BRIEF SUMMARY

TREMILIMUMAB- acti-(Sep 2022)

Indn-   To treat Insomnia    

Comp-  Injection: 25 mg/1.25 mL (20 mg/mL) solution in a single-dose vial. (3) Injection: 300 mg/15 mL (20 mg/mL) solution in a single-dose vial.   Administer IMJUDO as an intravenous infusion over 60 minutes after dilution.

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

CI-  None.

 WARNINGS-

 Immune-Mediated Adverse Reactions

 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.

 Monitor for early identification and management. Evaluate liver enzymes, creatinine,

Pat inform-

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 personnel

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

=================================================================

U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 27

Name of the Drug-    

Active Ingredient -   Tremlimmumab-acti

Pharmacological Classification- To treat Insomnia                                                                                                                                                                                                         Date of Approval-          Sep 2022                                                                    

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                       IMJUDOsafely 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).

 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 (2.1) 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(2.1) 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. (3) Injection: 300 mg/15 mL (20 mg/mL) solution in a single-dose vial.

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:

 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. (5.3, 8.1, 8.3)-----------------

7 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 [see Warnings and Precautions (5.1)]:

 Pneumonitis: Advise patients to contact their healthcare pr

 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 infusion related reactions [see Warnings and Precautions (5.2)]

. 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 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].

? Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of IMJUDO [see Use in Specific Populations (8.3)].

Lactation: ? Advise female patients not to breastfeed while taking IMJUDO and for 3 months after the last dose [see Warnings and Precautions (5.3) and Use in Specific Populations (8.2)]. 19 Reference ID: 5068514

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 202

CLINICAL PHARMACOLOGY

12.1 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.

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

12.3 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.

The pharmacokinetics of tremelimumab-actl as a single dose of 300 mg were evaluated in patients with HCC. The AUC of tremelimumab-actl increased proportionally from 1 mg/kg to 10 mg/kg every 4 weeks (1 to 10-times the approved recommended dosage) and steady state was achieved at approximately 12 weeks.

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 tremelimumab actl was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady state.

Specific Populations 15 Reference ID: 5068514 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 < 3xULN and any AST).

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

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

Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of tremelimumab-actl. In the HIMALAYA study, of the 182 patients who were treated with a single dose of tremelimumab-actl in combination with durvalumab once in every 4 weeks therapy and evaluable for the presence of ADAs against tremelimumab-actl at predose week 0 and week 4, 11% (20/182) of patients tested positive for anti-tremelimumab-actl antibodies. Among the 20 patients who tested positive for ADAs 40% (8/20) tested positive for neutralizing antibodies against tremelimumab-actl. There was no identified clinically significant effect of anti-tremelimumab antibodies on the pharmacokinetics or safety of tremelimumab actl; however, the effect of ADAs and neutralizing antibodies on the effectiveness of tremelimumab-actl is unknown.

USE IN SPECIFIC POPULATIONS 8.1 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 [see Clinical Pharmacology (12.1)].

There are no available data on the use of IMJUDO in pregnant women. In animal studies, CTLA-4 blockade is associated with increased risk of immune-mediated rejection of the developing fetus and fetal death (see Data).

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. Data Animal Data

13 Reference ID: 5068514 In reproduction studies, administration of tremelimumab-actl to pregnant cynomolgus monkeys during the period of organogenesis through delivery was not associated with maternal toxicity or effects on embryo-fetal development at exposure levels approximately 31-times higher than those observed at a recommended dose of 300 mg (based on AUC). CTLA-4 plays a role in maintaining maternal immune tolerance to the fetus to preserve pregnancy and in immune regulation of the newborn. In a murine model of pregnancy, CTLA-4 blockade resulted in increased resorptions and reduced live fetuses.

Mated genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-) gave birth to CTLA-4+/- offspring and offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-) that appeared healthy at birth. The CTLA-4-/- homozygous negative offspring developed signs of a lymphoproliferative disorder and died by 3 to 4 weeks of age with multiorgan tissue destruction. Based on its mechanism of action, fetal exposure to tremelimumab-actl may increase the risk of developing immune-mediated disorders or altering the normal immune response.

8.2 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.

8.3 Females and Males of Reproductive Potential IMJUDO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

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

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

8.5 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. 14 Reference ID: 5068514