U.S.  APPROVED DRUGS SURING 2022                                        

Serial No 27

Name-        IMJUDO

Active  Ingredient -  Tremelimumab

Pharmacological clssificiation-        To treat unresectable hepacellular carcinoma                                                                                                                                                                                                                                                                                             Date of Approval-         10/21/2022    

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                                  IMJUDO safely and effectively.                                                                                      See full prescribing information for IMJUDO. IMJUDO® (tremelimumab-actl) injection, for intravenous use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE

 IMJUDO is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody indicated in combination with durvalumab, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).

ADVERSE REACTIONS-

 Most common adverse reactions (= 20%) of patients with uHCC are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.

Most common laboratory abnormalities (= 40%) of patients with uHCC are AST increased, ALT increased, hemoglobin decreased, sodium decreased, bilirubin increased, alkaline phosphatase increased, and lymphocytes decreased.

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 dermatologic adverse reactions, immune mediated nephritis with renal dysfunction and immune-mediated pancreatitis.

o Monitor for early identification and management.Evaluate liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function at baseline and before each dose.

o Withhold or permanently discontinue based on severity and type of reaction.

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

 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-

 Administer IMJUDO as an intravenous infusion over 60 minutes after dilution. 

 uHCC: o Weight 30 kg and more: IMJUDO 300 mg as a single dose in combination with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab as a single agent every 4 weeks 

o Weight less than 30 kg: IMJUDO 4 mg/kg as a single dose in combination with durvalumab 20 mg/kg at Cycle 1/Day 1, followed by durvalumab as a single agent every 4 weeks

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

 DOSAGE FORMS AND STRENGTHS

 Injection: 25 mg/1.25 mL (20 mg/mL) solution in a single-dose vial.

 Injection: 300 mg/15 mL (20 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-

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMJUDO in combination with durvalumab, including

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

 Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.

 Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.

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

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

 Dermatological Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions.

Pancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis.

 Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of aseptic meningitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis.

Infusion-Related Reactions:  Advise patients to contact their healthcare provider immediately for signs or symptoms of infusionrelated reactions.

Embryo-Fetal Toxicity:  Advise females of reproductive potential that IMJUDO 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 3 months after the last dose of IMJUDO.

Lactation:  Advise female patients not to breastfeed while taking IMJUDO and for 3 months after the last dose.

Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 Manufactured By: AstraZeneca AB Södertälje, Sweden SE-15185 US License No. 2059 IMJUDO® is a registered trademark of AstraZeneca group of companies. ©AstraZeneca 2022

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                          CTLA-4 is a negative regulator of T-cell activity. Tremelimumab-actl is a monoclonal antibody that binds to CTLA-4 and blocks the interaction with its ligands CD80 and CD86, releasing CTLA-4-mediated inhibition of T-cell activation.

In synergistic mouse tumor models, blocking CTLA-4 activity resulted in decreased tumor growth and increased proliferation of T cells in tumors.

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

3. Pharmacokinetics-                                                                                                        The pharmacokinetics of tremelimumab-actl was studied in patients with other solid tumors following administration of doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) administered once every 4 weeks for 4 doses.

Distribution-                                                                                                                  The geometric mean (% coefficient of variation [CV%]) of tremelimumab-actl for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively.

Elimination-                                                                                                                   The geometric mean (CV%) terminal half-life of tremelimumab-actl was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady state.

The geometric mean (CV%) clearance of tremelimumabactl was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady state.

Specific Populations -                                                                                                        There were no clinically significant differences in the pharmacokinetics of tremelimumab-actl based on body weight (34 to149 kg), age (18 to 87 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or American Indian), serum albumin levels (0.3 to 396 g/L), lactate dehydrogenase levels (12 to 5570 U/L), soluble PD-L1 (67 to 349 pg/mL), organ dysfunction including mild to moderate renal impairment (CLcr 30 to 89 mL/min), and mild to moderate hepatic impairment (bilirubin < 3 x ULN and any AST).

The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin > 3 x ULN and any AST) on the pharmacokinetics of tremelimumab-actl is unknown.

USE IN SPECIFIC POPULATIONS-

1. Pregnancy Risk summary-                                                                                    Based on findings from animal studies and its mechanism of action, IMJUDO can cause fetal harm when administered to a pregnant woman..

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

Human immunoglobulin G2 (IgG2) is known to cross the placental barrier; therefore, IMJUDO has the potential to be transmitted from the mother to the developing fetus.

Advise pregnant women and females of reproductive potential 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 are no data on the presence of tremelimumab-actl in human milk, its effects on a 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 IMJUDO are unknown.

Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IMJUDO and for 3 months after the last dose.

Refer to the Prescribing Information for agents administered in combination with IMJUDO for breastfeeding recommendations, as appropriate.

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

Pregnancy Testing-                                                                                                         Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMJUDO.

Contraception-                                                                                                               Advise females of reproductive potential to use effective contraception during treatment with IMJUDO and for 3 months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMJUDO for recommended contraception duration, as appropriate

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

5. Geriatric Use--                                                                                                             Of the 393 patients with uHCC treated with IMJUDO in combination with durvalumab, 50% of patients were 65 years or older and 13% of patients were 75 years or older.

No overall differences in safety or efficacy of IMJUDO have been observed between patients 65 years or older and younger adult patients.