DRUG INTERACTIONS-

For certain CYP substrates where minimal concentration changes may lead to serious adverse reactions, monitor for toxicities or drug concentrations of such CYP substrates when coadministered with COLUMVI.

Glofitamab-gxbm causes the release of cytokines  that may suppress the activity of CYP enzymes, resulting in increased exposure of CYP substrates.

Increased exposure of CYP substrates is more likely to occur after the first dose of COLUMVI on Cycle 1 Day 8 and up to 14 days after the first 30 mg dose on Cycle 2 Day 1 and during and after CRS

BRIEF SUMMARY

GOFITAMAB- (June 2023)

Indication-  To treat diffuse large C-cell lymphoma, not otherwise arising  from follicular lymphoma after ywo or more lines of systemic  therapy

Dosage- Pretreat with a single 1,000 mg dose of obinutuzumab intravenously 7 days before initiation. Administer premedications as recommended. and only as an intravenous infusion.

ADR- The most common (= 20%) adverse reactions, excluding laboratory abnormalities, are cytokine release syndrome, musculoskeletal pain, rash, and fatigue.

CI-  None. 

 WARNINGS AND PRECAUTIONS-

 Neurologic Toxicity: Can cause serious neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Monitor for neurologic toxicity; withhold or permanently discontinue based on severity.

 Serious Infections: Can cause serious or fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately.

Pat inform- Inform patients of the risk of CRS. Advise patients to seek immediate medical attention if they experience signs and symptoms of CRS (fever, hypoxia, hypotension, chills and tachycardia) 

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U.S. FDA APPROVED  DRUGS DURING 2023

Sr.No-  23

 ADVERSE REACTIONS-

 The most common (= 20%) adverse reactions, excluding laboratory abnormalities, are cytokine release syndrome, musculoskeletal pain, rash, and fatigue.

The most common (= 20%) Grade 3 to 4 laboratory abnormalities are lymphocyte count decreased, phosphate decreased, neutrophil count decreased, uric acid increased, and fibrinogen decreased.

 CONTRAINDICATIONS-

 None. 

 WARNINGS AND PRECAUTIONS-

 Neurologic Toxicity: Can cause serious neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Monitor for neurologic toxicity; withhold or permanently discontinue based on severity.

 Serious Infections: Can cause serious or fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately.

 Tumor Flare: Can cause serious tumor flare reactions. Monitor patients at risk for complications of tumor flare.

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

(5.5, 8.1, 8.3) ------------------------------ ADVERSE REACTIONS ------------------------------ The most common (= 20%) adverse reactions, excluding laboratory abnormalities, are cytokine release syndrome, musculoskeletal pain, rash, and fatigue. The most common (= 20%) Grade 3 to 4 laboratory abnormalities are lymphocyte count decreased, phosphate decreased, neutrophil count decreased, uric acid increased, and fibrinogen decreased. (6.1) --------------------------USE IN SPECIFIC POPULATIONS---------------- Lactation: Advise not to breastfeed. (8.2) To report SUSPECTED ADVERSE REA

PATIENT COUNSELING INFORMATION-

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

Cytokine Release Syndrome-

 Inform patients of the risk of CRS. Advise patients to seek immediate medical attention if they experience signs and symptoms of CRS (fever, hypoxia, hypotension, chills and tachycardia) 

Provide patients with the Patient Wallet Card that they should carry with them at all times. This card describes symptoms of CRS which, if experienced, should prompt the patient to seek immediate medical attention.

Neurologic Toxicity -

Discuss the signs and symptoms associated with neurologic toxicity, including ICANS, headache, peripheral neuropathy, dizziness, or mental status changes.

Advise patients to immediately contact their healthcare provider if they experience any signs or symptoms of neurologic toxicity.

Advise patients who experience neurologic toxicity that impairs consciousness to refrain from driving or operating heavy or potentially dangerous machinery until neurologic toxicity resolves.

Serious Infections -

Advise patients that COLUMVI can cause serious infections. Advise patients to notify their healthcare provider immediately if they develop any signs of infection (e.g., fever, chills, weakness) 

Tumor Flare-

Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event (e.g., localized pain and swelling) to their healthcare provider for evaluation.

Embryo-Fetal Toxicity-

 Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant. Advise females of reproductive potential to use effective contraception during treatment with COLUMVI and for 1 month after the last dose .

Advise women not to breastfeed while receiving treatment with COLUMVI and for 1 month after the last dose .

COLUMVITM [glofitamab-gxbm]

Manufactured by: Genentech, Inc. A Member of the Roche Group COLUMVITM is a trademark of 1 DNA Way Genentech, Inc. South San Francisco, CA 94080-4990 U.S. License No.: 1048 ©2023 Genentech, Inc. All rights reserved.

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-

 Glofitamab-gxbm is a bispecific antibody that binds to CD20 expressed on the surface of B cells, and to CD3 receptor expressed on the surface of T cells.

Glofitamab-gxbm causes T-cell activation and proliferation, secretion of cytokines, and the lysis of CD20-expressing B cells. Glofitamab-gxbm showed anti-tumor activity in vivo in mouse models of DLBCL.

2. Pharmacodynamics-

 Circulating B Cell Count Peripheral B cell counts decreased to undetectable levels (< 5 cells/microliter) in 86.5% of patients by Cycle 1 Day 7 after obinutuzumab pretreatment of 1,000 mg on Cycle 1 Day 1, and in 88.2% of patients by Cycle 1 Day 10 after the first glofitamab-gxbm dose of 2.5 mg on Cycle 1 Day 8. Cytokine Concentrations Plasma concentrations of cytokines (IL-2, IL-6, IL-10,

After administration of the recommended dosage of COLUMVI, the highest elevation of cytokines was generally observed within 6 hours after the first glofitamab-gxbm dose of 2.5 mg on Cycle 1 Day 8.

The elevated cytokine levels generally returned to baseline within 48 hours after the first 30 mg dose on Cycle 2 Day 1.

3. Pharmacokinetics-

The pharmacokinetics of glofitamab-gxbm was determined following pretreatment with a single dose of obinutuzumab of 1,000 mg and the pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise specified.

Elimination-

 At steady state, the glofitamab-gxbm terminal half-life is 7.6 days (24%) and the clearance is 0.617 L/day (33%). 

Metabolism-

Glofitamab-gxbm is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations-

No clinically significant changes in the pharmacokinetics of glofitamab-gxbm were observed based on age (21 to 90 years), body weight (31 to 148 kg), sex, mild to moderate renal impairment (CLcr 30 to < 90 mL/min as estimated by Cockcroft-Gault formula) and mild hepatic impairment (total bilirubin > ULN to = 1.5 x ULN or AST > ULN).

The effects of severe renal impairment (CLcr 15 to < 30 mL/min), end-stage renal disease (CLcr < 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and any AST), and race/ethnicity on the pharmacokinetics of glofitamab-gxbm are unknown.

Drug Interaction Studies-

No clinical studies evaluating the drug interaction potential of glofitamab-gxbm have been conducted. 12.6 Immunogenicity The observed incidence of antidrug 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 study described below with the incidence of ADA in other studies, including those of glofitamab-gxbm.

During treatment in Study NP30179 (up to 9 months) , using an enzyme-linked immunosorbent assay (ELISA), the incidence of anti-glofitamab antibody formation was 1.1% (5/448) in patients treated with COLUMVI.

Because of the low occurrence of ADAs, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of glofitamab-gxbm is unknown.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -

 Based on its mechanism of action COLUMVI may cause fetal harm when administered to a pregnant woman

There are no available data on the use of COLUMVI in pregnant women to evaluate for a drug-associated risk.

It  is known to cross the placenta; therefore, COLUMVI has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the 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 glofitamab-gxbm in human milk or the effects on the breastfed child or milk production.

Because human IgG is present in human milk, and there is potential for glofitamab-gxbm absorption leading to B-cell depletion, advise women not to breastfeed during treatment with COLUMVI and for 1 month after the last dose of COLUMVI.

3. Females and Males of Reproductive Potential-

 COLUMVI may cause fetal harm when administered to a pregnant woman 

Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating COLUMVI.

Contraception- Females-

Advise female patients of reproductive potential to use effective contraception during treatment with COLUMVI and for 1 month after the last dose of COLUMVI

3.Pediatric Use-

The safety and efficacy of COLUMVI in pediatric patients have not been established.

4. Geriatric Use -

Of the 145 patients with relapsed or refractory LBCL who received COLUMVI in study NP30179, 55% were 65 years of age or older, and 23% were 75 years of age or older.

There was a higher rate of fatal adverse reactions, primarily from COVID-19, in patients 65 years of age or older compared to younger patients 

No overall differences in efficacy were observed between patients 65 years of age or older and younger patients.