZ is 500 mg as an intravenous infusion over 30 minutes every 4 weeks.

 See full Prescribing Information for dosage modifications for adverse reactions  and preparation and administration instructions.

 DOSAGE FORMS AND STRENGTHS-

Injection: 500 mg/20 mL (25 mg/mL) solution in a single-dose vial.

PATIENT COUNSELING INFORMATION-

 Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions Advise patients that ZYNYZ can cause immune-mediated adverse reactions including the following.

• Pneumonitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pneumonitis, including new or worsening symptoms of cough, chest pain, or shortness of breath. 16 Reference ID: 5145703

• Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of colitis, including diarrhea, blood or mucus in stools, or severe abdominal pain.

• Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis.

• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, or type 1 diabetes mellitus.

• Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.

• Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop a new rash.

• Other immune-mediated adverse reactions: - Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms.

Infusion-Related Reactions =Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions .

Complications of Allogeneic HSCT or Solid Organ Transplant Rejection- Advise patients to contact their healthcare provider immediately if they develop signs or symptoms of post-allogeneic HSCT complications or of solid organ transplant rejection .

Embryo-Fetal Toxicity Advise females of reproductive potential that ZYNYZ can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of ZYNYZ.

Lactation- Advise female patients not to breastfeed while taking ZYNYZ and for 4 months after the last dose.

Manufactured by: Incyte Corporation Wilmington, DE 19803 U.S. License No. 2228 ZYNYZ and the ZYNYZ logo are trademarks of Incyte. © 2023 Incyte Corporation. All rights reserved.

CLINICAL PHARMACOLOGY

1. 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.

2 Pharmacodynamics-                                                                                                  The exposure-response relationship and time course of pharmacodynamic response for safety and effectiveness of retifanlimab-dlwr have not been fully characterized.

3. Pharmacokinetics- The pharmacokinetics of retifanlimab-dlwr were evaluated in patients with various solid tumors, including patients with MCC.

Retifanlimab-dlwr exposures (maximum concentration [Cmax] and area under the curve [AUC]) increased proportionally over a dosage range from 375 mg to 750 mg (0.75- to 1.5-fold of the approved recommended dose).

Following administration of retifanlimab-dlwr at 500 mg every 4 weeks, steady-state concentrations were achieved at Cycle 6 (approximately 6 months) and systemic accumulation was 1.3-fold.

Distribution -                                                                                                                 The geometric mean volume of distribution at steady state for retifanlimab-dlwr is 6.0 L (coefficient of variation [CV]: 20%).

Elimination-                                                                                                                        The elimination half-life of retifanlimab-dlwr at steady state is 19 days (CV: 29%). Clearance of retifanlimab-dlwr after the first dose was 0.31 L/day (CV: 36%) and decreased over time by approximately 23%, resulting in a steady-state clearance of 0.24 L/day.

Specific Populations-                                                                                                         The following factors have no clinically meaningful effect on the pharmacokinetics of retifanlimab-dlwr: age (18 to 94 years), sex, body weight (35 to 133 kg), race (White, Black, Asian), albumin level (21 to 54 g/L), Eastern Cooperative Oncology Group (ECOG) score (0 to 2), tumor burden (sum of the target lesion diameters: 10 to 360 mm), HIV status, renal function (estimated glomerular filtration rate = 26 mL/min/1.73 m2 ), or mild hepatic impairment (total bilirubin less than or equal to the ULN and AST greater than ULN or total bilirubin greater than ULN and less than or equal to 1.5 times ULN and any AST).

The pharmacokinetics of retifanlimab-dlwr have not been studied in patients with moderate or severe hepatic impairment. 

6. Immunogenicity -                                                                                                      The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of ZYNYZ or of other retifanlimab products. ADAs were tested in 104 patients with MCC who received ZYNYZ.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -                                                                                          Based on its mechanism of action, ZYNYZ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].

There are no available data on the use of ZYNYZ in pregnant women.

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.

2. Lactation Risk Summary-                                                                                           There is no information regarding the presence of retifanlimab-dlwr in human milk, or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk.

The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to ZYNYZ are unknown.

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose of ZYNYZ.

3. Females and Males of Reproductive Potential -                                                      ZYNYZ can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing-                                                                                                        Verify pregnancy status in females of reproductive potential prior to initiating ZYNYZ 

Contraception -Advise females of reproductive potential to use effective contraception during treatment with ZYNYZ and for 4 months after the last dose.

4. Pediatric Use The safety and effectiveness of ZYNYZ have not been established in pediatric patients.

4.Geriatric Use Of the 65 patients with metastatic or recurrent locally advanced MCC treated with ZYNYZ, 79% were 65 years or older, and 37% were 75 years or older.

Clinical studies of ZYNYZ did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.