Durvalumab- Imfinzi-@- (2017)- Anti-cancer
Drug Name:Durvalumab- Imfinzi-@- (2017)- Anti-cancer
List Of Brands:
Indication Type Description:
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Indication:
U.S. FDA APPROVED DRUGS DURING 2017
Sr.No- 19
Name of the Drug- Imfininzi
Active Ingredient- Durvalumab Pharmacological Classification-
To treat patients with locally advanced metastatic urothelial
carcinoma
Date of Approval- 05-01-2017
(Ref- FDA approved List 2017)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use IMFINZI safely and effectively.
See full prescribing information for IMFINZI.
IMFINZI. (durvalumab) injection, for intravenous use
Initial U.S. Approval: 2017
INDICATIONS AND USAGE
IMFINZI is a programmed death-ligand 1 (PD-L1) blocking antibody
indicated for the treatment of patients with:
Locally advanced or metastatic urothelial carcinoma who:
have disease progression during or following platinum-containing chemotherapy.
have disease progression within 12 months of neoadjuvant or adjuvant treatment
with platinum-containing chemotherapy.
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse events (reported in .15% of patients) were fatigue,
musculoskeletal pain, constipation, decreased appetite, nausea,
peripheral edema, and urinary tract infection.
Contra-Indications:
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Immune-Mediated Pneumonitis:
Withhold for moderate and permanently discontinue for severe or
life-threatening pneumonitis.
Immune-Mediated Hepatitis:
Monitor for changes in liver function.
Withhold for moderate and permanently discontinue for severe or life-
threatening transaminase or total bilirubin elevation.
Immune-Mediated Colitis:
Withhold for moderate and permanently discontinue for severe or
life-threatening colitis.
Immune-Mediated Endocrinopathies:
Adrenal Insufficiency, Hypophysitis, or Type 1 Diabetes Mellitus:
Withhold for moderate, severe or life-threatening.
Immune-Mediated Nephritis:
Monitor for changes in renal function.
Withhold for moderate and permanently discontinue for severe or life-
threatening nephritis.
Infection:
Withhold for severe or life-threatening infection.
Infusion-Related Reactions:
Interrupt infusion or slow the rate of infusion for mild or moderate
and permanently discontinue for severe or life-threatening
infusion-related reactions.
Embryo-Fetal Toxicity:
Can cause fetal harm. Advise females of reproductive potential of the
potential risk to a fetus and use of effective contraception.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
IMFINZI is a programmed death-ligand 1 (PD-L1) blocking antibody
indicated for the treatment of patients with:
Locally advanced or metastatic urothelial carcinoma who:
have disease progression during or following platinum-containing chemotherapy.
have disease progression within 12 months of neoadjuvant or adjuvant treatment
with platinum-containing chemotherapy.
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.
DOSAGE AND ADMINISTRATION
Administer 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks.
Dilute prior to intravenous infusion.
DOSAGE FORMS AND STRENGTHS
Injection: 500 mg/10mL (50 mg/mL) solution in a single-dose vial.
Injection: 120 mg/2.4mL (50 mg/mL) solution in a single-dose vial.
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the risk of immune-mediated adverse reactions that may require
corticosteroid treatment and interruption or discontinuation of IMFINZI, including:
Pneumonitis:
Advise patients to contact their healthcare provider immediately for any new or
worsening cough, chest pain, or shortness of breath.
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.
Colitis:
Advise patients to contact their healthcare provider immediately for diarrhea,
blood or mucus in stools, or severe abdominal pain.
Endocrinopathies:
Advise patients to contact their healthcare provider immediately for signs
or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency,
hypophysitis or type 1 diabetes mellitus.
Other Immune-Mediated Adverse Reactions:
Advise patients to contact their healthcare provider immediately for signs
or symptoms of rash, nephritis, aseptic meningitis, thrombocytopenic purpura,
myocarditis, hemolytic anemia, myositis, uveitis and keratitis.
Infection:
Advise patients to contact their healthcare provider immediately for infection.
Infusion-Related Reactions:
Advise patients to contact their healthcare provider immediately for signs
or symptoms of infusion-related reactions.
Embryo-Fetal Toxicity:
Advise females of reproductive potential that IMFINZI can cause harm to a fetus
and to inform their healthcare provider of a known or suspected pregnancy.
Use in Specific Populations
Advise females of reproductive potential to use effective contraception
during treatment and for at least 3 months after the last dose of IMFINZI.
Lactation:
Advise female patients not to breastfeed while taking IMFINZI and for at least
3 months after the last dose.
Manufactured for:
AstraZeneca Pharmaceuticals LP Wilmington, DE 19850
By: AstraZeneca UK Limited 1 Francis Crick Ave. Cambridge,
England CB2 0AA US License No. 2043
IMFINZI is a trademark of AstraZeneca group of companies.cAstraZeneca 2017
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Expression of programmed cell death ligand-1 (PD-L1) can be induced by
inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor
cells and tumor-associated immune cells in the tumor microenvironment.
PD-L1 blocks T-cell function and activation through interaction with PD-1 and
CD80 (B7.1).
By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation,
and cytokine production. Durvalumab is a human immunoglobulin G1 kappa
(IgG1ê) monoclonal antibody that blocks the interaction of PD-L1 with PD-1
and CD80 (B7.1).
Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition
of immune responses, without inducing antibody dependent cell-mediated
cytotoxicity (ADCC).
PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and
decreased tumor size in co-engrafted human tumor and immune cell xenograft
mouse models.
2. Pharmacodynamics
The exposure-response relationships for efficacy and safety are unknown.
Cardiac Electrophysiology
Durvalumab is unlikely to prolong the QT/QTc interval.
3. Pharmacokinetics
The pharmacokinetics of durvalumab was studied in 1324 patients with doses
ranging from 0.1 mg/kg (0.01 times the approved recommended dosage)
to 20 mg/kg (2 times the approved recommended dosage) administered
once every two, three or four weeks.
PK exposure increased more than dose-proportionally at doses less than
3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally
at doses greater than or equal to 3 mg/kg. Steady state was achieved at
approximately 16 weeks.
Distribution
The geometric mean (% coefficient of variation [CV%]) steady state volume of
distribution was 5.6 (17%) L.
Elimination
Durvalumab clearance decreases over time, with a mean maximal reduction
(CV%) from baseline values of approximately 22.9% (46.3%) resulting in a
geometric mean (CV%) steady state clearance (CLss) of 8.24 mL/h (37.3%);
the decrease in CLss is not considered clinically relevant.
The geometric mean (CV%) terminal half-life was approximately 17 (23.2%) days.
Specific Populations
Age (19-96 years), body weight (34-149 kg), sex, albumin levels, lactate
dehydrogenase (LDH) levels, creatinine levels, soluble PD-L1, tumor type, race,
mild renal impairment (creatinine clearance (CLcr) 60 to 89 mL/min), moderate
renal impairment (CLcr 30 to 59 mL/min), mild hepatic impairment (bilirubin less
than or equal to ULN and AST greater than ULN or bilirubin greater than
1.0 to 1.5 times ULN and any AST), or ECOG performance status had no clinically
significant effect on the pharmacokinetics of durvalumab.
The effect of severe renal impairment (CLcr 15 to 29 mL/min) or moderate hepatic impairment (bilirubin greater than 1.5 to 3.0 times ULN and any AST) or severe hepatic impairment (bilirubin greater than 3.0 times ULN and any AST) on the pharmacokinetics of durvalumab is unknown.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk summary
Based on its mechanism of action and data from animal studies, IMFINZI can
cause fetal harm when administered to a pregnant woman.
There are no data on the use of IMFINZI in pregnant women.
In animal reproduction studies, administration of durvalumab to pregnant
cynomolgus monkeys from the confirmation of pregnancy through delivery
resulted in increased in premature delivery, fetal loss and premature
neonatal death.
Human immunoglobulin G1 (IgG1) is known to cross the placental barrier;
therefore, durvalumab has the potential to be transmitted from the mother to the
developing fetus. Apprise pregnant 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 2-4% and 15-20%, respectively.
2. Lactation
Risk Summary
There is no information regarding the presence of durvalumab in human milk,
the effects on the breastfed infant, or the effects on milk production.
Human IgG1 is excreted in human milk. Durvalumab was present in the milk
of lactating cynomolgus monkeys and was associated with premature neonatal
death.
Because of the potential for adverse reactions in breastfed infants from durvalumab,
advise a lactating woman not to breastfeed during treatment with IMFINZI and for
at least 3 months after the last dose.
3 Females and Males of Reproductive Potential
Contraception
Females
Based on its mechanism of action, IMFINZI can cause fetal harm when administered
to a pregnant woman. Advise females of reproductive potential to use effective
contraception during treatment with IMFINZI, and for at least 3 months following
the last dose of IMFINZI.
4. Pediatric Use
The safety and effectiveness of IMFINZI have not been established in pediatric patients.
5. Geriatric Use
Of the 182 patients treated with IMFINZI, 112 patients were 65 years or older and
34 patients were 75 years or older. The overall response rate in patients 65 years
or older was 15.2% (17/112) and was 11.8% (4/34) in patients 75 years or older.
Grade 3 or 4 adverse reactions occurred in 38% (42/112) of patients 65 years
or older and 35% (12/34) of patients 75 years or older. Study results in
patients > 65 years of age and particularly in those > 75 years of age should
be viewed with caution given the small number of patients.
OVERDOSAGE
There is no information on overdose with IMFINZI.